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

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 pharmacodynamics (PD) of SAR442168

Study Overview

• Status: Completed
• Conditions: Relapsing Multiple Sclerosis
• Intervention / Treatment: Drug: Tolebrutinib; Drug: Placebo to match Teriflunomide; Drug: Teriflunomide HMR1726; Drug: Placebo to match Tolebrutinib

Detailed Description

Study duration varied per participant in this event driven trial with a treatment duration of approximately 18 to 36 months. Participants completing the study were offered to participate in a long term safety study.

• Study Type: Interventional
• Enrollment (Actual): 899
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • San Miguel de Tucuman, Argentina, T4000AXL
    • Investigational Site Number :0320005
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1023AAB
      • Investigational Site Number :0320004
    • Capital Federal, Buenos Aires, Argentina, 1012
      • Investigational Site Number :0320002
  • Ciudad De Buenos Aires
    • Caba, Ciudad De Buenos Aires, Argentina, C1061
      • Investigational Site Number :0320001
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • Investigational Site Number :0320003
• Belgium
  • Brugge, Belgium, B-8000
    • Investigational Site Number :0560005
  • Gent, Belgium, 9000
    • Investigational Site Number :0560004
  • Mons, Belgium, 7000
    • Investigational Site Number :0560002
  • Pelt, Belgium, 3900
    • Investigational Site Number :0560001
• Brazil
  • Curitiba, Brazil, 81210-310
    • Investigational Site Number :0760002
  • Sao Paulo, Brazil, 01228-000
    • Investigational Site Number :0760007
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90610-000
      • Investigational Site Number :0760001
• Canada
  • Gatineau, Canada, J8Y1W2
    • Investigational Site Number :1240006
  • Quebec, Canada, G1W 4R4
    • Investigational Site Number :1240021
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2C8
      • Investigational Site Number :1240002
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Investigational Site Number : 1240012
    • London, Ontario, Canada, N6A 5A5
      • Investigational Site Number :1240014
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2J2
      • Investigational Site Number :1240005
• Chile
  • Concepción, Chile
    • Investigational Site Number :1520006
  • Valdivia, Chile, 5110683
    • Investigational Site Number :1520004
  • Reg Metropolitana De Santiago
    • Santiago, Reg Metropolitana De Santiago, Chile, 7650568
      • Investigational Site Number :1520002
    • Santiago, Reg Metropolitana De Santiago, Chile, 833-0024
      • Investigational Site Number :1520005
    • Santiago, Reg Metropolitana De Santiago, Chile, 8380456
      • Investigational Site Number :1520001
    • Santiago, Reg Metropolitana De Santiago, Chile, 8431657
      • Investigational Site Number :1520003
• Croatia
  • Zagreb, Croatia, 10000
    • Investigational Site Number :1910001
  • Zagreb, Croatia, 10000
    • Investigational Site Number :1910002
  • Zagreb, Croatia, 10000
    • Investigational Site Number :1910003
• Czechia
  • Brno, Czechia, 65691
    • Investigational Site Number :2030002
  • Hradec Kralove, Czechia, 50005
    • Investigational Site Number :2030011
  • Jihlava, Czechia, 58633
    • Investigational Site Number :2030001
  • Praha 10, Czechia, 10034
    • Investigational Site Number :2030008
  • Praha 5 - Motol, Czechia, 15006
    • Investigational Site Number :2030005
• France
  • Besancon, France, 25000
    • Investigational Site Number :2500019
  • Bordeaux, France
    • Investigational Site Number :2500018
  • Bron, France, 69500
    • Investigational Site Number :2500011
  • Clermont Ferrand, France, 63003
    • Investigational Site Number :2500005
  • Montpellier, France, 34295
    • Investigational Site Number :2500006
  • Nantes, France, 44093
    • Investigational Site Number :2500010
  • Nice, France, 06002
    • Investigational Site Number :2500002
  • Nimes, France, 30029
    • Investigational Site Number :2500017
  • Paris, France, 75019
    • Investigational Site Number :2500007
  • Poissy, France, 78300
    • Investigational Site Number :2500004
  • Rennes, France, 35033
    • Investigational Site Number :2500003
  • Strasbourg, France, 67098
    • Investigational Site Number :2500001
• Germany
  • Bayreuth, Germany, 95445
    • Investigational Site Number :2760005
  • Berlin, Germany, 10713
    • Investigational Site Number :2760015
  • Berlin, Germany, 12099
    • Investigational Site Number :2760014
  • Bochum, Germany, 44791
    • Investigational Site Number :2760020
  • Essen, Germany, 45147
    • Investigational Site Number :2760012
  • Würzburg, Germany, 97070
    • Investigational Site Number :2760003
• Greece
  • Athens, Greece, 115 28
    • Investigational Site Number :3000001
  • Athens, Greece, 11535
    • Investigational Site Number :3000006
  • Athens, Greece, 12462
    • Investigational Site Number :3000002
  • Athens, Greece, 15125
    • Investigational Site Number :3000007
  • Athens, Greece
    • Investigational Site Number :3000009
  • Larissa, Greece, 41110
    • Investigational Site Number :3000004
  • Thessaloniki, Greece, 546 36
    • Investigational Site Number :3000003
• Hungary
  • Budapest, Hungary, 1135
    • Investigational Site Number :3480105
  • Budapest, Hungary, 1145
    • Investigational Site Number :3480102
  • Kaposvár, Hungary, 7400
    • Investigational Site Number :3480106
  • Tatabánya, Hungary, 2800
    • Investigational Site Number :3480103
• India
  • Chandigarh, India, 160012
    • Investigational Site Number :3560005
  • Gurgaon, India, 122001
    • Investigational Site Number :3560007
  • Gurgaon, India, 122002
    • Investigational Site Number :3560008
  • New Delhi, India, 110060
    • Investigational Site Number :3560002
  • Thiruvananthapuram, India, 695004
    • Investigational Site Number :3560004
• Israel
  • Ashkelon, Israel, 78278
    • Investigational Site Number :3760002
  • Haifa, Israel, 31096
    • Investigational Site Number :3760003
  • Rehovot, Israel, 76100
    • Investigational Site Number :3760006
  • Safed, Israel, 13100
    • Investigational Site Number :3760004
  • Tel HaShomer, Israel, 52621
    • Investigational Site Number :3760001
• Korea, Republic of
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of, 10408
      • Investigational Site Number :4100001
  • Seoul-teukbyeolsi
    • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03080
      • Investigational Site Number :4100003
    • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03722
      • Investigational Site Number :4100006
    • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 06351
      • Investigational Site Number :4100002
• Latvia
  • Riga, Latvia, LV-1002
    • Investigational Site Number :4280002
  • Riga, Latvia, LV-1005
    • Investigational Site Number :4280003
• Netherlands
  • Amsterdam, Netherlands, 1081 GN
    • Investigational Site Number :5280001
• Norway
  • Namsos, Norway, 7800
    • Investigational Site Number :5780002
  • Oslo, Norway, 0450
    • Investigational Site Number :5780001
• Portugal
  • Braga, Portugal, 4710-243
    • Investigational Site Number :6200001
  • Coimbra, Portugal, 3000-075
    • Investigational Site Number :6200005
  • Lisboa, Portugal, 1162-050
    • Investigational Site Number :6200011
  • Lisboa, Portugal, 1649-035
    • Investigational Site Number :6200006
  • Matosinhos, Portugal, 4464-513
    • Investigational Site Number :6200002
  • Porto, Portugal, 4099-001
    • Investigational Site Number :6200010
  • Santa Maria da Feira, Portugal, 4520-211
    • Investigational Site Number :6200004
• Puerto Rico
  • Guaynabo, Puerto Rico, 00969
    • San Juan MS Center-Site Number:8400015
• Russian Federation
  • Barnaul, Russian Federation, 656024
    • Investigational Site Number :6430006
  • Bryansk, Russian Federation, 241033
    • Investigational Site Number :6430013
  • Ekaterinburg, Russian Federation, 620102
    • Investigational Site Number :6430012
  • Kazan, Russian Federation, 420021
    • Investigational Site Number :6430001
  • Kirov, Russian Federation, 610998
    • Investigational Site Number :6430010
  • Moscow, Russian Federation, 117997
    • Investigational Site Number :6430007
  • Moscow, Russian Federation, 127015
    • Investigational Site Number :6430005
  • Novosibirsk, Russian Federation, 630087
    • Investigational Site Number :6430003
  • Saint-Petersburg, Russian Federation, 192242
    • Investigational Site Number :6430014
  • Saint-Petersburg, Russian Federation, 197110
    • Investigational Site Number :6430002
  • Saransk, Russian Federation, 430032
    • Investigational Site Number :6430011
  • St-Petersburg, Russian Federation, 197022
    • Investigational Site Number :6430004
• Serbia
  • Belgrade, Serbia, 11000
    • Investigational Site Number :6880001
  • Belgrade, Serbia, 11000
    • Investigational Site Number :6880003
  • Belgrade, Serbia, 11000
    • Investigational Site Number :6880006
  • Kragujevac, Serbia, 34000
    • Investigational Site Number :6880002
  • Nis, Serbia, 18000
    • Investigational Site Number :6880004
  • Novi Sad, Serbia, 21000
    • Investigational Site Number :6880005
• Slovakia
  • Bratislava, Slovakia, 82606
    • Investigational Site Number :7030001
  • Martin, Slovakia, 03659
    • Investigational Site Number :7030002
  • Nitra, Slovakia, 950 01
    • Investigational Site Number :7030004
• Spain
  • Hospitalet de Llobregat, Spain, 08907
    • Investigational Site Number :7240007
  • La Coruña, Spain, 15006
    • Investigational Site Number :7240008
  • Lleida, Spain, 25198
    • Investigational Site Number :7240005
  • Madrid, Spain, 28007
    • Investigational Site Number :7240003
  • Madrid, Spain, 28034
    • Investigational Site Number :7240001
  • Madrid, Spain, 28040
    • Investigational Site Number :7240002
  • Málaga, Spain, 29010
    • Investigational Site Number :7240010
  • Pozuelo De Alarcón, Spain, 28223
    • Investigational Site Number :7240012
  • Andalucia
    • Sevilla, Andalucia, Spain, 41009
      • Investigational Site Number :7240011
  • Barcelona [Barcelona]
    • Barcelona, Barcelona [Barcelona], Spain, 08036
      • Investigational Site Number :7240006
  • Bizkaia
    • Barakaldo, Bizkaia, Spain, 48903
      • Investigational Site Number :7240009
  • Girona [Gerona]
    • Salt, Girona [Gerona], Spain, 17190
      • Investigational Site Number :7240004
  • Las Palmas
    • Las Palmas de Gran Canaria, Las Palmas, Spain, 35010
      • Investigational Site Number :7240013
• Switzerland
  • Aarau, Switzerland, 5001
    • Investigational Site Number :7560003
  • Bern, Switzerland, 3010
    • Investigational Site Number :7560002
  • Lugano, Switzerland, 6903
    • Investigational Site Number :7560004
• Turkey
  • Ankara, Turkey, 06100
    • Investigational Site Number :7920002
  • Besevler / Ankara, Turkey, 06500
    • Investigational Site Number :7920005
  • Istanbul, Turkey, 34896
    • Investigational Site Number :7920006
  • Kuttahta, Turkey, 43100
    • Investigational Site Number :7920004
  • Samsun, Turkey
    • Investigational Site Number :7920001
  • Trabzon, Turkey, 61080
    • Investigational Site Number :7920003
• Ukraine
  • Chernihiv, Ukraine, 14029
    • Investigational Site Number :8040020
  • Chernivtsi, Ukraine, 58000
    • Investigational Site Number :8040002
  • Chernivtsi, Ukraine, 58023
    • Investigational Site Number :8040019
  • Dnipro, Ukraine, 49005
    • Investigational Site Number :8040005
  • Kharkiv, Ukraine, 61103
    • Investigational Site Number :8040022
  • Kharkiv, Ukraine, 61166
    • Investigational Site Number :8040018
  • Kyiv, Ukraine, 02091
    • Investigational Site Number :8040007
  • Lviv, Ukraine, 79013
    • Investigational Site Number :8040006
  • Vinnytsia, Ukraine, 21050
    • Investigational Site Number :8040003
• United Kingdom
  • Bristol, United Kingdom, BS10 5NB
    • Investigational Site Number :8260009
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Investigational Site Number :8260003
  • Kent
    • Canterbury, Kent, United Kingdom, CT1 3NG
      • Investigational Site Number :8260016
• United States
  • Alabama
    • Cullman, Alabama, United States, 35058
      • North Central Neurology Associates, PC-Site Number:8400009
  • Arizona
    • Phoenix, Arizona, United States, 84018
      • Center for Neurology and Spine-Site Number:8400089
  • California
    • Arcadia, California, United States, 91006
      • Arcadia Neurology Center-Site Number:8400070
    • Newport Beach, California, United States, 92663
      • Multiple Sclerosis Center of California-Site Number:8400135
    • Torrance, California, United States, 90502
      • Harbor UCLA-Site Number:8400088
  • Colorado
    • Basalt, Colorado, United States, 81621
      • Mountain Neurological Research Center, Inc.-Site Number:8400128
    • Fort Collins, Colorado, United States, 80528
      • Advanced Neurosciences Research-Site Number:8400025
  • Florida
    • Boca Raton, Florida, United States, 33487
      • South Florida Neurology Associates-Site Number:8400029
    • Gainesville, Florida, United States, 32608
      • University of Florida Health-Site Number:8400159
    • Maitland, Florida, United States, 32761
      • Neurology Associates, PA-Site Number:8400004
    • Miami, Florida, United States, 33136
      • University of Miami-Site Number:8400063
    • Sunrise, Florida, United States, 33351
      • Infinity Clinical Research-Site Number:8400008
    • Tampa, Florida, United States, 33612
      • University of South Florida-Site Number:8400006
  • Georgia
    • Savannah, Georgia, United States, 31406
      • Meridian Clinical Research-Site Number:8400003
  • Illinois
    • Northbrook, Illinois, United States, 60062
      • Consultants In Neurology-Site Number:8400011
    • Springfield, Illinois, United States, 62701
      • Prairie Education and Research Cooperative-Site Number:8400071
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Fort Wayne Neurological Center-Site Number:8400039
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • CHI Saint Joseph Medical Group Neurology-Site Number:8400110
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky-Site Number:8400106
    • Louisville, Kentucky, United States, 40207
      • Norton Neurology MS Services-Site Number:8400127
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70810
      • The NeuroMedical Center-Site Number:8400057
  • Maryland
    • Lutherville-Timonium, Maryland, United States, 21093
      • International Neurorehabilitation Institute-Site Number:8400034
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University-Site Number:8400046
  • Minnesota
    • Minneapolis, Minnesota, United States, 55422
      • Minneapolis Clinic of Neurology-Site Number:8400051
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital-Site Number:8400153
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • West Omaha Family Physicians-Site Number:8400139
    • Omaha, Nebraska, United States, 68198
      • University Of Nebraska-Site Number:8400129
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Hospital-Site Number:8400047
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico-Site Number:8400032
  • New York
    • Patchogue, New York, United States, 11772
      • South Shore Neurologic Associates-Site Number:8400100
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Novant Health Multiple Sclerosis Care Center - South Park-Site Number:8400120
    • Raleigh, North Carolina, United States, 27607
      • Meridian Clinical Research, LLC-Site Number:8400005
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Sanford Brain & Spine Center-Site Number:8400126
  • Ohio
    • Centerville, Ohio, United States, 45459
      • Dayton Center for Neurological Disorders-Site Number:8400081
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson Neurology Associates-Site Number:8400016
  • South Carolina
    • Greer, South Carolina, United States, 29650
      • Premier Neurology-Site Number:8400069
  • Tennessee
    • Franklin, Tennessee, United States, 37064
      • Advanced Neuroscience Center-Site Number:8400035
    • Knoxville, Tennessee, United States, 37922
      • Sibyl Wray, MD, Neurology, PC-Site Number:8400007
  • Texas
    • Katy, Texas, United States, 77450
      • Mt Olympus Medical Research-Site Number:8400163
    • San Antonio, Texas, United States, 78258
      • Neurology Center of San Antonio-Site Number:8400036
    • Sherman, Texas, United States, 75092
      • Texas Institute for Neuroogical Disorders-Sherman-Site Number:8400151
  • Virginia
    • Richmond, Virginia, United States, 23229
      • Neurological Associates-Site Number:8400097
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Wheaton Franciscan Healthcare-Site Number:8400022

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) and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for the same period of time.

  • 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 multiplesclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiplesclerosis (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, hepatitis B or C, 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; Dose 1 of oral SAR442168 daily + 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; Oral 14 mg oral teriflunomide + placebo to match the SAR442168 tablet once daily	Drug: Teriflunomide HMR1726; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Placebo to match Tolebrutinib; 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)
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and 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 treatment 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
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)

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• EFC16034 Plain language Results Summary

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2020
• Primary Completion (Actual): July 16, 2024
• Study Completion (Actual): July 16, 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: EFC16034; U1111-1238-1373 (Registry Identifier: ICTRP); 2020-000644-55 (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
• product manufactured in and exported from the U.S.: No