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

Myasthenia Gravis Clinical Trial

— URSA  

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05132569
• Other study ID #: EFC17262
• Secondary ID: U1111-1265-63782
• Status: Terminated
• Phase: Phase 3
• Start date: December 3, 2021
• Est. completion date: February 21, 2023

Study information

• Verified date: February 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This was 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 generalized myasthenia gravis (gMG), who received Standard of Care (SoC). The double-blind (DB) treatment period of 26 weeks comprised of 7 site visits followed by a 2-year open label extension (OLE) period with quarterly visits. The efficacy of tolebrutinib versus placebo during the DB period was assessed by clinical evaluations, including scales based on physician examination or direct participant feedback i.e., patient reported outcomes (PROs). These evaluations continued during the OLE to measure long term efficacy and safety.

Description:

The duration of the DB period was 26 weeks. The OLE was planned up to 104 weeks. The duration of the whole study DB+OLE was planned up to130 weeks.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: February 21, 2023
• Est. primary completion date: February 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Participants were 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 myasthenia gravis foundation of America (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-acetylcholine receptor (anti-AChR) or anti-muscle-specific kinase (anti-MuSK) autoantibody at screening OR

• Seronegative for both anti-AChR and anti-MuSK autoantibodies and with prior diagnosis supported by greater than or equal to (>=) 1 of the following 3 tests:

1. History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation.

2. History of positive edrophonium chloride test.

3. Participant had demonstrated improvement in gMG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician.

• The participant had a total score >=6 on myasthenia gravis-activities of daily living scale at screening and Day 1 with greater than half of the score attributed to non-ocular items.

Exclusion Criteria:

• MGFA Class I (ocular MG) or Class V.

• Participants had undergone thymectomy within 6 months of screening or having a planned thymectomy during the trial period.

• The participant had a history of infection or might 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 required treatment with antibiotics, antivirals, or antifungals; Fever within 4 weeks of the Screening Visit (>=38 degree Celsius; however, if due to brief and mild ear, nose, throat viral infection participant might 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 had been resected or were considered as cured by any treatment with no evidence of metastatic disease for >=3 years) will be exclusionary.

• Conditions that might predispose the participant to excessive bleeding.

• Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Related Conditions & MeSH terms

• Muscle Weakness
• Myasthenia Gravis

Intervention

Drug:
• Tolebrutininb
Pharmaceutical form: Film-coated tablet Route of administration: Oral
• Placebo
Pharmaceutical form: Film-coated tablet Route of administration: Oral

Locations

Country	Name	City	State
Canada	Investigational Site Number :1240004	Edmonton	Alberta
Canada	Investigational Site Number :1240003	London	Ontario
China	Investigational Site Number :1560003	Chengdu
China	Investigational Site Number :1560001	Shanghai
China	Investigational Site Number :1560002	Wuhan
Hungary	Investigational Site Number :3480002	Pécs
Hungary	Investigational Site Number :3480001	Szeged
Italy	Investigational Site Number :3800001	Milano
Italy	Investigational Site Number :3800002	Milano	Lombardia
Italy	Investigational Site Number :3800004	Napoli
Italy	Investigational Site Number :3800003	Roma
Japan	Investigational Site Number :3920002	Sagamihara-shi	Kanagawa
Poland	Investigational Site Number :6160001	Zabrze
Spain	Investigational Site Number :7240003	Hospitalet de Llobregat	Catalunya [Cataluña]
Spain	Investigational Site Number :7240005	Madrid	Madrid, Comunidad De
United Kingdom	Investigational Site Number :8260002	Exeter	Devon
United Kingdom	Investigational Site Number :8260001	Liverpool
United States	SFM Clinical Research, LLC-Site Number:8400006	Boca Raton	Florida
United States	Harvard Medical School - Brigham and Women's Hospital-Site Number:8400004	Boston	Massachusetts
United States	Neurology Center of San Antonio, PA-Site Number:8400009	San Antonio	Texas
United States	University of South Florida Health- Morsani Center for Advanced Healthcare-Site Number:8400001	Tampa	Florida
United States	Georgetown University-Site Number:8400008	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Canada,  China,  Hungary,  Italy,  Japan,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DB Period: Change From Baseline in Myasthenia Gravis-activities of Daily Living (MG-ADL) Total Score at Week 26	The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.	Baseline (Day 1), Week 26
Primary	OLE Period: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interests (AESIs)	An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. A SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. An AESI was defined as one of scientific & medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was considered appropriate. Relatedness to study vaccine was based on Investigator's discretion.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Primary	OLE Period: Number of Participants With Hematological Abnormalities	Hematological parameters assessed were: platelet count, red blood cell count, hemoglobin, hematocrit, white blood cell, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Only those categories in which at least 1 participant had data were reported.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Primary	OLE Period: Number of Participants With Clinical Chemistry Parameter Abnormalities	Clinical chemistry parameters assessed were blood urea nitrogen, creatinine, glucose, total and direct bilirubin, potassium, sodium, chloride, bicarbonate, calcium, albumin, creatine phosphokinase, alkaline phosphatase, aspartate aminotransferase/serum glutamic-oxaloacetic transaminase, alanine aminotransferase/serum glutamic-pyruvic transaminase, lipase, and total protein. Only the category (Alkaline phosphatase) in which at least 1 participant had data were reported.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Primary	OLE Period: Number of Participants With Electrocardiogram (ECG) Abnormalities	ECG parameters assessed were heart rate, pulse rate, QRS interval, QT interval and QT interval corrected using Fridericia's formula [QTcF]).	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Primary	OLE Period: Number of Participants With Vital Signs Abnormalities	Vital signs assessed were heart rate, systolic blood pressure, diastolic blood pressure, weight and temperature. Only those category (Weight >=5% decrease from Baseline) in which at least 1 participant had data were reported.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Secondary	DB Period: Change From Baseline in Quantitative Myasthenia Gravis (QMG) Total Score at Week 26	The QMG is a clinician-reported outcome to assess muscle weakness in participants with MG. The QMG test consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is scored on 3-point scale ranged from 0 (none) to 3 (severe), where higher score represents most severe muscle weakness. The QMG total score is the sum of each individual item score which ranged from 0 (normal) to 39 (severe). Higher score represents greater disease activity. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.	Baseline (Day 1), Week 26
Secondary	DB Period: Change From Baseline in Quantitative Myasthenia Gravis (QMG) Total Score at Week 12	The QMG is a clinician-reported outcome to assess muscle weakness in participants with MG. The QMG test consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is scored on 3-point scale ranged from 0 (none) to 3 (severe), where higher score represents most severe muscle weakness. The QMG total score is the sum of each individual item score which ranged from 0 (normal) to 39 (severe). Higher score represents greater disease activity. The QMG total score at Week 12 is reported in this outcome measure. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.	Baseline (Day 1), Week 12
Secondary	DB Period: Change From Baseline in Myasthenia Gravis Impairment Index (MGII) Total Score at Week 26	MGII: measure of MG severity, with demonstrated fatigability, reliability and construct validity. It consists of 22-item patient-reported questionnaire and 6 clinician-assessment items. MGII can be divided into 2 sub-scale-scores: ocular (8 items) & generalized (20 items) impairments. Ocular sub-score: calculated by summing 1 to 6 items from patient questionnaire and items 1 & 2 of clinician-assessment. Generalized score: calculated by adding items 7 to 22 from patient questionnaire & items 3 to 6 from the clinician-assessment. Each item is scored on 4-point scale: from 0 (none) to 3 (severe), where higher score=more disease severity. MGII total score: sum of each item of patient questionnaire (total score:0 [normal] to 23 [severe]) & clinician assessment items (total score:0 [normal] to 61 [severe]); ranged from 0 (normal) to 84 (severe). Higher scores=greater disease severity. DB period Baseline: defined as last available value prior to 1st dose of study medication in the DB period.	Baseline (Day 1), Week 26
Secondary	DB Period: Change From Baseline in Myasthenia Gravis-quality of Life 15-item Scale (MG-QoL15) Total Score at Week 26	The MG-QOL15 is a 15-item, participant self-reported QoL instrument for participants with MG. The instrument is developed and validated to evaluate general QoL of participants with MG by a clinician in the practice setting. The domains covered by the questionnaire are mobility (9 items), symptoms (3 items), general contentment (1 item) and emotional well-being (2 items). Each item is scored on a scale of 0 (not at all) to 4 (very much), where higher score indicates severe QoL impairment. The MG-QOL15 total score is the sum of each individual item score and ranged from 0 (none) to 60 (severe). Higher scores indicates greater extent and dissatisfaction with MG-related dysfunction. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.	Baseline (Day 1), Week 26
Secondary	DB Period: Percentage of Participants With Greater Than Equal to (>=) 2-point Improvement (Reduction) in Myasthenia Gravis-activities of Daily Living Total Score at Week 26	The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG.	Week 26
Secondary	DB Period: Percentage of Participants With >=3-point Improvement (Reduction) in Quantitative Myasthenia Gravis Total Score at Week 26	The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG.	Week 26
Secondary	DB Period: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interests (AESIs)	An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. A SAEs was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. AESI was defined as one of scientific & medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was considered appropriate. Relatedness to study vaccine was based on Investigator's discretion.	From Day 1 up to Week 26
Secondary	DB Period: Number of Participants With Hematological Abnormalities	Hematological parameters assessed were: platelet count, red blood cell count, hemoglobin, hematocrit, white blood cell, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Only those categories in which at least 1 participant had data were reported.	From Day 1 up to Week 26
Secondary	DB Period: Number of Participants With Clinical Chemistry Parameter Abnormalities	Clinical chemistry parameters assessed were blood urea nitrogen, creatinine, glucose, total and direct bilirubin, potassium, sodium, chloride, bicarbonate, calcium, albumin, creatine phosphokinase, alkaline phosphatase, aspartate aminotransferase/serum glutamic-oxaloacetic transaminase, alanine aminotransferase/serum glutamic-pyruvic transaminase, lipase, and total protein. Only those categories in which at least 1 participant had data were reported.	From Day 1 up to Week 26
Secondary	DB Period: Number of Participants With Electrocardiogram Abnormalities	ECG parameters assessed were heart rate, pulse rate, QRS interval, QT interval and QTcF.	From Day 1 up to Week 26
Secondary	DB Period: Number of Participants With Vital Signs Abnormalities	Vital signs assessed were heart rate, systolic blood pressure, diastolic blood pressure, weight and temperature. Only those category (Weight >=5% increase from Baseline) in which at least 1 participant had data were reported.	From Day 1 up to Week 26
Secondary	OLE Period: Change From Baseline in Myasthenia Gravis-activities of Daily Living Total Score	The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Secondary	OLE Period: Change From Baseline in Quantitative Myasthenia Gravis Total Score	The QMG is a clinician-reported outcome to assess muscle weakness in participants with MG. The QMG test consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is scored on 3-point scale ranged from 0 (none) to 3 (severe), where higher score represents most severe muscle weakness. The QMG total score is the sum of each individual item score which ranged from 0 (normal) to 39 (severe). Higher score represents greater disease activity. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Secondary	OLE Period: Change From Baseline in Myasthenia Gravis Impairment Index Total Score	MGII: measure of MG severity, with demonstrated fatigability, reliability and construct validity. It consists of 22-item patient-reported questionnaire & 6 clinician-assessment items. MGII can be divided into 2 sub-scale-scores: ocular (8 items) & generalized (20 items) impairments. Ocular sub-score: calculated by summing 1 to 6 items from patient questionnaire and items 1 & 2 of clinician-assessment. Generalized score: calculated by adding items 7 to 22 from patient questionnaire & items 3 to 6 from the clinician-assessment. Each item is scored on 4-point scale: from 0 (none) to 3 (severe), where higher score=more disease severity. MGII total score: sum of each item of patient questionnaire (total score:0 [normal] to 23 [severe]) & clinician assessment items (total score:0 [normal] to 61 [severe]); ranged from 0 (normal) to 84 (severe). Higher scores=greater disease severity. OLE period Baseline:defined as last available value prior to 1st dose of study medication in the OLE period.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Secondary	OLE Period: Change From Baseline in Myasthenia Gravis-quality of Life 15-item Scale Total Score	The MG-QOL15 is a 15-item, participant self-reported QoL instrument for participants with MG. The instrument is developed and validated to evaluate general QoL of participants with MG by a clinician in the practice setting. The domains covered by the questionnaire are mobility (9 items), symptoms (3 items), general contentment (1 item) and emotional well-being (2 items). Each item is scored on a scale of 0 (not at all) to 4 (very much), where higher score indicates severe QoL impairment. The MG-QOL15 total score is the sum of each individual item score and ranged from 0 (none) to 60 (severe). Higher scores indicate greater extent and dissatisfaction with MG-related dysfunction.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Secondary	OLE Period: Percentage of Participants With >=2-point Improvement (Reduction) in Myasthenia Gravis-activities of Daily Living Total Score	The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Secondary	OLE Period: Percentage of Participants With >=3-point Improvement (Reduction) in Quantitative Myasthenia Gravis Total Score	The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life, including talking, chewing, swallowing, breathing, brushing their teeth or combing their hair, getting up from a chair, double vision and eyelid droop. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 to 24, where a higher score represents severe disability due to MG. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.	From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)
Secondary	OLE Period: Percentage of Participants Achieving Any Reduction From Baseline of Daily Dose of Oral Corticosteroids (OCS) at Week 61	The use of rescue therapy for generalized MG worsening is allowed at any time during both the DB and OLE parts of the study at discretion of the Investigator in case of at least a 2-point increase of individual non-ocular MG-ADL items compared to the Day 1 MG-ADL value or new or worsening of respiratory/ bulbar symptoms. Rescue therapy includes intravenous immunoglobulin, plasma exchange, change in the standard of care OCS dose or any use of new CS. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.	Baseline (Day 1), Week 61