Trial Outcomes & Findings for Efficacy and Safety of Tolebrutinib (SAR442168) Tablets in Adult Participants With Generalized Myasthenia Gravis (NCT NCT05132569)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

6 participants

Primary outcome timeframe

Baseline (Day 1), Week 26

Results posted on

2025-09-09

Participant Flow

Study was conducted at 22 sites in 9 countries from 03-Dec-2021 to 21-Feb-2023. A total of 6 participants were randomized in a 1:1 ratio to receive treatment with tolebrutinib or placebo.

Randomization was stratified by Myasthenia Gravis Foundation of America (MGFA) class (II, IIIa/IVa, or IIIb/IVb) and region (United States \[US\], non-US). Due to early termination of the study by sponsor, several planned efficacy analysis were not performed for the study.

Participant milestones

Participant milestones
Measure	Placebo/Tolebrutinib Participants with moderate-to-severe generalized myasthenia gravis (gMG) received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their Standard of Care (SoC) for 26 weeks in the double-blind (DB) treatment period. Participants who completed DB period entered the open label extension (OLE) period and received tolebrutinib 60 milligrams (mg) orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).	Tolebrutinib/Tolebrutinib Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period. Participants who completed DB period entered the OLE period and continued to receive tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).
DB Period: 26 Weeks STARTED	3	3
DB Period: 26 Weeks COMPLETED	2	1
DB Period: 26 Weeks NOT COMPLETED	1	2
OLE: Week 27 Till Termination (Week 61) STARTED	2	1
OLE: Week 27 Till Termination (Week 61) COMPLETED	0	0
OLE: Week 27 Till Termination (Week 61) NOT COMPLETED	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo/Tolebrutinib Participants with moderate-to-severe generalized myasthenia gravis (gMG) received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their Standard of Care (SoC) for 26 weeks in the double-blind (DB) treatment period. Participants who completed DB period entered the open label extension (OLE) period and received tolebrutinib 60 milligrams (mg) orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).	Tolebrutinib/Tolebrutinib Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period. Participants who completed DB period entered the OLE period and continued to receive tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).
DB Period: 26 Weeks Withdrawal by Subject	0	1
DB Period: 26 Weeks Study terminated by sponsor	1	1
OLE: Week 27 Till Termination (Week 61) Study terminated by sponsor	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Participants n=6 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet or matched placebo tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period. Participants who received treatment with tolebrutinib 60 mg orally daily in the DB period entered the OLE period and continued the same treatment in the OLE period. Participants who received matched placebo in the DB period received tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).
Age, Continuous	56.0 years STANDARD_DEVIATION 12.4 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1), Week 26

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Analysis was performed on the safety population which included all randomized participants who took at least 1 dose of study intervention and were analyzed according to the intervention they actually received.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=2 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=1 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
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) AEs	2 Participants	0 Participants
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) SAEs	0 Participants	0 Participants
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) AEs leading to permanent study intervention discontinuation	0 Participants	0 Participants
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) AESIs	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Analysis was performed on safety population.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=2 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=1 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
OLE Period: Number of Participants With Hematological Abnormalities Hematocrit	1 Participants	0 Participants
OLE Period: Number of Participants With Hematological Abnormalities Hemoglobin	1 Participants	0 Participants
OLE Period: Number of Participants With Hematological Abnormalities White blood cells	1 Participants	0 Participants
OLE Period: Number of Participants With Hematological Abnormalities Monocytes	2 Participants	0 Participants

PRIMARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Analysis was performed on the safety population.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=2 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=1 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
OLE Period: Number of Participants With Clinical Chemistry Parameter Abnormalities	0 Participants	1 Participants

PRIMARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Analysis was performed on the safety population.

ECG parameters assessed were heart rate, pulse rate, QRS interval, QT interval and QT interval corrected using Fridericia's formula \[QTcF\]).

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=2 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=1 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
OLE Period: Number of Participants With Electrocardiogram (ECG) Abnormalities	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Analysis was performed on the safety population.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=2 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=1 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
OLE Period: Number of Participants With Vital Signs Abnormalities	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 26

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 12

Population: Analysis was performed on modified intention-to-treat (mITT) population which included all randomized and treated participants with a Baseline value and at least 1 post-baseline value for any efficacy assessment. Data for this outcome measure was not collected and analyzed for OLE period of the study.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=3 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=3 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
DB Period: Change From Baseline in Quantitative Myasthenia Gravis (QMG) Total Score at Week 12	-2.0 score on a scale Standard Deviation 7.9	-1.7 score on a scale Standard Deviation 2.9

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 26

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 26

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 26

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 26

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Day 1 up to Week 26

Population: Analysis was performed on safety population.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=3 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=3 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
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) AEs	1 Participants	2 Participants
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) SAEs	1 Participants	1 Participants
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) AEs leading to permanent study intervention discontinuation	0 Participants	0 Participants
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) AESIs	1 Participants	1 Participants

SECONDARY outcome

Timeframe: From Day 1 up to Week 26

Population: Analysis was performed on safety population.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=3 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=3 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
DB Period: Number of Participants With Hematological Abnormalities Hematocrit	1 Participants	1 Participants
DB Period: Number of Participants With Hematological Abnormalities Hemoglobin	1 Participants	0 Participants
DB Period: Number of Participants With Hematological Abnormalities Monocytes	1 Participants	0 Participants
DB Period: Number of Participants With Hematological Abnormalities Eosinophils	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From Day 1 up to Week 26

Population: Analysis was performed on safety population.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=3 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=3 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
DB Period: Number of Participants With Clinical Chemistry Parameter Abnormalities Protein	1 Participants	1 Participants
DB Period: Number of Participants With Clinical Chemistry Parameter Abnormalities Alanine aminotransferase	1 Participants	0 Participants
DB Period: Number of Participants With Clinical Chemistry Parameter Abnormalities Aspartate aminotransferase	1 Participants	0 Participants
DB Period: Number of Participants With Clinical Chemistry Parameter Abnormalities Alkaline phosphatase	0 Participants	1 Participants
DB Period: Number of Participants With Clinical Chemistry Parameter Abnormalities Total bilirubin	0 Participants	1 Participants

SECONDARY outcome

Timeframe: From Day 1 up to Week 26

Population: Analysis was performed on safety population.

ECG parameters assessed were heart rate, pulse rate, QRS interval, QT interval and QTcF.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=3 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=3 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
DB Period: Number of Participants With Electrocardiogram Abnormalities	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From Day 1 up to Week 26

Population: Analysis was performed on safety population.

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.

Outcome measures

Outcome measures
Measure	DB Period: Placebo n=3 Participants Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	DB Period: Tolebrutinib n=3 Participants Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.
DB Period: Number of Participants With Vital Signs Abnormalities	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 61

Population: Evaluable data was collected for 3 participants only; and thus, was not presented to protect participant confidentiality.

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.

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Tolebrutinib

Serious events: 1 serious events

Other events: 3 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=3 participants at risk Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	Tolebrutinib n=5 participants at risk Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period. Participants who completed the DB period entered the OLE period and continued to receive tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61). Additionally, participants who received placebo in DB period and completed DB period entered the OLE period and received tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).
Infections and infestations Covid-19 Pneumonia	0.00% 0/3 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Nervous system disorders Dizziness	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Injury, poisoning and procedural complications Head Injury	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.

Other adverse events

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=3 participants at risk Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period.	Tolebrutinib n=5 participants at risk Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period. Participants who completed the DB period entered the OLE period and continued to receive tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61). Additionally, participants who received placebo in DB period and completed DB period entered the OLE period and received tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).
Infections and infestations Covid-19	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Infections and infestations Upper Respiratory Tract Infection	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Blood and lymphatic system disorders Increased Tendency To Bruise	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Metabolism and nutrition disorders Hyperuricaemia	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Gastrointestinal disorders Abdominal Pain Upper	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Gastrointestinal disorders Toothache	0.00% 0/3 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Hepatobiliary disorders Hepatic Function Abnormal	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Skin and subcutaneous tissue disorders Dry Skin	0.00% 0/3 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Musculoskeletal and connective tissue disorders Muscle Spasms	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Investigations Bilirubin Conjugated Increased	0.00% 0/3 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Investigations Blood Creatine Phosphokinase Increased	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Investigations Haemoglobin Decreased	33.3% 1/3 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	0.00% 0/5 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/3 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Injury, poisoning and procedural complications Thermal burn	0.00% 0/3 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.
Infections and infestations Oral herpes	0.00% 0/3 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.	20.0% 1/5 • Number of events 1 • From Day 1 up to Week 26 for DB period and from Week 27 up to Week 61 for OLE period Analysis was performed on safety population. Based on the low enrolment number and in order to protect and maintain participant privacy/confidentiality, period (DB and OLE) wise data were not reported and only combined analysis was performed.