Trial Outcomes & Findings for Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES) (NCT NCT04411641)

Last Updated: 2025-07-02

Results Overview

The EDSS is a disability scale that assesses the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS ranges from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]) (0.5 increments from 1-10; next increase after 0 is 1). Higher scores indicated increased disability. Time to onset of 6-month CDP was defined as the time from randomization to the onset of a sustained increase from baseline in EDSS score of \>=1.0 point from the baseline EDSS score when the baseline score was \<=5.0 or of \>=0.5 points when the baseline EDSS score was \>5.0 confirmed after a minimum 6-month interval.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1131 participants

Primary outcome timeframe

Baseline (Day 1) up to approximately 47 months

Results posted on

2025-07-02

Participant Flow

A total of 1438 participants were screened at 267 centers in 31 countries between 24-Sep-2020 and 02-Dec-2022, of which 307 were screen failures mainly due to not meeting eligibility criteria.

A total of 1131 participants were randomized in this study in a 2:1 ratio to receive either tolebrutinib or matching placebo in the double-blind (DB) period. Participants with 6-month confirmed disability progression (CDP) were given the option to receive open-label (OL) tolebrutinib. This was an event-driven (6-month CDP) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 47 months).

Participant milestones

Participant milestones
Measure	DB: Placebo Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
DB Period STARTED	377	754	0	0
DB Period COMPLETED	192	434	0	0
DB Period NOT COMPLETED	185	320	0	0
OL STARTED	0	0	76	120
OL COMPLETED	0	0	67	95
OL NOT COMPLETED	0	0	9	25

Reasons for withdrawal

Reasons for withdrawal
Measure	DB: Placebo Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
DB Period Other	7	27	0	0
DB Period Withdrawal by Subject	67	122	0	0
DB Period Progressive disease	76	116	0	0
DB Period Poor compliance to protocol	1	5	0	0
DB Period Lack of Efficacy	19	19	0	0
DB Period Adverse Event	13	29	0	0
DB Period Randomized and not treated	2	2	0	0
OL Withdrawal by Subject	0	0	6	17
OL Progressive disease	0	0	1	2
OL Poor compliance to protocol	0	0	1	0
OL Adverse Event	0	0	1	0
OL Other	0	0	0	6

Baseline Characteristics

Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DB: Placebo n=377 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=754 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	Total n=1131 Participants Total of all reporting groups
Age, Continuous	48.9 years STANDARD_DEVIATION 8.0 • n=5 Participants	48.9 years STANDARD_DEVIATION 8.0 • n=7 Participants	48.9 years STANDARD_DEVIATION 8.0 • n=5 Participants
Sex: Female, Male Female	242 Participants n=5 Participants	454 Participants n=7 Participants	696 Participants n=5 Participants
Sex: Female, Male Male	135 Participants n=5 Participants	300 Participants n=7 Participants	435 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	19 Participants n=5 Participants	36 Participants n=7 Participants	55 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) White	348 Participants n=5 Participants	703 Participants n=7 Participants	1051 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) up to approximately 47 months

Population: The intent-to-treat (ITT) population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

Outcome measures

Outcome measures
Measure	DB: Placebo n=377 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=754 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS)	11.97 months Interval 0.5 to 39.1	12.04 months Interval 2.8 to 37.4	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to approximately 47 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

The EDSS is a disability scale that assesses the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS ranges from 0 (normal) to 10 (death due to MS) (0.5 increments from 1-10; next increase after 0 is 1). Higher scores indicated increased disability. Time to onset of 3-month CDP was defined as the time from randomization to the onset of a sustained increase from baseline in EDSS score (of \>=1.0 point from the baseline EDSS score when the baseline score is \<=5.0, of \>=0.5 points when the baseline EDSS score is \>5.0) confirmed after a minimum 3-month interval. The confirmation of 3-month CDP followed the same criteria as that of 6-month CDP.

Outcome measures

Outcome measures
Measure	DB: Placebo n=377 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=754 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Time to Onset of 3-month Confirmed Disability Progression as Assessed by Expanded Disability Status Scale	11.96 months Interval 0.5 to 39.1	12.04 months Interval 2.8 to 39.5	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to approximately 47 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

Magnetic resonance imaging (MRI) of the brain was performed to identify number of new and/or enlarging T2-hyperintense lesions defined as the sum of the individual number of new and/or enlarging T2 lesions from baseline up to and including the EOS visit.

Outcome measures

Outcome measures
Measure	DB: Placebo n=377 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=754 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Mean Number of New and/or Enlarging T2-hyperintense Lesions Per Year	2.948 number of T2 lesions Interval 2.239 to 3.88	1.835 number of T2 lesions Interval 1.441 to 2.336	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to approximately 47 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

The 9-HPT is a brief, standardized, quantitative test of upper extremity function and the time to complete the 9-HPT is used to assess a participant's manual dexterity and fine motor skills. A participant was asked to place the pegs into the holes and remove them with the dominant and non-dominant hand; two successful trials for each hand. The amount of time (in seconds) required to place and remove all nine pegs was recorded for each trial (ranging from 10 to 300 seconds). The mean time to test completion served for assessment of the participant's hand dexterity. Higher value indicated worse outcome. An increase of \>20% from the baseline in the 9-HPT was considered meaningful worsening; time to onset of sustained 20% increase for at least 3 months is presented.

Outcome measures

Outcome measures
Measure	DB: Placebo n=377 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=754 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Time to Onset of Sustained 20% Increase in the 9-hole Peg Test (HPT) for at Least 3 Months	12.39 months Interval 2.5 to 33.3	12.21 months Interval 2.8 to 39.2	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to approximately 47 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

The T25-FW test is a quantitative mobility and leg function performance test used to assess a participant's walking ability. A participant was directed to one end of a clearly marked 25-foot course and instructed to walk 25 feet as quickly as safely possible for 2 trials. The amount of time (in seconds) to walk 25 feet was recorded (ranging from 2.2 to 180 seconds). The mean walk time was used for assessment of the participant's walking ability. Higher value indicated worse outcome. An increase of \>20% from the baseline in the T25-FW test was considered meaningful worsening; time to onset of sustained 20% increase for at least 3 months is presented.

Outcome measures

Outcome measures
Measure	DB: Placebo n=377 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=754 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Time to Onset of Sustained 20% Increase in the Timed 25-foot Walk (T25-FW) for at Least 3 Months	9.25 months Interval 2.5 to 36.3	9.54 months Interval 2.8 to 39.3	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to approximately 47 months

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.

Outcome measures

Outcome measures
Measure	DB: Placebo n=377 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=754 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Time to Onset of 6-month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale	12.04 months Interval 3.0 to 24.1	11.89 months Interval 2.9 to 33.0	—	—

SECONDARY outcome

Timeframe: Month 6 to EOS (up to approximately 47 months)

Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only those participants with data collected at specified timepoints are reported.

MRI of the brain was performed to evaluate percent change in brain volume which is considered as a marker of the central nervous system degenerative process. Least squares (LS) mean is presented.

Outcome measures

Outcome measures
Measure	DB: Placebo n=223 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=451 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Percent Change in Brain Volume at EOS Compared to Month 6	-0.776 percent change Standard Error 0.0479	-0.694 percent change Standard Error 0.0336	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 47 months)

The SDMT is used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involves a simple substitution task using a reference key. The number of correct substitutions and number of items completed within a 90 second interval (maximum 110 seconds) are recorded. A decrease of 4 points from baseline on the SDMT is considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicated better outcome. LS mean is presented. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	DB: Placebo n=271 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=546 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Change From Baseline in Cognitive Function as Assessed by Symbol Digit Modalities Test (SDMT) at EOS	0.171 score on a scale Standard Error 0.0373	0.136 score on a scale Standard Error 0.0264	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 47 months)

The CVLT-II is a verbal learning and memory test consisting of recall and recognition of a list of 16 words. The list was read by the examiner, participants listened to the list and reported as many of the items as possible. For each assessment, 5 trials were completed. Standardized scores were used for analysis. The maximum possible score was 80 and a minimum was 0. A higher score indicated better recall meaning improved cognitive function. LS mean is presented. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	DB: Placebo n=262 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=531 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Change From Baseline in Cognitive Function as Assessed by California Verbal Learning Test Second Edition (CVLT-II) at EOS	13.448 score on a scale Standard Error 0.9571	14.169 score on a scale Standard Error 0.6759	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 47 months)

MSQoL-54 is standardized instrument with generic and MS-specific items which generates 12 subscales \& 2 single-item measures (satisfaction with sexual function \[1 item\] \& change in health \[1 item\].12 subscales are as follows:a:physical health (10 items),b:health perceptions (5 items), c:energy (5 items),d:role limitation physical (4 items),e:sexual function (4 items),f:pain (3 items),g:social function (3 items),h:health distress (4 items),i:overall quality of life (2 items),j:emotional well-being (5 items),k:role limitations emotional (3 items) and l:cognitive function (4 items).Physical health composite score was calculated as weighted sum of 'a to h' subscales and mental health composite score was calculated as weighted sum of 'i to l' subscales mentioned above.Each composite score was transformed linearly to common 0 (worst) to 100 (best) score range;LS mean is presented.Higher score indicated improved QoL.Baseline:last available value prior to first dose of study intervention.

Outcome measures

Outcome measures
Measure	DB: Placebo n=268 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=552 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Change From Baseline in Multiple Sclerosis Quality of Life-54 (MSQoL-54) Questionnaire Score at EOS Physical health composite score	-3.979 score on a scale Standard Error 0.8032	-3.455 score on a scale Standard Error 0.5623	—	—
Change From Baseline in Multiple Sclerosis Quality of Life-54 (MSQoL-54) Questionnaire Score at EOS Mental health composite score	-4.648 score on a scale Standard Error 0.9964	-3.944 score on a scale Standard Error 0.6959	—	—

SECONDARY outcome

Timeframe: From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months

Population: The safety population included all randomized participants exposed to study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received.

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. TEAEs were defined as AEs that developed, worsened or became serious during the TE period.

Outcome measures

Outcome measures
Measure	DB: Placebo n=375 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=752 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg n=76 Participants Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg n=120 Participants Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Number of Participants With Treatment-emergent Adverse Events (AEs), Treatment-emergent Serious AEs, Treatment-emergent AEs Leading to Permanent Study Intervention Discontinuation, and Treatment-emergent Adverse Events of Special Interest (AESIs) TEAEs	293 Participants	613 Participants	47 Participants	80 Participants
Number of Participants With Treatment-emergent Adverse Events (AEs), Treatment-emergent Serious AEs, Treatment-emergent AEs Leading to Permanent Study Intervention Discontinuation, and Treatment-emergent Adverse Events of Special Interest (AESIs) TESAEs	39 Participants	113 Participants	9 Participants	11 Participants
Number of Participants With Treatment-emergent Adverse Events (AEs), Treatment-emergent Serious AEs, Treatment-emergent AEs Leading to Permanent Study Intervention Discontinuation, and Treatment-emergent Adverse Events of Special Interest (AESIs) TEAEs Leading to Permanent Study Intervention Discontinuation	11 Participants	29 Participants	1 Participants	0 Participants
Number of Participants With Treatment-emergent Adverse Events (AEs), Treatment-emergent Serious AEs, Treatment-emergent AEs Leading to Permanent Study Intervention Discontinuation, and Treatment-emergent Adverse Events of Special Interest (AESIs) TEAESIs	20 Participants	75 Participants	6 Participants	10 Participants

SECONDARY outcome

Timeframe: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12

Population: The PK population included all participants in the safety population with at least 1 non-missing PK sample after first dose of the study intervention. Only those participants with data collected at specified timepoints are reported.

Blood samples were collected at specified timepoints to assess Cmax of tolebrutinib and M2 metabolite using a population pharmacokinetics (PopPK) model.

Outcome measures

Outcome measures
Measure	DB: Placebo n=669 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite Tolebrutinib	9.94 nanogram/milliliter (ng/mL) Standard Deviation 6.18	—	—	—
Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite M2 Metabolite	27.5 nanogram/milliliter (ng/mL) Standard Deviation 17.3	—	—	—

SECONDARY outcome

Timeframe: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12

Blood samples were collected at specified timepoints to assess Tmax of tolebrutinib and M2 metabolite using a PopPK model.

Outcome measures

Outcome measures
Measure	DB: Placebo n=669 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite Tolebrutinib	1.42 hour (h) Standard Deviation 0.674	—	—	—
Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite M2 Metabolite	1.52 hour (h) Standard Deviation 0.667	—	—	—

SECONDARY outcome

Timeframe: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12

Blood samples were collected at specified timepoints to assess AUC0-24 of tolebrutinib and M2 metabolite using a PopPK model.

Outcome measures

Outcome measures
Measure	DB: Placebo n=669 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite Tolebrutinib	29.6 ng*h/mL Standard Deviation 17.8	—	—	—
Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite M2 Metabolite	84.6 ng*h/mL Standard Deviation 53.7	—	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 47 months)

Population: The safety population included all randomized participants exposed to study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only those participants with data collected at specified timepoints are reported.

Blood samples were collected at specified timepoints to assess change from baseline in NfL and Chi3L1. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	DB: Placebo n=171 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=410 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS NfL	1.070 picogram/mL Interval -1.285 to 3.615	1.900 picogram/mL Interval -0.37 to 4.47	—	—
Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS Chi3L1	5156.900 picogram/mL Interval -1555.7 to 12099.2	3132.250 picogram/mL Interval -2822.1 to 13407.1	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 47 months)

Blood samples were collected at specified timepoints to assess change from baseline in CD19+ B cells. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	DB: Placebo n=26 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=58 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS	10.000 cells/microliter Interval -18.0 to 77.0	-63.000 cells/microliter Interval -105.0 to -8.0	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 47 months)

Blood samples were collected at specified timepoints to assess change from baseline in IgG and IgM levels. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	DB: Placebo n=149 Participants Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=323 Participants Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS IgM	0.050 gram/liter Interval -0.08 to 0.15	-0.240 gram/liter Interval -0.45 to -0.12	—	—
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS IgG	0.350 gram/liter Interval -0.28 to 1.31	-0.085 gram/liter Interval -0.845 to 0.665	—	—

Adverse Events

DB: Placebo

Serious events: 39 serious events

Other events: 182 other events

Deaths: 1 deaths

DB: Tolebrutinib 60 mg

Serious events: 113 serious events

Other events: 368 other events

Deaths: 2 deaths

OL: Placebo/Tolebrutinib 60 mg

Serious events: 9 serious events

Other events: 25 other events

Deaths: 0 deaths

OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg

Serious events: 11 serious events

Other events: 41 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	DB: Placebo n=375 participants at risk Participants received placebo matched to tolebrutinib orally once daily up to approximately 47 months.	DB: Tolebrutinib 60 mg n=752 participants at risk Participants received tolebrutinib 60 mg tablet orally once daily up to approximately 47 months.	OL: Placebo/Tolebrutinib 60 mg n=76 participants at risk Participants who received placebo in DB period and achieved 6-month CDP were given the option to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.	OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg n=120 participants at risk Participants who received tolebrutinib 60 mg in DB period and achieved 6-month CDP were given the option to continue to receive OL tolebrutinib 60 mg tablet orally once daily up to approximately 39 months in the OL.
Infections and infestations Covid-19	22.7% 85/375 • Number of events 96 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	24.6% 185/752 • Number of events 225 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	5.3% 4/76 • Number of events 4 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	11.7% 14/120 • Number of events 14 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Infections and infestations Influenza	3.5% 13/375 • Number of events 14 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	5.5% 41/752 • Number of events 60 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	2.6% 2/76 • Number of events 2 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	4.2% 5/120 • Number of events 6 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Infections and infestations Nasopharyngitis	6.9% 26/375 • Number of events 35 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	9.3% 70/752 • Number of events 94 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	2.6% 2/76 • Number of events 3 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	6.7% 8/120 • Number of events 10 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Infections and infestations Urinary Tract Infection	13.1% 49/375 • Number of events 81 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	10.9% 82/752 • Number of events 152 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	18.4% 14/76 • Number of events 22 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	10.0% 12/120 • Number of events 19 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Nervous system disorders Headache	7.2% 27/375 • Number of events 31 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	7.2% 54/752 • Number of events 79 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	2.6% 2/76 • Number of events 2 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	3.3% 4/120 • Number of events 4 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Musculoskeletal and connective tissue disorders Arthralgia	5.1% 19/375 • Number of events 21 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	6.5% 49/752 • Number of events 55 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	0.00% 0/76 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	1.7% 2/120 • Number of events 2 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Musculoskeletal and connective tissue disorders Back Pain	6.4% 24/375 • Number of events 25 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	6.2% 47/752 • Number of events 56 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	1.3% 1/76 • Number of events 1 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	2.5% 3/120 • Number of events 3 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Injury, poisoning and procedural complications Accidental Overdose	5.1% 19/375 • Number of events 22 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	3.3% 25/752 • Number of events 29 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	0.00% 0/76 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	2.5% 3/120 • Number of events 3 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.
Injury, poisoning and procedural complications Fall	10.7% 40/375 • Number of events 54 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	9.3% 70/752 • Number of events 106 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	5.3% 4/76 • Number of events 4 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.	5.0% 6/120 • Number of events 7 • From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months Analysis was performed on safety population. All-cause mortality was performed on randomized population. This was an event-driven (6-month CDP) trial with a variable treatment duration, EOS: up to approximately 47 months.

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.
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