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

A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis

Primary Objective:

To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS

Secondary Objective:

To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life To evaluate the safety and tolerability of daily SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168

Study Overview

• Status: Completed
• Conditions: Relapsing Multiple Sclerosis
• Intervention / Treatment: Drug: Tolebrutinib; Drug: Placebo to match Teriflunomide; Drug: Placebo to match Tolebrutinib; Drug: Teriflunomide

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 974
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4021
    • Investigational Site Number :0400004
• Belarus
  • Vitebsk, Belarus, 210009
    • Investigational Site Number :1120005
  • Vitebsk, Belarus, 210037
    • Investigational Site Number :1120004
• Bulgaria
  • Pleven, Bulgaria, 5800
    • Investigational Site Number :1000002
  • Plovdiv, Bulgaria, 4000
    • Investigational Site Number :1000005
  • Sofia, Bulgaria, 1113
    • Investigational Site Number :1000004
  • Sofia, Bulgaria, 1407
    • Investigational Site Number :1000008
  • Sofia, Bulgaria, 1431
    • Investigational Site Number :1000001
  • Sofia, Bulgaria, 1431
    • Investigational Site Number :1000006
  • Sofia, Bulgaria, 1680
    • Investigational Site Number :1000009
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
      • Investigational Site Number :1240016
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Investigational Site Number :1240003
    • Toronto, Ontario, Canada, M5B 1W8
      • Investigational Site Number :1240013
  • Quebec
    • Gatineau, Quebec, Canada, J8Y 1W2
      • Investigational Site Number :1240006
• China
  • Baotou, China, 014010
    • Investigational Site Number :1560022
  • Beijing, China, 100034
    • Investigational Site Number :1560006
  • Beijing, China, 100050
    • Investigational Site Number :1560010
  • Beijing, China, 100053
    • Investigational Site Number :1560012
  • Beijing, China, 100191
    • Investigational Site Number :1560023
  • Beijing, China, 100730
    • Investigational Site Number :1560001
  • Beijing, China, 100730
    • Investigational Site Number :1560009
  • Beijing, China, 100730
    • Investigational Site Number :1560025
  • Beijing, China, 100853
    • Investigational Site Number :1560021
  • Changchun, China, 130021
    • Investigational Site Number :1560004
  • Changsha, China, 410008
    • Investigational Site Number :1560015
  • Chengdu, China, 610041
    • Investigational Site Number :1560005
  • Chongqing, China, 400016
    • Investigational Site Number :1560019
  • Fuzhou, China, 350005
    • Investigational Site Number :1560035
  • Guangzhou, China, 510080
    • Investigational Site Number :1560016
  • Guangzhou, China, 510515
    • Investigational Site Number :1560028
  • Guangzhou, China, 510630
    • Investigational Site Number :1560002
  • Hohhot, China, 010050
    • Investigational Site Number :1560027
  • Nanjing, China, 210008
    • Investigational Site Number :1560044
  • Nanjing, China, 210029
    • Investigational Site Number :1560042
  • Shanghai, China, 200040
    • Investigational Site Number :1560003
  • Shenyang, China, 110004
    • Investigational Site Number :1560018
  • Shijiazhuang, China, 050000
    • Investigational Site Number :1560014
  • Taiyuan, China, 030001
    • Investigational Site Number :1560008
  • Tianjin, China, 300052
    • Investigational Site Number :1560020
  • Wuhan, China, 430030
    • Investigational Site Number :1560011
  • Xi'an, China, 710038
    • Investigational Site Number :1560017
  • Yinchuan, China, 750004
    • Investigational Site Number :1560033
• Czechia
  • Hradec Kralove, Czechia, 50005
    • Investigational Site Number :2030004
  • Pardubice, Czechia, 53203
    • Investigational Site Number :2030009
  • Teplice, Czechia, 415 29
    • Investigational Site Number :2030003
  • Zlin, Czechia, 76275
    • Investigational Site Number :2030007
• Denmark
  • Esbjerg, Denmark, 6700
    • Investigational Site Number :2080001
  • Holstebro, Denmark, 7500
    • Investigational Site Number :2080005
• Estonia
  • Tallinn, Estonia, 11315
    • Investigational Site Number :2330001
  • Tartu, Estonia, 50406
    • Investigational Site Number :2330002
• Finland
  • Helsinki, Finland, 00180
    • Investigational Site Number :2460003
  • Tampere, Finland, 33520
    • Investigational Site Number :2460001
  • Turku, Finland, 20520
    • Investigational Site Number :2460002
• Germany
  • Dresden, Germany, 01307
    • Investigational Site Number :2760001
  • Düsseldorf, Germany, 40225
    • Investigational Site Number :2760019
  • Hamburg, Germany, 22179
    • Investigational Site Number :2760016
  • Münster, Germany, 48149
    • Investigational Site Number :2760008
  • Rostock, Germany, 18055
    • Investigational Site Number :2760004
  • Ulm, Germany, 89081
    • Investigational Site Number :2760011
• Hong Kong
  • Shatin, NT, Hong Kong
    • Investigational Site Number : 3440001
• Italy
  • Bergamo, Italy, 24127
    • Investigational Site Number :3800011
  • Catania, Italy, 95123
    • Investigational Site Number :3800015
  • Firenze, Italy, 50134
    • Investigational Site Number :3800012
  • Genova, Italy, 16132
    • Investigational Site Number :3800014
  • Milano, Italy, 20132
    • Investigational Site Number :3800001
  • Milano, Italy, 20133
    • Investigational Site Number :3800010
  • Napoli, Italy, 80131
    • Investigational Site Number :3800003
  • Napoli, Italy, 80131
    • Investigational Site Number :3800006
  • Pavia, Italy, 27100
    • Investigational Site Number :3800008
  • Roma, Italy, 00152
    • Investigational Site Number :3800005
  • Roma, Italy, 00168
    • Investigational Site Number :3800009
  • Roma, Italy, 00189
    • Investigational Site Number :3800013
  • Isernia
    • Pozzilli, Isernia, Italy, 86077
      • Investigational Site Number :3800002
  • Torino
    • Orbassano, Torino, Italy, 10043
      • Investigational Site Number :3800007
• Japan
  • Sagamihara-shi, Japan, 252-0392
    • Investigational Site Number :3920023
  • Chiba
    • Chiba-shi, Chiba, Japan, 260-8677
      • Investigational Site Number :3920016
  • Fukushima
    • Koriyama-shi, Fukushima, Japan, 963-8052
      • Investigational Site Number :3920008
  • Ibaraki
    • Tsukuba-shi, Ibaraki, Japan, 305-0005
      • Investigational Site Number :3920012
  • Iwate
    • Morioka-shi, Iwate, Japan, 020-8505
      • Investigational Site Number :3920022
  • Niigata
    • Niigata-shi, Niigata, Japan, 951-8520
      • Investigational Site Number :3920005
  • Osaka
    • Moriguchi-shi, Osaka, Japan, 570-8507
      • Investigational Site Number :3920004
    • Osaka-shi, Osaka, Japan, 556-0016
      • Investigational Site Number :3920001
  • Saitama
    • Kawagoe-shi, Saitama, Japan, 350-8550
      • Investigational Site Number :3920018
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8431
      • Investigational Site Number :3920014
    • Kodaira-shi, Tokyo, Japan, 187-8551
      • Investigational Site Number :3920003
    • Ota-ku, Tokyo, Japan, 146-0065
      • Investigational Site Number :3920010
    • Shinjuku-ku, Tokyo, Japan, 162-8666
      • Investigational Site Number :3920013
  • Yamaguchi
    • Ube-shi, Yamaguchi, Japan, 755-8505
      • Investigational Site Number :3920009
• Lithuania
  • Kaunas, Lithuania, 50161
    • Investigational Site Number :4400003
  • Klaipeda, Lithuania, 92288
    • Investigational Site Number :4400002
  • Siauliai, Lithuania, LT-76231
    • Investigational Site Number :4400004
  • Vilnius, Lithuania, 08661
    • Investigational Site Number :4400001
• Mexico
  • Mexico, Mexico, 03100
    • Investigational Site Number :4840002
  • Mexico, Mexico, 06700
    • Investigational Site Number :4840001
  • Veracruz, Mexico, 91910
    • Investigational Site Number :4840003
• Poland
  • Lodz, Poland, 90-549
    • Investigational Site Number :6160001
  • Kujawsko-pomorskie
    • Bydgoszcz, Kujawsko-pomorskie, Poland, 85-796
      • Investigational Site Number :6160003
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 01-211
      • Investigational Site Number :6160005
    • Warszawa, Mazowieckie, Poland, 01-684
      • Investigational Site Number :6160006
  • Podkarpackie
    • Glogow Mlp., Podkarpackie, Poland, 36-060
      • Investigational Site Number :6160009
  • Slaskie
    • Katowice, Slaskie, Poland, 40-571
      • Investigational Site Number :6160002
    • Katowice, Slaskie, Poland, 40-686
      • Investigational Site Number :6160004
  • Wielkopolskie
    • Plewiska, Wielkopolskie, Poland, 62-064
      • Investigational Site Number :6160008
• Romania
  • Brasov, Romania, 500283
    • Investigational Site Number :6420015
  • Bucuresti, Romania, 022328
    • Investigational Site Number :6420008
  • Campulung, Romania, 115100
    • Investigational Site Number :6420004
  • Constanta, Romania, 900123
    • Investigational Site Number :6420003
  • Oradea, Romania, 410169
    • Investigational Site Number :6420010
  • Sibiu, Romania, 550052
    • Investigational Site Number :6420005
  • Targu Mures, Romania, 540136
    • Investigational Site Number :6420001
  • Timisoara, Romania, 300736
    • Investigational Site Number :6420002
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660029
    • Investigational Site Number :6430014
  • Moscow, Russian Federation, 125367
    • Investigational Site Number :6430002
  • Moscow, Russian Federation, 129128
    • Investigational Site Number :6430008
  • Nizhny Novgorod, Russian Federation, 603137
    • Investigational Site Number :6430011
  • Nizhny Novgorod, Russian Federation, 603155
    • Investigational Site Number :6430003
  • Pyatigorsk, Russian Federation, 357538
    • Investigational Site Number :6430007
  • Rostov-on-Don, Russian Federation, 344022
    • Investigational Site Number :6430012
  • Samara, Russian Federation, 443095
    • Investigational Site Number :6430005
  • Smolensk, Russian Federation, 214018
    • Investigational Site Number :6430009
  • St-Petersburg, Russian Federation, 194044
    • Investigational Site Number :6430001
  • Tyumen, Russian Federation, 625000
    • Investigational Site Number :6430006
  • Ufa, Russian Federation, 450005
    • Investigational Site Number :6430004
• Spain
  • Córdoba, Spain, 14004
    • Investigational Site Number :7240004
  • Murcia, Spain, 30120
    • Investigational Site Number :7240006
  • Málaga, Spain, 29010
    • Investigational Site Number :7240005
  • Valencia, Spain, 46026
    • Investigational Site Number :7240007
  • Andalucia
    • Sevilla, Andalucia, Spain, 41009
      • Investigational Site Number :7240003
  • Barcelona [Barcelona]
    • Barcelona, Barcelona [Barcelona], Spain, 08035
      • Investigational Site Number :7240009
  • Madrid
    • Pozuelo De Alarcón, Madrid, Spain, 28223
      • Investigational Site Number :7240001
  • Pais Vasco
    • Donostia, Pais Vasco, Spain, 20014
      • Investigational Site Number :7240008
• Sweden
  • Göteborg, Sweden, 413 45
    • Investigational Site Number :7520001
  • Stockholm, Sweden, 113 65
    • Investigational Site Number :7520002
• Taiwan
  • Hsinchu City, Taiwan, 30059
    • Investigational Site Number :1580007
  • Kaohsiung, Taiwan, 833
    • Investigational Site Number :1580005
  • Taichung, Taiwan, 402
    • Investigational Site Number :1580003
  • Taipei, Taiwan, 112
    • Investigational Site Number :1580002
  • Taoyuang, Taiwan, 333
    • Investigational Site Number :1580006
• Turkey
  • Eskisehir, Turkey
    • Investigational Site Number :7920005
  • Hatay, Turkey
    • Investigational Site Number :7920011
  • Istanbul, Turkey, 34098
    • Investigational Site Number :7920002
  • Istanbul, Turkey, 34688
    • Investigational Site Number :7920009
  • Istanbul, Turkey, 34785
    • Investigational Site Number :7920007
  • Istanbul, Turkey
    • Investigational Site Number :7920003
  • Izmir, Turkey, 35100
    • Investigational Site Number :7920008
  • Izmir, Turkey
    • Investigational Site Number :7920010
  • Kocaeli, Turkey, 41380
    • Investigational Site Number :7920001
  • Mersin, Turkey, 33070
    • Investigational Site Number :7920006
• Ukraine
  • Ivano-Frankivsk, Ukraine, 76493
    • Investigational Site Number :8040011
  • Kharkiv, Ukraine, 61068
    • Investigational Site Number :8040016
  • Kharkiv, Ukraine, 61103
    • Investigational Site Number :8040013
  • Kherson, Ukraine, 73000
    • Investigational Site Number :8040008
  • Kyiv, Ukraine, 03115
    • Investigational Site Number :8040014
  • Lutsk, Ukraine, 43005
    • Investigational Site Number :8040010
  • Lviv, Ukraine, 79010
    • Investigational Site Number :8040001
  • Odesa, Ukraine, 65025
    • Investigational Site Number :8040009
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama MS Center-Site Number:8400013
  • California
    • San Francisco, California, United States, 94158
      • University of San Francisco, Sandler Neurosciences Center-Site Number:8400137
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado-Site Number:8400012
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center-Site Number:8400119
  • Florida
    • Fort Myers, Florida, United States, 33919
      • Beth Israel Deaconess Medical Center-Site Number:8400064
    • Tampa, Florida, United States, 33612
      • University of South Florida-Site Number:8400006
    • Tampa, Florida, United States, 33609-4052
      • Axiom Clinical Research of Florida-Site Number:8400001
  • Georgia
    • Savannah, Georgia, United States, 31406
      • Meridian Clinical Research-Site Number:8400003
  • Illinois
    • Northbrook, Illinois, United States, 60062
      • Consultants In Neurology-Site Number:8400011
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center-Site Number:8400072
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Michigan Institute For Neurological Disorders-Site Number:8400058
    • Owosso, Michigan, United States, 48867
      • The Memorial Hospital-Site Number:8400033
  • Missouri
    • Ozark, Missouri, United States, 65721
      • Sharlin Health & Neurology-Site Number:8400093
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center-Site Number:8400019
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Meridian Clinical Research, LLC-Site Number:8400005
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center-Site Number:8400116
  • Ohio
    • Columbus, Ohio, United States, 43221
      • The Ohio State University Wexner Medical Center-Site Number:8400150
    • Columbus, Ohio, United States, 43235
      • Optimed Research, LTD-Site Number:8400147
    • Westerville, Ohio, United States, 40382
      • Columbus Neuroscience-Site Number:8400010
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma Medical Research Foundation-Site Number:8400018
  • Oregon
    • Portland, Oregon, United States, 97225
      • Providence Multiple Sclerosis Center-Site Number:8400020
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center-Site Number:8400077
  • Washington
    • Seattle, Washington, United States, 98122
      • Multiple Sclerosis Center, Swedish Neuroscience Institute-Site Number:8400121

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria :

• The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent
• The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria
• The participant has an expanded disability status scale (EDSS) score ≤5.5 at the first Screening Visit

• The participant must have at least 1 of the following prior to screening:

  • ≥1 documented relapse within the previous year OR
  • ≥2 documented relapses within the previous 2 years, OR
  • ≥1 documented Gd enhancing lesion on an MRI scan within the previous year
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

• Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure:

  • Refrain from donating sperm

Plus either:

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
• Must agree to use contraception/barrier as detailed below:

Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions apply:

  • Is not a WOCBP OR
  • Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the intervention period and until accelerated elimination procedure is completed (or for at least 10 days after the last dose of SAR442168, if the case was unblinded)
• A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24hours before the first dose of study intervention.
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant's legally authorized representative

Exclusion criteria:

• The participant has been diagnosed with primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiple sclerosis (SPMS)
• The participant has a history of infection or may be at risk for infection including but not limited to: HIV, transplantation, live attenuated vaccines, progressive multifocal leukoencephalopathy, tuberculosis, any persistent chronic or active recurring infection
• Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.

• The participant has conditions or situations that would adversely affect participation in this study, including but not limited to:

  • A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist
  • Medical condition(s) or concomitant disease(s) making them nonevaluable for the primary efficacy endpoint or that would adversely affect participation in this study, as judged by the Investigator
  • A requirement for concomitant treatment that could bias the primary evaluation
• The participant has a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study
• At screening, the participant is positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or is positive for hepatitis C antibody

• The participant has any of the following:

  • A bleeding disorder or known platelet dysfunction at any time prior to the screening visit
  • A platelet count <150 000/μL at the screening visit
• The participant has a lymphocyte count below the lower limit of normal (LLN) at the screening visit
• The presence of psychiatric disturbance or substance abuse
• Prior/concomitant therapy
• The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes
• The participant is receiving anticoagulant/antiplatelet therapies

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAR442168; 60 mg oral SAR442168 + placebo to match the teriflunomide tablet once daily	Drug: Tolebrutinib; Pharmaceutical form: Tablet Route of administration: Oral; Other Names: SAR442168; Drug: Placebo to match Teriflunomide; Pharmaceutical form: Tablet Route of administration: Oral
Active Comparator: Teriflunomide; 14 mg oral teriflunomide + placebo to match the SAR442168 tablet once daily	Drug: Placebo to match Tolebrutinib; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Teriflunomide; Pharmaceutical form: Tablet Route of administration: Oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses	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.	Baseline (Day 1) to approximately 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	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.	Baseline (Day 1) to approximately 48 months
Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale	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.	Baseline (Day 1) to approximately 48 months
Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year	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.	Baseline (Day 1) to approximately 48 months
Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan	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.	Baseline (Day 1) to approximately 48 months
Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS	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.	Baseline (Day 1) to EOS (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	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.	Baseline (Day 1) to EOS (up to approximately 48 months)
Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale	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.	Baseline (Day 1) to approximately 48 months
Percent Change in Brain Volume Loss at EOS Compared to Month 6	MRI of the brain was performed at the specified timepoints to detect the changes in brain volume loss.	Month 6 to EOS (up to approximately 48 months)
Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS	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.	Baseline (Day 1) to EOS (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	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.	Baseline (Day 1) to EOS (up to approximately 48 months)
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS	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.	Baseline (Day 1) to EOS (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)	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.	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
Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite	Blood samples were collected at specified timepoints to assess Cmax of tolebrutinib and M2 metabolite using population pharmacokinetic (PK) model.	30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite	Blood samples were collected at specified timepoints to assess Tmax of tolebrutinib and M2 metabolite using population PK model.	30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite	Blood samples were collected at specified timepoints to assess AUC0-24 of tolebrutinib and M2 metabolite using population PK model.	30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS	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.	Baseline (Day 1) to EOS (up to approximately 48 months)

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

Helpful Links

• EFC16033 Plain language Results Summary

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2020
• Primary Completion (Actual): July 15, 2024
• Study Completion (Actual): July 15, 2024

Study Registration Dates

• First Submitted: May 28, 2020
• First Submitted That Met QC Criteria: May 28, 2020
• First Posted (Actual): June 1, 2020

Study Record Updates

• Last Update Posted (Actual): July 2, 2025
• Last Update Submitted That Met QC Criteria: June 30, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Teriflunomide
• Other Study ID Numbers: EFC16033; U1111-1238-1418 (Registry Identifier: ICTRP); 2020-000637-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No