Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168)

Study Overview
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Brief Summary
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Primary Objective: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in NRSPMS Secondary Objective: To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168

Detailed Description
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Study duration will vary per participant in this event driven trial with a treatment duration of approximately 24 to 48 months. Participants completing the treatment period will be proposed to enroll in a separate long term safety study.

Official Title
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A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Nonrelapsing Secondary Progressive Multiple Sclerosis

Conditions
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Secondary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: Tolebrutinib
* Drug: Placebo to match Tolebrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : 18 to 60 years of age inclusive Diagnosis of nonrelapsing secondary progressive multiple sclerosis according to the 2017 McDonald criteria Expanded disability status scale (EDSS) between 3.0 to 6.5 points inclusive, at screening The participant must have documented evidence of disability progression observed during the 12 months before screening Absence of clinical relapses for at least 24 months Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a WOCBP OR Is a WOCBP and agrees to use an acceptable contraceptive method Exclusion criteria: The participant has conditions that would adversely affect study participation such as short life expectancy. History of organ transplant. Evidence of infection with human immuodeficiency virus (HIV), transplantation, progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infections that would adversely affect study participation. Persistent chronic or active or recurring system infection, that may adversely affect participation or IMP administration in this study, as judged by the Investigator. History of malignancy within 5 years prior to screening. History of alcohol or drug abuse within 1 year prior to screening. Hospitalized for psychiatric disease within 2 years prior to screening. Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at screening Bleeding disorder, known platelet dysfunctionat any time prior to the screening visit A platelet count <150 000/μL at the screening visit A history of significant bleeding event within 6 months prior to screening, according to the Investigator's judgment such as, but not limited to cerebral or gastrointestinal bleeding. Lymphocyte count below the lower limit of normal at screening. Recent live (attenuated) vaccine within 2 months before the first treatment visit. Recent major surgery (within 4 weeks of screening) or planned major surgery during the study. The participant has received medications/treatments for MS within a specified time frame. Receiving potent and moderate inducers or inhibitors of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes. Receiving anticoagulant or antiplatelet therapy (such as aspirin>81mg/day, clopidogrel, warfarin). Contraindications to magnetic resonance imaging (MRI). The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR442168<br>Dose 1 of oral SAR442168 once daily | Drug: Tolebrutinib<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral<br>* Other names: SAR442168;|
| Placebo Comparator: Placebo<br>Placebo tablet to match SAR442168 once daily | Drug: Placebo to match Tolebrutinib<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month confirmed disability progression (CDP) | Time to onset of 6 months CDP defined as follows: -Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.0, or -Increase of ≥0.5 point when the baseline EDSS score is >5.0 - | Up to 48 approximately months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-months change in T25-FW and 9-HPT | Time to onset of composite CDP, confirmed over at least 3 months (3-month CCDP), by the EDSS Plus composite (EDSS score increase, or 20% increase in the T25 FW test, or 20% increase in the 9 hole peg test (9 HPT) | Up to approximately 48 months | 
| 3-month CDP | Time to onset of 3-month CDP as assessed by EDSS score | Up to approximately48 months | 
| New and enlarging T2 hyperintense lesions by MRI | Total number of new or enlarging T2 hyperintense lesions as detected by MRI | From Baseline up to approximately 48 months | 
| Time to onset of confirmed disability improvement (CDI) | Time to CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months | From Baseline up to approximately 48 months | 
| Brain volume loss (BVL) | Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6 | From 6 Months up to approximately 48 months | 
| Change in cognitive function | Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) and by the California Verbal Learning Test (CVLT-II) | From Baseline up to approximately 48 months | 
| Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) | Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS | From Baseline up to approximately 48 months | 
| Safety and Tolerability | Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI) | From Screening until end of study up to approximately 48 months | 
| Population pharmacokinetics | Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12 | Months 6, 9 and 12 | 
| Change in plasma neurofilament light chain (NfL) | Change in NfL levels at the EOS compared to baseline | From Baseline up to approximately 48 months | 
| Changes in serum Immunoglobulin level | Changes in serum Immunoglobulin level at the EOS compared to baseline | From Baseline up to approximately 48 months | 
| Change in lymphocyte phenotype subsets | Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants | From Baseline up to approximately 48 months | 
| Change in serum chitinase-3 like protein 1 (Chi3L1) | Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline | From Baseline up to approximately 48 months |