Efficacy and Safety of Tolebrutinib (SAR442168) Tablets in Adult Participants With Generalized Myasthenia Gravis

Study Overview
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Brief Summary
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This is a multicenter, randomized, double blind, placebo-controlled, Phase 3 study to evaluate the efficacy and safety of tolebrutinib compared with placebo in adult participants aged 18 to 85 years old with moderate-to-severe gMG, who are receiving Standard of Care (SoC). The double-blind (DB) treatment period of 26 weeks will comprise of 7 site visits followed by a 2-year open label extension (OLE) period with quarterly visits. The efficacy of tolebrutinib versus placebo during DB period will be assessed by clinical evaluations, that include scales based on physician examination or direct participant feedback i.e., patient reported outcomes (PROs). These evaluations will continue during the OLE in order to measure long term efficacy and safety.

Detailed Description
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The duration of the DB period will be 26 weeks. The OLE is up to 104 weeks. The duration of the whole study DB+OLE is 130 weeks.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Tolebrutinib (SAR442168) in Adults With Generalized Myasthenia Gravis (MG)

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: Tolebrutininb
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be 18 years of age to 85 years of age inclusive, at the time of signing the informed consent Participants with a diagnosis of gMG at screening with generalized muscle weakness meeting the clinical criteria for diagnosis of MG, as defined by the MGFA Clinical Classification Class II, III, or IV, and likely not in need of a respirator for the duration of the study, as judged by the Investigator Positive serologic testing for anti-AChR or anti-MuSK autoantibody at screening OR Seronegative for both anti-AChR and anti-MuSK autoantibodies and with prior diagnosis supported by ≥1 of the following 3 tests: History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation History of positive edrophonium chloride test Participant has demonstrated improvement in gMG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician. The participant must have a total score ≥6 on MG-ADL scale at screening and D1 with greater than half of the score attributed to non-ocular items Exclusion Criteria: MGFA Class I (ocular MG) or Class V Participants having undergone thymectomy within 6 months of screening or having a planned thymectomy during the trial period. The participant has a history of infection or may be at risk for infection: A history of active or latent tuberculosis (TB); Participants at risk of developing or having reactivation of hepatitis; Persistent chronic or active recurring infection requiring treatment with antibiotics, antivirals, or antifungals; Fever within 4 weeks of the Screening Visit (≥38°C; however, if due to brief and mild ear, nose, throat viral infection participant may be included based on the Investigator's judgment); A history of infection with human immunodeficiency virus (HIV); A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solid organ, stem cell, and bone marrow transplantation) and/or antirejection therapy Any malignancy within the past 5 years prior Screening Visit (except for effectively treated carcinoma in situ of the cervix, adequately treated non-metastatic squamous or basal cell carcinoma of the skin and malignant thymoma that have been resected or are considered as cured by any treatment with no evidence of metastatic disease for ≥3 years) will be exclusionary Conditions that may predispose the participant to excessive bleeding Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening 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: 85 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR442168<br>Tolebrutinib oral daily dose from baseline until Week 130 | Drug: Tolebrutininb<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral<br>|
| Placebo Comparator: Placebo<br>Matching placebo oral daily dose only for DB period | 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 |
| --- | --- | --- |
| DB period: Change from baseline in Myasthenia gravis-activities of daily living (MG-ADL) total score | The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs symptoms that are typically affected in MG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0 to 24). | Baseline, Week 26 | 
| OLE: Number of participants with adverse events (AEs) /SAEs | Incidence of adverse events (AEs) and serious adverse events (SAEs) | From Week 26 until Week 130 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Quantitative MG (QMG) total score | Quantitative Myasthenia Gravis is clinician-reported outcome/assessment to assess muscle weakness in people with MG. The QMG consists of 13 items ranging from 0 to 3 with 3 being the most severe. | DB period: Baseline, Week 12, Week 26 OLE: Baseline, Week 130 | 
| Change from baseline in MG Impairment Index (MGII) total score | The Myasthenia Gravis Impairment Index (MGII) is a measure of MG impairment focused on the severity of MG impairment and the concept of fatigability. Consists of a 22-item patient-reported questionnaire with 6 clinician assessment items. Higher scores indicate greater disease severity. | DB period: Baseline, Week 26 OLE: Baseline, Week 130 | 
| Change from baseline in MG Quality of Life Questionnaire (MG-QOL15) total score | The MG-QoL15 is a 15-item measure of people with MG QoL instrument that will be self-reported by the participant. The domains covered by the questionnaire are mobility (9 items), symptoms (3 items), general contentment (1 item) and emotional well-being (2 items). Responses to each question are scored from 0 (not at all) to 4 (very much) where higher scores representing worse QoL. | DB period: Baseline, Week 26 OLE: Baseline, Week 130 | 
| Proportion of participants with ≥ 2-point improvement (reduction) in MG-ADL total score |  | DB period: From Baseline until Week 26 OLE: From Baseline up to Week 130 | 
| Proportion of participants with ≥ 3-point improvement (reduction) in QMG total score |  | DB period: From Baseline until Week 26 OLE: From Baseline up to Week 130 | 
| DB: Number of participants with AEs /SAEs |  | From Baseline until Week 26 | 
| OLE: Change from baseline in MG-ADL total score | The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs symptoms that are typically affected in MG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0 to 24). | Baseline, Week 130 | 
| OLE: Proportion of participants achieving any reduction from baseline in daily dose of oral corticosteroids (OCS) |  | From Baseline until Week 130 |