Trial Outcomes & Findings for Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1) (NCT NCT04410978)

Last Updated: 2025-07-02

Results Overview

Multiple sclerosis (MS) relapse was defined as a monophasic, acute or subacute onset of new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for \>=24 hours with or without recovery, present at normal body temperature, and preceded by \>=30 days of clinical stability.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

974 participants

Primary outcome timeframe

Baseline (Day 1) to approximately 48 months

Results posted on

2025-07-02

Participant Flow

This study was conducted at 162 sites in 24 countries. A total of 1152 participants were screened from 30-Jun-2020 to 04-Aug-2022, of which 178 were screen failures. Screen failures were mainly due to not meeting eligibility criteria.

A total of 974 participants were randomized in this study in a 1:1 ratio to either teriflunomide 14 milligrams (mg) or tolebrutinib 60 mg group. This was an event-driven (6-month confirmed disability worsening \[CDW\]) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 48 months).

Participant milestones

Participant milestones
Measure	Teriflunomide 14 mg Participants received teriflunomide 14 mg tablet orally once daily (QD) along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Overall Study STARTED	488	486
Overall Study COMPLETED	415	409
Overall Study NOT COMPLETED	73	77

Reasons for withdrawal

Reasons for withdrawal
Measure	Teriflunomide 14 mg Participants received teriflunomide 14 mg tablet orally once daily (QD) along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Overall Study Poor compliance to protocol	2	4
Overall Study Withdrawal by Subject	64	66
Overall Study Other	6	7
Overall Study Missing study status	1	0

Baseline Characteristics

Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.	Total n=974 Participants Total of all reporting groups
Age, Continuous	36.6 years STANDARD_DEVIATION 9.4 • n=5 Participants	36.8 years STANDARD_DEVIATION 9.0 • n=7 Participants	36.7 years STANDARD_DEVIATION 9.2 • n=5 Participants
Sex: Female, Male Female	325 Participants n=5 Participants	334 Participants n=7 Participants	659 Participants n=5 Participants
Sex: Female, Male Male	163 Participants n=5 Participants	152 Participants n=7 Participants	315 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) Asian	67 Participants n=5 Participants	78 Participants n=7 Participants	145 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	10 Participants n=5 Participants	4 Participants n=7 Participants	14 Participants n=5 Participants
Race (NIH/OMB) White	406 Participants n=5 Participants	395 Participants n=7 Participants	801 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) to approximately 48 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	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses	0.122 relapses per participant year Interval 0.1 to 0.15	0.130 relapses per participant year Interval 0.108 to 0.156

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 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 was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 6-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 6 months that was not attributable to another etiology.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	17.97 months Interval 2.9 to 33.9	15.38 months Interval 2.6 to 36.8

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 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 was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 3-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 3 months that was not attributable to another etiology.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	17.96 months Interval 2.9 to 39.3	14.93 months Interval 0.2 to 41.0

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 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 starting from baseline up to and including the EOS visit.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year	5.175 number of new and or enlarging T2lesions Interval 4.447 to 6.024	5.611 number of new and or enlarging T2lesions Interval 4.826 to 6.524

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 months

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

MRI of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions defined as the sum of the individual number of new Gd- enhancing T1-hyperintense lesions starting from baseline up to and including the EOS visit.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan	0.285 number of new Gd-enhancing T1 lesions Interval 0.221 to 0.367	0.530 number of new Gd-enhancing T1 lesions Interval 0.439 to 0.641

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 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 participants with data collected at specified timepoints are reported.

The SDMT was used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involved 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) were recorded. A decrease of 4 points from baseline on the SDMT was considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicating a better outcome. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=396 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=393 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS	0.329 score on a scale Standard Error 0.0318	0.364 score on a scale Standard Error 0.0318

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

The CVLT-II was a verbal learning and memory test consisting of recall and recognition of a list of 16 words. For each assessment, 5 trials were completed. Total Correct Recall Trials 1-5 was scaled to a normalized T-score metric, which had a mean of 50 and standard deviation of 10, the maximum possible score was 80 and a minimum was 0. Higher values indicated improved cognitive function. Baseline was defined as the last available value prior to the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=391 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=390 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS	15.827 T-score Standard Error 0.7241	17.700 T-score Standard Error 0.7236

SECONDARY outcome

Timeframe: Baseline (Day 1) to approximately 48 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	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale	12.04 months Interval 2.8 to 37.1	11.82 months Interval 2.8 to 33.0

SECONDARY outcome

Timeframe: Month 6 to EOS (up to approximately 48 months)

MRI of the brain was performed at the specified timepoints to detect the changes in brain volume loss.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=346 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=351 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Percent Change in Brain Volume Loss at EOS Compared to Month 6	-0.884 percent change Standard Error 0.0368	-0.688 percent change Standard Error 0.0369

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

MSQoL-54 was standardized instrument comprising generic and MS-specific items. This 54-item instrument generated 12 subscales and 2 single-item measures (satisfaction with sexual function \[1 item\]; change in health \[1 item\]). 12 subscales were: a: physical health (10 items), b: health perceptions (5 items), c: energy (5 items), d: role limit 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 and mental health composite score were calculated as weighted sum of 'a to h' and 'i to l' subscales respectively. Each composite score was transformed linearly to common 0 (worst) to 100 (best) score range; higher score indicated improved quality of life. Baseline was defined as last available value prior to first dose of study intervention.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=400 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=399 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS Physical health composite score	-2.468 score on a scale Standard Error 0.7014	-0.460 score on a scale Standard Error 0.7021
Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS Mental health composite score	-2.070 score on a scale Standard Error 0.8346	-0.729 score on a scale Standard Error 0.8359

SECONDARY outcome

Timeframe: From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months

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	Teriflunomide 14 mg n=488 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) TEAEs	423 Participants	407 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) TESAEs	40 Participants	42 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) TEAEs leading to permanent study intervention discontinuation	24 Participants	23 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) TEAESIs	57 Participants	53 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 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 population pharmacokinetic (PK) model.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=444 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite Tolebrutinib	12.0 nanogram/milliliter (ng/mL) Standard Deviation 7.75	—
Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite M2 Metabolite	28.3 nanogram/milliliter (ng/mL) Standard Deviation 15.8	—

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 population PK model.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=444 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite M2 Metabolite	1.40 hour (h) Standard Deviation 0.508	—
Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite Tolebrutinib	1.28 hour (h) Standard Deviation 0.513	—

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 population PK model.

Outcome measures

Outcome measures
Measure	Teriflunomide 14 mg n=444 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite Tolebrutinib	30.5 ng*h/mL Standard Deviation 18.2	—
Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite M2 Metabolite	76.7 ng*h/mL Standard Deviation 44.1	—

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 months)

Population: The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only participants with data collected at specified timepoints for the specified categories 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	Teriflunomide 14 mg n=344 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=350 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS NfL	-1.665 picogram/mL Interval -6.1 to 0.83	-0.325 picogram/mL Interval -3.505 to 2.22
Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS Chi3L1	1017.100 picogram/mL Interval -4494.85 to 7672.45	1572.250 picogram/mL Interval -2582.0 to 6356.6

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 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	Teriflunomide 14 mg n=95 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=100 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS	-45.000 cells/microliter Interval -81.0 to -5.0	-60.500 cells/microliter Interval -97.5 to -28.5

SECONDARY outcome

Timeframe: Baseline (Day 1) to EOS (up to approximately 48 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	Teriflunomide 14 mg n=263 Participants Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=266 Participants Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS IgG	-0.660 gram/liter Interval -1.46 to 0.15	0.235 gram/liter Interval -0.5 to 1.02
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS IgM	-0.150 gram/liter Interval -0.33 to -0.03	-0.340 gram/liter Interval -0.52 to -0.19

Adverse Events

Teriflunomide 14 mg

Serious events: 40 serious events

Other events: 321 other events

Deaths: 0 deaths

Tolebrutinib 60 mg

Serious events: 42 serious events

Other events: 296 other events

Deaths: 0 deaths

Serious adverse events

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	Teriflunomide 14 mg n=488 participants at risk Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months.	Tolebrutinib 60 mg n=486 participants at risk Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months.
Infections and infestations Covid-19	27.7% 135/488 • Number of events 150 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	24.1% 117/486 • Number of events 133 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Infections and infestations Influenza	5.3% 26/488 • Number of events 35 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	3.9% 19/486 • Number of events 24 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Infections and infestations Nasopharyngitis	8.4% 41/488 • Number of events 61 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	12.1% 59/486 • Number of events 88 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Infections and infestations Upper Respiratory Tract Infection	9.4% 46/488 • Number of events 65 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	9.5% 46/486 • Number of events 69 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Infections and infestations Urinary Tract Infection	5.5% 27/488 • Number of events 32 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	7.0% 34/486 • Number of events 45 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Infections and infestations Viral Upper Respiratory Tract Infection	7.0% 34/488 • Number of events 48 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	6.4% 31/486 • Number of events 54 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Blood and lymphatic system disorders Neutropenia	11.9% 58/488 • Number of events 93 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	2.9% 14/486 • Number of events 22 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Psychiatric disorders Depression	5.5% 27/488 • Number of events 27 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	2.3% 11/486 • Number of events 11 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Nervous system disorders Headache	9.0% 44/488 • Number of events 62 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	11.5% 56/486 • Number of events 100 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Vascular disorders Hypertension	5.5% 27/488 • Number of events 28 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	3.3% 16/486 • Number of events 19 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Gastrointestinal disorders Diarrhoea	7.4% 36/488 • Number of events 50 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	4.5% 22/486 • Number of events 24 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Skin and subcutaneous tissue disorders Alopecia	15.0% 73/488 • Number of events 75 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	7.4% 36/486 • Number of events 36 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Musculoskeletal and connective tissue disorders Arthralgia	5.5% 27/488 • Number of events 31 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	3.7% 18/486 • Number of events 25 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Musculoskeletal and connective tissue disorders Back Pain	6.1% 30/488 • Number of events 34 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	6.4% 31/486 • Number of events 35 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).
Investigations Alanine Aminotransferase Increased	8.2% 40/488 • Number of events 43 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).	4.7% 23/486 • Number of events 26 • From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months. Analysis was performed on the safety population. This was an event-driven (6-month CDW) trial with a variable treatment duration (EOS duration: up to approximately 48 months).