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

NCT04410991 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: EFC16034U1111-1238-13732020-000644-55
• Study Type: interventional
• Target: 899
• Locations: 28 countries
• Sites: 186

Brief Summary

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

Conditions

Relapsing Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale

  Baseline (Day 1) to approximately 48 months

• Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale

  Baseline (Day 1) to approximately 48 months

• Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year

  Baseline (Day 1) to approximately 48 months

• Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan

  Baseline (Day 1) to approximately 48 months

• 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)

Study Arms (2)

SAR442168

EXPERIMENTAL

Dose 1 of oral SAR442168 daily + placebo to match the teriflunomide tablet once daily

Drug: Tolebrutinib; Drug: Placebo to match Teriflunomide

Teriflunomide

ACTIVE COMPARATOR

Oral 14 mg oral teriflunomide + placebo to match the SAR442168 tablet once daily

Drug: Teriflunomide HMR1726; Drug: Placebo to match Tolebrutinib

Interventions

Tolebrutinib DRUG

Pharmaceutical form: Tablet Route of administration: Oral

Also known as: SAR442168

SAR442168

Teriflunomide HMR1726 DRUG

Pharmaceutical form: Tablet Route of administration: Oral

Teriflunomide

Placebo to match Tolebrutinib DRUG

Pharmaceutical form: Tablet Route of administration: Oral

Teriflunomide

Placebo to match Teriflunomide DRUG

Pharmaceutical form: Tablet Route of administration: Oral

SAR442168

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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:

You may not qualify if:

• 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

Sponsors & Collaborators

• Sanofi: lead

Study Sites (186)

North Central Neurology Associates, PC-Site Number:8400009

Cullman, Alabama, 35058, United States

Location

Center for Neurology and Spine-Site Number:8400089

Phoenix, Arizona, 84018, United States

Location

Arcadia Neurology Center-Site Number:8400070

Arcadia, California, 91006, United States

Location

Multiple Sclerosis Center of California-Site Number:8400135

Newport Beach, California, 92663, United States

Location

Harbor UCLA-Site Number:8400088

Torrance, California, 90502, United States

Location

Mountain Neurological Research Center, Inc.-Site Number:8400128

Basalt, Colorado, 81621, United States

Location

Advanced Neurosciences Research-Site Number:8400025

Fort Collins, Colorado, 80528, United States

Location

South Florida Neurology Associates-Site Number:8400029

Boca Raton, Florida, 33487, United States

Location

University of Florida Health-Site Number:8400159

Gainesville, Florida, 32608, United States

Location

Neurology Associates, PA-Site Number:8400004

Maitland, Florida, 32761, United States

Location

University of Miami-Site Number:8400063

Miami, Florida, 33136, United States

Location

Infinity Clinical Research-Site Number:8400008

Sunrise, Florida, 33351, United States

Location

University of South Florida-Site Number:8400006

Tampa, Florida, 33612, United States

Location

Meridian Clinical Research-Site Number:8400003

Savannah, Georgia, 31406, United States

Location

Consultants In Neurology-Site Number:8400011

Northbrook, Illinois, 60062, United States

Location

Prairie Education and Research Cooperative-Site Number:8400071

Springfield, Illinois, 62701, United States

Location

Fort Wayne Neurological Center-Site Number:8400039

Fort Wayne, Indiana, 46804, United States

Location

CHI Saint Joseph Medical Group Neurology-Site Number:8400110

Lexington, Kentucky, 40509, United States

Location

University of Kentucky-Site Number:8400106

Lexington, Kentucky, 40536, United States

Location

Norton Neurology MS Services-Site Number:8400127

Louisville, Kentucky, 40207, United States

Location

The NeuroMedical Center-Site Number:8400057

Baton Rouge, Louisiana, 70810, United States

Location

International Neurorehabilitation Institute-Site Number:8400034

Lutherville-Timonium, Maryland, 21093, United States

Location

Wayne State University-Site Number:8400046

Detroit, Michigan, 48201, United States

Location

Minneapolis Clinic of Neurology-Site Number:8400051

Minneapolis, Minnesota, 55422, United States

Location

Saint Luke's Hospital-Site Number:8400153

Kansas City, Missouri, 64111, United States

Location

West Omaha Family Physicians-Site Number:8400139

Omaha, Nebraska, 68130, United States

Location

University Of Nebraska-Site Number:8400129

Omaha, Nebraska, 68198, United States

Location

Hackensack University Hospital-Site Number:8400047

Hackensack, New Jersey, 07601, United States

Location

University of New Mexico-Site Number:8400032

Albuquerque, New Mexico, 87131, United States

Location

South Shore Neurologic Associates-Site Number:8400100

Patchogue, New York, 11772, United States

Location

Novant Health Multiple Sclerosis Care Center - South Park-Site Number:8400120

Charlotte, North Carolina, 28210, United States

Location

Meridian Clinical Research, LLC-Site Number:8400005

Raleigh, North Carolina, 27607, United States

Location

Sanford Brain & Spine Center-Site Number:8400126

Fargo, North Dakota, 58103, United States

Location

Dayton Center for Neurological Disorders-Site Number:8400081

Centerville, Ohio, 45459, United States

Location

Jefferson Neurology Associates-Site Number:8400016

Philadelphia, Pennsylvania, 19107, United States

Location

Premier Neurology-Site Number:8400069

Greer, South Carolina, 29650, United States

Location

Advanced Neuroscience Center-Site Number:8400035

Franklin, Tennessee, 37064, United States

Location

Sibyl Wray, MD, Neurology, PC-Site Number:8400007

Knoxville, Tennessee, 37922, United States

Location

Mt Olympus Medical Research-Site Number:8400163

Katy, Texas, 77450, United States

Location

Neurology Center of San Antonio-Site Number:8400036

San Antonio, Texas, 78258, United States

Location

Texas Institute for Neuroogical Disorders-Sherman-Site Number:8400151

Sherman, Texas, 75092, United States

Location

Neurological Associates-Site Number:8400097

Richmond, Virginia, 23229, United States

Location

Wheaton Franciscan Healthcare-Site Number:8400022

Milwaukee, Wisconsin, 53215, United States

Location

Investigational Site Number :0320004

CABA, Buenos Aires, C1023AAB, Argentina

Location

Investigational Site Number :0320002

Capital Federal, Buenos Aires, 1012, Argentina

Location

Investigational Site Number :0320001

CABA, Buenos Aires F.D., C1061, Argentina

Location

Investigational Site Number :0320003

Rosario, Santa Fe Province, 2000, Argentina

Location

Investigational Site Number :0320005

San Miguel de Tucumán, T4000AXL, Argentina

Location

Investigational Site Number :0560005

Bruges, B-8000, Belgium

Location

Investigational Site Number :0560004

Ghent, 9000, Belgium

Location

Investigational Site Number :0560002

Mons, 7000, Belgium

Location

Investigational Site Number :0560001

Overpelt, 3900, Belgium

Location

Investigational Site Number :0760001

Porto Alegre, Rio Grande do Sul, 90610-000, Brazil

Location

Investigational Site Number :0760002

Curitiba, 81210-310, Brazil

Location

Investigational Site Number :0760007

São Paulo, 01228-000, Brazil

Location

Investigational Site Number :1240002

Edmonton, Alberta, T6G 2C8, Canada

Location

Investigational Site Number : 1240012

Hamilton, Ontario, L8L 2X2, Canada

Location

Investigational Site Number :1240014

London, Ontario, N6A 5A5, Canada

Location

Investigational Site Number :1240005

Greenfield Park, Quebec, J4V 2J2, Canada

Location

Investigational Site Number :1240006

Gatineau, J8Y1W2, Canada

Location

Investigational Site Number :1240021

Québec, G1W 4R4, Canada

Location

Investigational Site Number :1520002

Santiago, Reg Metropolitana de Santiago, 7650568, Chile

Location

Investigational Site Number :1520005

Santiago, Reg Metropolitana de Santiago, 833-0024, Chile

Location

Investigational Site Number :1520001

Santiago, Reg Metropolitana de Santiago, 8380456, Chile

Location

Investigational Site Number :1520003

Santiago, Reg Metropolitana de Santiago, 8431657, Chile

Location

Investigational Site Number :1520006

Concepción, Chile

Location

Investigational Site Number :1520004

Valdivia, 5110683, Chile

Location

Investigational Site Number :1910001

Zagreb, 10000, Croatia

Location

Investigational Site Number :1910002

Zagreb, 10000, Croatia

Location

Investigational Site Number :1910003

Zagreb, 10000, Croatia

Location

Investigational Site Number :2030002

Brno, 65691, Czechia

Location

Investigational Site Number :2030011

Hradec Králové, 50005, Czechia

Location

Investigational Site Number :2030001

Jihlava, 58633, Czechia

Location

Investigational Site Number :2030008

Prague, 10034, Czechia

Location

Investigational Site Number :2030005

Praha 5 - Motol, 15006, Czechia

Location

Investigational Site Number :2500019

Besançon, 25000, France

Location

Investigational Site Number :2500018

Bordeaux, France

Location

Investigational Site Number :2500011

Bron, 69500, France

Location

Investigational Site Number :2500005

Clermont-Ferrand, 63003, France

Location

Investigational Site Number :2500006

Montpellier, 34295, France

Location

Investigational Site Number :2500010

Nantes, 44093, France

Location

Investigational Site Number :2500002

Nice, 06002, France

Location

Investigational Site Number :2500017

Nîmes, 30029, France

Location

Investigational Site Number :2500007

Paris, 75019, France

Location

Investigational Site Number :2500004

Poissy, 78300, France

Location

Investigational Site Number :2500003

Rennes, 35033, France

Location

Investigational Site Number :2500001

Strasbourg, 67098, France

Location

Investigational Site Number :2760005

Bayreuth, 95445, Germany

Location

Investigational Site Number :2760015

Berlin, 10713, Germany

Location

Investigational Site Number :2760014

Berlin, 12099, Germany

Location

Investigational Site Number :2760020

Bochum, 44791, Germany

Location

Investigational Site Number :2760012

Essen, 45147, Germany

Location

Investigational Site Number :2760003

Würzburg, 97070, Germany

Location

Investigational Site Number :3000001

Athens, 115 28, Greece

Location

Investigational Site Number :3000006

Athens, 11535, Greece

Location

Investigational Site Number :3000002

Athens, 12462, Greece

Location

Investigational Site Number :3000007

Athens, 15125, Greece

Location

Investigational Site Number :3000009

Athens, Greece

Location

Investigational Site Number :3000004

Larissa, 41110, Greece

Location

Investigational Site Number :3000003

Thessaloniki, 546 36, Greece

Location

Investigational Site Number :3480105

Budapest, 1135, Hungary

Location

Investigational Site Number :3480102

Budapest, 1145, Hungary

Location

Investigational Site Number :3480106

Kaposvár, 7400, Hungary

Location

Investigational Site Number :3480103

Tatabánya, 2800, Hungary

Location

Investigational Site Number :3560005

Chandigarh, 160012, India

Location

Investigational Site Number :3560007

Gūrgaon, 122001, India

Location

Investigational Site Number :3560008

Gūrgaon, 122002, India

Location

Investigational Site Number :3560002

New Delhi, 110060, India

Location

Investigational Site Number :3560004

Thiruvananthapuram, 695004, India

Location

Investigational Site Number :3760002

Ashkelon, 78278, Israel

Location

Investigational Site Number :3760003

Haifa, 31096, Israel

Location

Investigational Site Number :3760006

Rehovot, 76100, Israel

Location

Investigational Site Number :3760004

Safed, 13100, Israel

Location

Investigational Site Number :3760001

Tel Litwinsky, 52621, Israel

Location

Investigational Site Number :4280002

Riga, LV-1002, Latvia

Location

Investigational Site Number :4280003

Riga, LV-1005, Latvia

Location

Investigational Site Number :5280001

Amsterdam, 1081 GN, Netherlands

Location

Investigational Site Number :5780002

Namsos, 7800, Norway

Location

Investigational Site Number :5780001

Oslo, 0450, Norway

Location

Investigational Site Number :6200001

Braga, 4710-243, Portugal

Location

Investigational Site Number :6200005

Coimbra, 3000-075, Portugal

Location

Investigational Site Number :6200011

Lisbon, 1162-050, Portugal

Location

Investigational Site Number :6200006

Lisbon, 1649-035, Portugal

Location

Investigational Site Number :6200002

Matosinhos Municipality, 4464-513, Portugal

Location

Investigational Site Number :6200010

Porto, 4099-001, Portugal

Location

Investigational Site Number :6200004

Santa Maria da Feira, 4520-211, Portugal

Location

San Juan MS Center-Site Number:8400015

Guaynabo, 00969, Puerto Rico

Location

Investigational Site Number :6430006

Barnaul, 656024, Russia

Location

Investigational Site Number :6430013

Bryansk, 241033, Russia

Location

Investigational Site Number :6430001

Kazan', 420021, Russia

Location

Investigational Site Number :6430010

Kirov, 610998, Russia

Location

Investigational Site Number :6430007

Moscow, 117997, Russia

Location

Investigational Site Number :6430005

Moscow, 127015, Russia

Location

Investigational Site Number :6430003

Novosibirsk, 630087, Russia

Location

Investigational Site Number :6430014

Saint Petersburg, 192242, Russia

Location

Investigational Site Number :6430004

Saint Petersburg, 197022, Russia

Location

Investigational Site Number :6430002

Saint Petersburg, 197110, Russia

Location

Investigational Site Number :6430011

Saransk, 430032, Russia

Location

Investigational Site Number :6430012

Yekaterinburg, 620102, Russia

Location

Investigational Site Number :6880001

Belgrade, 11000, Serbia

Location

Investigational Site Number :6880003

Belgrade, 11000, Serbia

Location

Investigational Site Number :6880006

Belgrade, 11000, Serbia

Location

Investigational Site Number :6880002

Kragujevac, 34000, Serbia

Location

Investigational Site Number :6880004

Niš, 18000, Serbia

Location

Investigational Site Number :6880005

Novi Sad, 21000, Serbia

Location

Investigational Site Number :7030001

Bratislava, 82606, Slovakia

Location

Investigational Site Number :7030002

Martin, 03659, Slovakia

Location

Investigational Site Number :7030004

Nitra, 950 01, Slovakia

Location

Investigational Site Number :4100001

Goyang-si, Gyeonggi-do, 10408, South Korea

Location

Investigational Site Number :4100003

Seoul, Seoul-teukbyeolsi, 03080, South Korea

Location

Investigational Site Number :4100006

Seoul, Seoul-teukbyeolsi, 03722, South Korea

Location

Investigational Site Number :4100002

Seoul, Seoul-teukbyeolsi, 06351, South Korea

Location

Investigational Site Number :7240011

Seville, Andalusia, 41009, Spain

Location

Investigational Site Number :7240006

Barcelona, Barcelona [Barcelona], 08036, Spain

Location

Investigational Site Number :7240009

Barakaldo, Bizkaia, 48903, Spain

Location

Investigational Site Number :7240004

Salt, Girona [Gerona], 17190, Spain

Location

Investigational Site Number :7240013

Las Palmas de Gran Canaria, Las Palmas, 35010, Spain

Location

Investigational Site Number :7240008

A Coruña, 15006, Spain

Location

Investigational Site Number :7240007

L'Hospitalet de Llobregat, 08907, Spain

Location

Investigational Site Number :7240005

Lleida, 25198, Spain

Location

Investigational Site Number :7240003

Madrid, 28007, Spain

Location

Investigational Site Number :7240001

Madrid, 28034, Spain

Location

Investigational Site Number :7240002

Madrid, 28040, Spain

Location

Investigational Site Number :7240010

Málaga, 29010, Spain

Location

Investigational Site Number :7240012

Pozuelo de Alarcón, 28223, Spain

Location

Investigational Site Number :7560003

Aarau, 5001, Switzerland

Location

Investigational Site Number :7560002

Bern, 3010, Switzerland

Location

Investigational Site Number :7560004

Lugano, 6903, Switzerland

Location

Investigational Site Number :7920002

Ankara, 06100, Turkey (Türkiye)

Location

Investigational Site Number :7920005

Besevler / Ankara, 06500, Turkey (Türkiye)

Location

Investigational Site Number :7920006

Istanbul, 34896, Turkey (Türkiye)

Location

Investigational Site Number :7920004

Kuttahta, 43100, Turkey (Türkiye)

Location

Investigational Site Number :7920001

Samsun, Turkey (Türkiye)

Location

Investigational Site Number :7920003

Trabzon, 61080, Turkey (Türkiye)

Location

Investigational Site Number :8040020

Chernihiv, 14029, Ukraine

Location

Investigational Site Number :8040002

Chernivtsi, 58000, Ukraine

Location

Investigational Site Number :8040019

Chernivtsi, 58023, Ukraine

Location

Investigational Site Number :8040005

Dnipro, 49005, Ukraine

Location

Investigational Site Number :8040022

Kharkiv, 61103, Ukraine

Location

Investigational Site Number :8040018

Kharkiv, 61166, Ukraine

Location

Investigational Site Number :8040007

Kyiv, 02091, Ukraine

Location

Investigational Site Number :8040006

Lviv, 79013, Ukraine

Location

Investigational Site Number :8040003

Vinnytsia, 21050, Ukraine

Location

Investigational Site Number :8260003

Exeter, Devon, EX2 5DW, United Kingdom

Location

Investigational Site Number :8260016

Canterbury, Kent, CT1 3NG, United Kingdom

Location

Investigational Site Number :8260009

Bristol, BS10 5NB, United Kingdom

Location

Related Publications (1)

• Oh J, Arnold DL, Cree BAC, Ionete C, Kim HJ, Sormani MP, Syed S, Chen Y, Maxwell CR, Benoit P, Turner TJ, Wallstroem E, Wiendl H; Tolebrutinib Phase 3 GEMINI 1 and 2 Trial Group. Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. 2025 May 15;392(19):1893-1904. doi: 10.1056/NEJMoa2415985. Epub 2025 Apr 8.

  PMID: 40202623 DERIVED

Related Links

• EFC16034 Plain language Results Summary

MeSH Terms

Interventions

teriflunomide

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2020
• First Posted: June 1, 2020
• Study Start: June 11, 2020
• Primary Completion: July 16, 2024
• Study Completion: July 16, 2024
• Last Updated: July 2, 2025
• Results First Posted: June 18, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share

Locations

CA (6); ES (13); NO (2); PT (7); LA (2); CH (3); KR (4); DE (6); US (43); CZ (5); PR (1); SE (6); CR (3); NL (1); GB (3); IN (5); AR (5); IL (5); SL (3); TU (6); RU (12); BE (4); CL (6); GR (7); FR (12); UA (9); HU (4); BR (3)