PPMS Study of Bruton's tyrosine kinase (BTK) inhibitor SAR442168 (PERSEUS)

INTERVENTION: Product Code: SAR442168 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Not available CAS Number: 1971920‐73‐6 Current Sponsor code: SAR442168 Other descriptive name: PRN2246 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 60‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use CONDITION: Primary Progressive Multiple Sclerosis ; MedDRA version: 21.1 Level: PT Classification code 10063401 Term: Primary progressive multiple sclerosis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in Primary Progressive Multiple Sclerosis (PPMS) Primary end point(s): 6 month Confirmed Disability Progression (CDP) ; Time to onset of 6 month CDP defined as follows:; Increase of =1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is =5.5, or Increase of =0.5 points when the baseline EDSS score is >5.5; 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 in PPMS and its relationship to efficacy and safety; To evaluate pharmacodynamics of SAR442168 ; Timepoint(s) of evaluation of this end point: Up to approximately 48 months INCLUSION CRITERIA: ‐ 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 ‐ Disease duration from the onset of MS symptoms of <15 years if screening EDSS score of >5.0 OR <10 years if screening EDSS score of =5.0. ‐ 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 1320 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range SECONDARY OUTCOME: Secondary end point(s): 1 ‐ 3‐month confirmed disability progression (CDP) ; Time to onset of 3‐month CDP as assessed by EDSS score; 2 ‐ 3‐month change in 9‐hole peg test (9‐HPT) ; Time to onset of sustained 20% increase in the 9‐HPT test confirmed over at least 3 months ; 3 ‐ 3‐month change in timed 25 foot walk (T25‐FW) ; Time to onset of sustained 20% increase in the T25‐FW confirmed over at least 3 months ; 4 ‐ 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); 5 ‐ 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; 6 ‐ Percent change in Brain volume loss (BVL) ; Percent change in brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6 ; 7 ‐ Change in cognitive function ; Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT); 8 ‐ Change in cognitive function ; Change in cognitive function at the EOS compared to baseline as assessed by the California Verbal Learning Test II (CVLT‐II) where available; 9 ‐ Change in Multiple Sclerosis Quality of Life ; Change in Multiple Sclerosis Quality of Life‐54 (MSQoL‐54) at the EOS compared to baseline; 10 ‐ 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); 11 ‐ Population pharmacokinetics ; Plasma concentration of SAR442168 (population PK assessment) at Months 6, 9, and 12; 12 ‐ Change in plasma neurofilament light chain (NfL) ; Change in NfL levels from at the EOS compared to baseline; 13 ‐ Change in lymphocyte phenotype subsets ; Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline; 14 ‐ Changes in serum Immunoglobulin level ; Changes in serum Immunoglobulin level at the EOS compared to baseline; 15 ‐ Change in serum chitinase‐3 like protein 1 (Chi3L1) ; Change in serum chitinase‐3 like protein 1 (Chi3L1) at EOS compared to baseline Timepoint(s) of evaluation of this end point: 1, 2, 3 : Up to approximately 48 months; 4 : From baseline to approximately 48 months ; 5 : From Baseline up to 48 approximately months; 6 : From 6 months up to approximately 48 months; 7, 8, 9, 12, 13, 14, 15 : From Baseline up to approximately 48 months; 10 : From screening up to approximately 48 months; 11 : Months 6, 9 and 12