Long-term Safety and Tolerability of Tolebrutinib in Relapsing and Progressive Multiple Sclerosis: A Phase 3 Extension Study
- Trial ID
- 2023-503631-18-00
- Protocol
- LTS17043
Trial statistics
Objectives
The primary objective of this Phase 3 extension 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 the therapeutic benefits of tolebrutinib can be sustained over an extended period without compromising patient safety, which is crucial for chronic conditions like multiple sclerosis.
Secondary objectives include assessing the long-term efficacy of open-label tolebrutinib on disability progression, relapse rate (only in participants with RMS), and magnetic resonance imaging (MRI) parameters in participants with RMS and PMS. These objectives are important for understanding the comprehensive impact of tolebrutinib on disease progression and neurological health, providing insights into its potential as a long-term treatment option for multiple sclerosis.
Participants
The clinical trial involves a total of **1552 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 spanning from 18 to 65 years. Participants were selected based on their completion of previous Phase 2b or Phase 3 pivotal tolebrutinib trials, or those who temporarily discontinued due to a national emergency but completed trial visits. The trial includes a vulnerable population, indicating careful consideration of ethical standards. Lifestyle factors such as diet and physical activity were not specified, and the trial does not emphasize any particular habits. The selection criteria ensure a representative sample of the target population, focusing on the long-term safety and tolerability of tolebrutinib in the specified conditions.
Plans and Procedures
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 methodology. The trial is expected to conclude by August 2029, with recruitment starting in March 2024. Participants will be involved for a maximum of 36 months, depending on their response and adherence to the study protocol.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as completion of prior Phase 2b or Phase 3 trials involving tolebrutinib. Follow-up visits will occur at regular intervals to assess safety endpoints, including the number of participants experiencing adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints will evaluate the time to onset of confirmed disability worsening or progression, annualized relapse rate, and changes in T2-hyperintense lesions. The end-of-study visit will finalize data collection and assess the overall safety profile of the intervention.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or choose to withdraw consent. The trial will utilize **AUBAGIO** and **COLESTYRAMINE** as auxiliary treatments, with matched placebos for comparator purposes. The primary objective is to ensure the long-term safety and tolerability of tolebrutinib, with a focus on maintaining participant health and collecting robust data to support future therapeutic decisions.
Treatment
The clinical trial involves the administration of **Tolebrutinib**, a film-coated tablet, as the primary experimental medication. Tolebrutinib is chemically derived and is administered orally. The maximum daily dose is 60 mg, with a total treatment period of up to 36 months. The active substance in Tolebrutinib is tolebrutinib itself, and it is developed by Sanofi Aventis Recherche et Développement (SAR). Participant compliance with the dosing schedule will be monitored throughout the study.
**AUBAGIO** 14 mg film-coated tablets, containing the active substance **Teriflunomide**, serve as a comparator treatment. This medication is also administered orally, with a maximum daily dose of 14 mg over a treatment period of up to 36 months. AUBAGIO is produced by Sanofi Winthrop Industrie and is classified under the ATC code L04AA31.
**Anhydrous Cholestyramine** is used as an auxiliary treatment in the study. It is a bile acid sequestrant administered orally. The pharmaceutical form is denoted as PHF00169MIG, and it is classified under the ATC code C10AC01. The maximum treatment period for this auxiliary treatment is 1 day.
Additionally, **Magnetic Resonance Imaging Contrast Media** is utilized as an auxiliary treatment. This substance is administered as a solution for injection and is classified under the ATC code V08C. The treatment period is limited to 1 day, and it is used to enhance imaging results during the trial.
The study also includes the use of a **Matched Placebo to Test** and a **Matched Placebo for Comparator Teriflunomide**. These placebos are designed to match the experimental and comparator treatments, respectively, in appearance and administration route, ensuring blinding in the trial. The pharmaceutical form and active substance details for these placebos are not specified.
Efficacy
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) who are from pivotal studies. 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.
Inclusion and Exclusion Criteria
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
- 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.
- ToleDYNAMIC Substudy: Exclusion criteria are those of the main study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Yet Recruiting | 18 Mar 2024 | 20 |
 The Netherlands | Not Yet Recruiting | 18 Mar 2024 | — |
| Netherlands | — | — | 55 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AUBAGIO 14 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 14 | 36 | PRD2675141 |
COLESTYRAMINE | Other | PHF00169MIG | ORAL USE | 0 | 1 | SCP30086892 |
- | Other | PHF00005MIG | ORAL | 0 | 1 | SCP4987633 |
Matched Placebo to Test | Placebo | N/A | — | — | — | N/A |
Matched Placebo for Comparator Teriflunomide | Placebo | N/A | — | — | — | N/A |
Tolebrutinib | Test | FILM-COATED TABLET | ORAL USE | 60 | 36 | PRD10454961 |
- | Other | - | SOLUTION FOR INJECTION | 0 | 1 | V08C |