Trial · NCT04410991

Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2)

NCT04410991, Phase 3, Completed, Sanofi; results first posted 2025-06-18

3 sourcestrials-2026-11-12-0.5.0

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ConductScience Library. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2). Trials, record NCT04410991. Release trials-2026-11-12-0.5.0, 12 Nov 2026. https://conductscience.org/library/trials/NCT04410991

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Trial

As registered on ClinicalTrials.gov, in the graph's capture of the registry.

Title: Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2)
NCT number: NCT04410991
Status: Completed
Phases: Phase 3
Enrollment: 899 participants, actual
Lead sponsor: Sanofi
Conditions: Relapsing Multiple Sclerosis
Interventions: Tolebrutinib, Teriflunomide HMR1726, Placebo to match Tolebrutinib, Placebo to match Teriflunomide
First posted: 2020-06-01
Last updated: 2025-07-02
Other registries' IDs: eudract:2020-000644-55
Results first posted: 2025-06-18

Source ClinicalTrials.gov

Registered outcomes13

Each outcome the trial registered, primary first, in ClinicalTrials.gov's words.

List	Outcome	Time frame	Description
Primary	Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses	Baseline (Day 1) to approximately 48 months	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.
Secondary	Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Baseline (Day 1) to approximately 48 months	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.
Secondary	Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Baseline (Day 1) to approximately 48 months	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.
Secondary	Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year	Baseline (Day 1) to approximately 48 months	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.
Secondary	Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan	Baseline (Day 1) to approximately 48 months	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.
Secondary	Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS	Baseline (Day 1) to EOS (up to approximately 48 months)	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.
Secondary	Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS	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.
Secondary	Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale	Baseline (Day 1) to approximately 48 months	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. CDI was defined as a decrease of \>=1 point from baseline in the EDSS score lasting at least 6 months.
Secondary	Percent Change in Brain Volume Loss at EOS Compared to Month 6	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.
Secondary	Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS	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.

1 to 10 of 13Source ClinicalTrials.gov

See all 13 registered outcomes

Outcomes13

Each outcome the trial posted results for, in ClinicalTrials.gov's words.

Type	Outcome	Time frame	Population	Units	Measured as
PRIMARY	Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses	Baseline (Day 1) to approximately 48 months	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.	relapses per participant year	NUMBER
SECONDARY	Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Baseline (Day 1) to approximately 48 months	The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.	months	MEDIAN
SECONDARY	Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Baseline (Day 1) to approximately 48 months	The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.	months	MEDIAN
SECONDARY	Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year	Baseline (Day 1) to approximately 48 months	The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.	number of new and/or enlarging T2lesions	MEAN
SECONDARY	Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan	Baseline (Day 1) to approximately 48 months	The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.	number of new Gd-enhancing T1 lesions	MEAN
SECONDARY	Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS	Baseline (Day 1) to EOS (up to approximately 48 months)	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.	score on a scale	LEAST_SQUARES_MEAN
SECONDARY	Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS	Baseline (Day 1) to EOS (up to approximately 48 months)	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.	T-score	LEAST_SQUARES_MEAN
SECONDARY	Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale	Baseline (Day 1) to approximately 48 months	The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.	months	MEDIAN
SECONDARY	Percent Change in Brain Volume Loss at EOS Compared to Month 6	Month 6 to EOS (up to approximately 48 months)	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.	percent change	LEAST_SQUARES_MEAN
SECONDARY	Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS	Baseline (Day 1) to EOS (up to approximately 48 months)	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 for the specified categories are reported.	score on a scale	LEAST_SQUARES_MEAN

1 to 10 of 13Source ClinicalTrials.gov

See all 13 outcomes

Results by group38

Each measurement the trial posted, group by group, in the words and numbers it posted.

Outcome	Group	Value	Spread	Units
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses	Teriflunomide 14 mg	0.109	95% Confidence Interval 0.088 to 0.134	relapses per participant year
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses	Tolebrutinib 60 mg	0.108	95% Confidence Interval 0.089 to 0.131	relapses per participant year
Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Teriflunomide 14 mg	12.14	Full Range 1.4 to 38.9	months
Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Tolebrutinib 60 mg	15.12	Full Range 2.0 to 37.1	months
Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Teriflunomide 14 mg	12.11	Full Range 1.4 to 39.1	months
Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	Tolebrutinib 60 mg	12.11	Full Range 2.0 to 42.1	months
Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year	Teriflunomide 14 mg	4.369	95% Confidence Interval 3.587 to 5.322	number of new and/or enlarging T2lesions
Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year	Tolebrutinib 60 mg	5.092	95% Confidence Interval 4.340 to 5.975	number of new and/or enlarging T2lesions
Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan	Teriflunomide 14 mg	0.217	95% Confidence Interval 0.169 to 0.280	number of new Gd-enhancing T1 lesions
Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan	Tolebrutinib 60 mg	0.460	95% Confidence Interval 0.365 to 0.581	number of new Gd-enhancing T1 lesions

1 to 10 of 38Source ClinicalTrials.gov

See all 38 results by group

Participant flow8

How many started, completed or left each group, period by period.

Period	Milestone	Group	Participants
Overall Study	STARTED	Teriflunomide 14 mg	452
Overall Study	STARTED	Tolebrutinib 60 mg	447
Overall Study	Randomized and Treated	Teriflunomide 14 mg	451
Overall Study	Randomized and Treated	Tolebrutinib 60 mg	447
Overall Study	COMPLETED	Teriflunomide 14 mg	378
Overall Study	COMPLETED	Tolebrutinib 60 mg	384
Overall Study	NOT COMPLETED	Teriflunomide 14 mg	74
Overall Study	NOT COMPLETED	Tolebrutinib 60 mg	63

Source ClinicalTrials.gov

Adverse events192

Each adverse event the trial posted, group by group: the participants affected out of those at risk.

Type	Event	Organ system	Group	Affected	At risk	Events
other	Covid-19	Infections and infestations	Teriflunomide 14 mg	115	451	131
other	Covid-19	Infections and infestations	Tolebrutinib 60 mg	106	447	126
other	Influenza	Infections and infestations	Teriflunomide 14 mg	25	451	35
other	Influenza	Infections and infestations	Tolebrutinib 60 mg	27	447	33
other	Nasopharyngitis	Infections and infestations	Teriflunomide 14 mg	64	451	97
other	Nasopharyngitis	Infections and infestations	Tolebrutinib 60 mg	60	447	102
other	Upper Respiratory Tract Infection	Infections and infestations	Teriflunomide 14 mg	36	451	49
other	Upper Respiratory Tract Infection	Infections and infestations	Tolebrutinib 60 mg	31	447	43
other	Urinary Tract Infection	Infections and infestations	Teriflunomide 14 mg	30	451	43
other	Urinary Tract Infection	Infections and infestations	Tolebrutinib 60 mg	25	447	35

1 to 10 of 192Source ClinicalTrials.gov

See all 192 adverse events

Adverse event totals6

The totals the trial posted for each group.

Total	Group	Affected	At risk
Total, all-cause mortality	Teriflunomide 14 mg	2	452
Total, all-cause mortality	Tolebrutinib 60 mg	1	447
Total, other adverse events	Teriflunomide 14 mg	313	451
Total, other adverse events	Tolebrutinib 60 mg	279	447
Total, serious adverse events	Teriflunomide 14 mg	37	451
Total, serious adverse events	Tolebrutinib 60 mg	49	447

Source ClinicalTrials.gov

Papers2

The papers the trial lists on ClinicalTrials.gov.

PMID	Listed as	Source
40202623	DERIVED	PubMed
42546561	DERIVED	PubMed

Grants0

The grants NIH RePORTER links to the trial, newest funded first: NIH's, and some of AHRQ's, CDC's, FDA's and VA's. Each shows its title, principal investigators, organization and funder in its newest year.

None in this release.

Trial comparisons2

Comparisons of the trial's two groups, calculated by ConductScience from the counts it posted.

Comparison	Source
Teriflunomide 14 mg vs Tolebrutinib 60 mg: deaths from any cause	Trial comparisons
Teriflunomide 14 mg vs Tolebrutinib 60 mg: serious adverse events	Trial comparisons

Tests2

The ConductCognition tests this trial's registered outcomes name, as ScienceGraph matched them in trial-tests-2026-11-12-0.2.1.

Test	Named as	Source
Symbol Coding	Secondary outcome	ConductCognition
Verbal Learning	Secondary outcome	ConductCognition

Data dates

The day each source was copied for this release.

ClinicalTrials.gov: 2026-11-12; ClinicalTrials.gov
Results, from AACT: 2026-03-23; AACT
NIH grant links: 2026-11-13; NIH RePORTER

Sources 3

ClinicalTrials.gov's posted results, through CTTI's AACTFreely available. Acknowledgement requested
ClinicalTrials.govNo license stated
NIH RePORTER's clinical studies and project filesPublic domain

Each source's terms

ClinicalTrials.gov's posted results, through CTTI's AACTClinicalTrials.gov data via Aggregate Analysis of ClinicalTrials.gov (AACT), CTTI. CTTI makes its materials freely available and requests acknowledgement. https://aact.ctti-clinicaltrials.org/documentation/299
ClinicalTrials.govnone stated
NIH RePORTER's clinical studies and project filesPublic domain (NIH RePORTER)

ClinicalTrials.gov's data carry an international copyright outside the United States: https://clinicaltrials.gov/about-site/terms-conditions.

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