Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS)

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 primary progressive multiple sclerosis (PPMS) Secondary Objectives: 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 in PPMS and its relationship to efficacy and safety To evaluate pharmacodynamics 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 12 to 60 months.

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

Conditions
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Primary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: Tolebrutinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - 18 to 55 years of age inclusive Diagnosis of PPMS according to the 2017 McDonald criteria Expanded disability status scale (EDSS) score between 2.0 to 6.5 points, at screening inclusive Positive cerebrospinal fluid oligoclonal bands and/or elevated Immunoglobulin G (IgG) index either during screening or documented previous history. Contraceptive use consistent with local regulations for individuals participating in clinical studies Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) or is a WOCBP and agrees to use an acceptable contraceptive method the participant must not have access to ocrelizumab (eg, ocrelizumab not available on the national market or not reimbursed for the approved indication). the participant must have access to and be eligible to be treated with ocrelizumab but: 1) does not tolerate it due to side effects or safety reasons; and/or 2) has failed ocrelizumab treatment due to perceived lack of efficacy Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Participant has conditions that would adversely affect study participation such as short life expectancy. Evidence of infection with human immunodeficiency virus (HIV), transplantation, progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infection 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. 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. 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 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 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). NOTE: Other Inclusion/Exclusion criteria may apply. 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: 55 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 to match the SAR442168 once daily | Drug: Placebo<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 |
| --- | --- | --- |
| 3-month composite Confirmed Disability Progression (cCDP) | Time to onset of 3-month cCDP defined as follows: Increase over at least 3 months of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.5, or ≥0.5 points when the baseline EDSS score is >5.5, or ≥20% from the baseline T25-FW, or ≥20% from the baseline 9-HPT | Up to approximately 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Confirmed Disability Progression (CDP) | Time to onset of 6-month CDP as assessed by EDSS score | Up to approximately 60 months | 
| 6-month composite Confirmed Disability Progression (cCDP) | Time to onset of 6-month cCDP | Up to approximately 60 months | 
| Change in T2 hyperintense lesions by MRI | Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI after baseline up to and including the end of study (EOS) | From screening MRI to approximately 60 months | 
| Time to onset of confirmed disability improvement (CDI) | Time to onset of CDI defined as ≥1.0-point decrease on the EDSS score from baseline confirmed over at least 6 months | Up to approximately 60 months | 
| Percent change in Brain volume (BV) | Percent change in brain volume (BV) as detected by brain MRI at the EOS compared to month 6 | From 6 months up to approximately 60 months | 
| Change in cognitive function as assessed by SDMT | Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) | From Baseline up to approximately 60 months | 
| Change in cognitive function as assessed by CVLT-II | Change in cognitive function at the EOS compared to baseline as assessed by the California Verbal Learning Test II (CVLT-II) where available | From Baseline up to approximately 60 months | 
| Change in Multiple Sclerosis Quality of Life | Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) at the EOS compared to baseline | From Baseline up to approximately 60 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 up to approximately 60 months | 
| Population pharmacokinetics | Plasma concentration of SAR442168 (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 from at the EOS compared to baseline | From Baseline up to approximately 60 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 60 months | 
| Changes in serum Immunoglobulin level | Changes in serum Immunoglobulin level at the EOS compared to baseline | From Baseline up to approximately 60 months | 
| Change in serum chitinase-3 like protein 1 (Chi3L1) | Change in serum Chi3L1 at EOS compared to baseline | From Baseline up to approximately 60 months |