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

NCT04410978 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: EFC16033U1111-1238-14182020-000637-41
• Study Type: interventional
• Target: 974
• Locations: 23 countries
• Sites: 171

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 population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety 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 (16)

• 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

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

Drug: Tolebrutinib; Drug: Placebo to match Teriflunomide

Teriflunomide

ACTIVE COMPARATOR

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

Drug: Teriflunomide; Drug: Placebo to match Tolebrutinib

Interventions

Placebo to match Tolebrutinib DRUG

Pharmaceutical form: Tablet Route of administration: Oral

Teriflunomide

Tolebrutinib DRUG

Pharmaceutical form: Tablet Route of administration: Oral

Also known as: SAR442168

SAR442168

Teriflunomide 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 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

Sponsors & Collaborators

• Sanofi: lead

Study Sites (179)

University of Alabama MS Center-Site Number:8400013

Birmingham, Alabama, 35233, United States

Location

University of San Francisco, Sandler Neurosciences Center-Site Number:8400137

San Francisco, California, 94158, United States

Location

University of Colorado-Site Number:8400012

Aurora, Colorado, 80045, United States

Location

Georgetown University Medical Center-Site Number:8400119

Washington D.C., District of Columbia, 20007, United States

Location

Beth Israel Deaconess Medical Center-Site Number:8400064

Fort Myers, Florida, 33919, United States

Location

Axiom Clinical Research of Florida-Site Number:8400001

Tampa, Florida, 33609-4052, 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

Tufts Medical Center-Site Number:8400072

Boston, Massachusetts, 02111, United States

Location

Michigan Institute For Neurological Disorders-Site Number:8400058

Farmington Hills, Michigan, 48334, United States

Location

The Memorial Hospital-Site Number:8400033

Owosso, Michigan, 48867, United States

Location

Sharlin Health & Neurology-Site Number:8400093

Ozark, Missouri, 65721, United States

Location

Missouri Baptist Medical Center-Site Number:8400019

St Louis, Missouri, 63131, United States

Location

Meridian Clinical Research, LLC-Site Number:8400005

Raleigh, North Carolina, 27607, United States

Location

Wake Forest University Baptist Medical Center-Site Number:8400116

Winston-Salem, North Carolina, 27157, United States

Location

The Ohio State University Wexner Medical Center-Site Number:8400150

Columbus, Ohio, 43221, United States

Location

Optimed Research, LTD-Site Number:8400147

Columbus, Ohio, 43235, United States

Location

Columbus Neuroscience-Site Number:8400010

Westerville, Ohio, 40382, United States

Location

Oklahoma Medical Research Foundation-Site Number:8400018

Oklahoma City, Oklahoma, 73104, United States

Location

Providence Multiple Sclerosis Center-Site Number:8400020

Portland, Oregon, 97225, United States

Location

University of Texas Southwestern Medical Center-Site Number:8400077

Dallas, Texas, 75390, United States

Location

Multiple Sclerosis Center, Swedish Neuroscience Institute-Site Number:8400121

Seattle, Washington, 98122, United States

Location

Investigational Site Number :0400004

Linz, 4021, Austria

Location

Investigational Site Number :1120005

Vitebsk, 210009, Belarus

Location

Investigational Site Number :1120004

Vitebsk, 210037, Belarus

Location

Investigational Site Number :1000002

Pleven, 5800, Bulgaria

Location

Investigational Site Number :1000005

Plovdiv, 4000, Bulgaria

Location

Investigational Site Number :1000004

Sofia, 1113, Bulgaria

Location

Investigational Site Number :1000008

Sofia, 1407, Bulgaria

Location

Investigational Site Number :1000001

Sofia, 1431, Bulgaria

Location

Investigational Site Number :1000006

Sofia, 1431, Bulgaria

Location

Investigational Site Number :1000009

Sofia, 1680, Bulgaria

Location

Investigational Site Number :1240016

Vancouver, British Columbia, V6T 2B5, Canada

Location

Investigational Site Number :1240003

Ottawa, Ontario, K1H 8L6, Canada

Location

Investigational Site Number :1240013

Toronto, Ontario, M5B 1W8, Canada

Location

Investigational Site Number :1240006

Gatineau, Quebec, J8Y 1W2, Canada

Location

Investigational Site Number :1560022

Baotou, 014010, China

Location

Investigational Site Number :1560006

Beijing, 100034, China

Location

Investigational Site Number :1560010

Beijing, 100050, China

Location

Investigational Site Number :1560012

Beijing, 100053, China

Location

Investigational Site Number :1560023

Beijing, 100191, China

Location

Investigational Site Number :1560001

Beijing, 100730, China

Location

Investigational Site Number :1560009

Beijing, 100730, China

Location

Investigational Site Number :1560025

Beijing, 100730, China

Location

Investigational Site Number :1560021

Beijing, 100853, China

Location

Investigational Site Number :1560004

Changchun, 130021, China

Location

Investigational Site Number :1560015

Changsha, 410008, China

Location

Investigational Site Number :1560005

Chengdu, 610041, China

Location

Investigational Site Number :1560019

Chongqing, 400016, China

Location

Investigational Site Number :1560035

Fuzhou, 350005, China

Location

Investigational Site Number :1560016

Guangzhou, 510080, China

Location

Investigational Site Number :1560028

Guangzhou, 510515, China

Location

Investigational Site Number :1560002

Guangzhou, 510630, China

Location

Investigational Site Number :1560027

Hohhot, 010050, China

Location

Investigational Site Number :1560044

Nanjing, 210008, China

Location

Investigational Site Number :1560042

Nanjing, 210029, China

Location

Investigational Site Number :1560003

Shanghai, 200040, China

Location

Investigational Site Number :1560018

Shenyang, 110004, China

Location

Investigational Site Number :1560014

Shijiazhuang, 050000, China

Location

Investigational Site Number :1560008

Taiyuan, 030001, China

Location

Investigational Site Number :1560020

Tianjin, 300052, China

Location

Investigational Site Number :1560011

Wuhan, 430030, China

Location

Investigational Site Number :1560017

Xi'an, 710038, China

Location

Investigational Site Number :1560033

Yinchuan, 750004, China

Location

Investigational Site Number :2030004

Hradec Králové, 50005, Czechia

Location

Investigational Site Number :2030009

Pardubice, 53203, Czechia

Location

Investigational Site Number :2030003

Teplice, 415 29, Czechia

Location

Investigational Site Number :2030007

Zlín, 76275, Czechia

Location

Investigational Site Number :2080001

Esbjerg, 6700, Denmark

Location

Investigational Site Number :2080005

Holstebro, 7500, Denmark

Location

Investigational Site Number :2330001

Tallinn, 11315, Estonia

Location

Investigational Site Number :2330002

Tartu, 50406, Estonia

Location

Investigational Site Number :2460003

Helsinki, 00180, Finland

Location

Investigational Site Number :2460001

Tampere, 33520, Finland

Location

Investigational Site Number :2460002

Turku, 20520, Finland

Location

Investigational Site Number :2760001

Dresden, 01307, Germany

Location

Investigational Site Number :2760019

Düsseldorf, 40225, Germany

Location

Investigational Site Number :2760016

Hamburg, 22179, Germany

Location

Investigational Site Number :2760008

Münster, 48149, Germany

Location

Investigational Site Number :2760004

Rostock, 18055, Germany

Location

Investigational Site Number :2760011

Ulm, 89081, Germany

Location

Investigational Site Number : 3440001

Shatin, NT, Hong Kong

Location

Investigational Site Number :3800002

Pozzilli, Isernia, 86077, Italy

Location

Investigational Site Number :3800007

Orbassano, Torino, 10043, Italy

Location

Investigational Site Number :3800011

Bergamo, 24127, Italy

Location

Investigational Site Number :3800015

Catania, 95123, Italy

Location

Investigational Site Number :3800012

Florence, 50134, Italy

Location

Investigational Site Number :3800014

Genova, 16132, Italy

Location

Investigational Site Number :3800001

Milan, 20132, Italy

Location

Investigational Site Number :3800010

Milan, 20133, Italy

Location

Investigational Site Number :3800003

Napoli, 80131, Italy

Location

Investigational Site Number :3800006

Napoli, 80131, Italy

Location

Investigational Site Number :3800008

Pavia, 27100, Italy

Location

Investigational Site Number :3800005

Roma, 00152, Italy

Location

Investigational Site Number :3800009

Roma, 00168, Italy

Location

Investigational Site Number :3800013

Roma, 00189, Italy

Location

Investigational Site Number :3920016

Chiba, Chiba, 260-8677, Japan

Location

Investigational Site Number :3920008

Koriyama-shi, Fukushima, 963-8052, Japan

Location

Investigational Site Number :3920012

Tsukuba, Ibaraki, 305-0005, Japan

Location

Investigational Site Number :3920022

Morioka, Iwate, 020-8505, Japan

Location

Investigational Site Number :3920005

Niigata, Niigata, 951-8520, Japan

Location

Investigational Site Number :3920004

Moriguchi-shi, Osaka, 570-8507, Japan

Location

Investigational Site Number :3920001

Osaka, Osaka, 556-0016, Japan

Location

Investigational Site Number :3920018

Kawagoe-shi, Saitama, 350-8550, Japan

Location

Investigational Site Number :3920014

Bunkyo-ku, Tokyo, 113-8431, Japan

Location

Investigational Site Number :3920003

Kodaira-shi, Tokyo, 187-8551, Japan

Location

Investigational Site Number :3920010

Ōta-ku, Tokyo, 146-0065, Japan

Location

Investigational Site Number :3920013

Shinjuku-ku, Tokyo, 162-8666, Japan

Location

Investigational Site Number :3920009

Ube-shi, Yamaguchi, 755-8505, Japan

Location

Investigational Site Number :3920023

Sagamihara-shi, 252-0392, Japan

Location

Investigational Site Number :4400003

Kaunas, 50161, Lithuania

Location

Investigational Site Number :4400002

Klaipėda, 92288, Lithuania

Location

Investigational Site Number :4400004

Šiauliai, LT-76231, Lithuania

Location

Investigational Site Number :4400001

Vilnius, 08661, Lithuania

Location

Investigational Site Number :4840002

México, 03100, Mexico

Location

Investigational Site Number :4840001

México, 06700, Mexico

Location

Investigational Site Number :4840003

Veracruz, 91910, Mexico

Location

Investigational Site Number :6160008

Plewiska, Greater Poland Voivodeship, 62-064, Poland

Location

Investigational Site Number :6160003

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-796, Poland

Location

Investigational Site Number :6160005

Warsaw, Masovian Voivodeship, 01-211, Poland

Location

Investigational Site Number :6160006

Warsaw, Masovian Voivodeship, 01-684, Poland

Location

Investigational Site Number :6160009

Glogow Mlp., Podkarpackie Voivodeship, 36-060, Poland

Location

Investigational Site Number :6160002

Katowice, Silesian Voivodeship, 40-571, Poland

Location

Investigational Site Number :6160004

Katowice, Silesian Voivodeship, 40-686, Poland

Location

Investigational Site Number :6160001

Lodz, 90-549, Poland

Location

Investigational Site Number :6420015

Brasov, 500283, Romania

Location

Investigational Site Number :6420008

Bucharest, 022328, Romania

Location

Investigational Site Number :6420004

Campulung Muscel, 115100, Romania

Location

Investigational Site Number :6420003

Constanța, 900123, Romania

Location

Investigational Site Number :6420010

Oradea, 410169, Romania

Location

Investigational Site Number :6420005

Sibiu, 550052, Romania

Location

Investigational Site Number :6420001

Târgu Mureş, 540136, Romania

Location

Investigational Site Number :6420002

Timișoara, 300736, Romania

Location

Investigational Site Number :6430014

Krasnoyarsk, 660029, Russia

Location

Investigational Site Number :6430002

Moscow, 125367, Russia

Location

Investigational Site Number :6430008

Moscow, 129128, Russia

Location

Investigational Site Number :6430011

Nizhny Novgorod, 603137, Russia

Location

Investigational Site Number :6430003

Nizhny Novgorod, 603155, Russia

Location

Investigational Site Number :6430007

Pyatigorsk, 357538, Russia

Location

Investigational Site Number :6430012

Rostov-on-Don, 344022, Russia

Location

Investigational Site Number :6430001

Saint Petersburg, 194044, Russia

Location

Investigational Site Number :6430005

Samara, 443095, Russia

Location

Investigational Site Number :6430009

Smolensk, 214018, Russia

Location

Investigational Site Number :6430006

Tyumen, 625000, Russia

Location

Investigational Site Number :6430004

Ufa, 450005, Russia

Location

Investigational Site Number :7240003

Seville, Andalusia, 41009, Spain

Location

Investigational Site Number :7240009

Barcelona, Barcelona [Barcelona], 08035, Spain

Location

Investigational Site Number :7240008

Donostia / San Sebastian, Basque Country, 20014, Spain

Location

Investigational Site Number :7240001

Pozuelo de Alarcón, Madrid, 28223, Spain

Location

Investigational Site Number :7240004

Córdoba, 14004, Spain

Location

Investigational Site Number :7240005

Málaga, 29010, Spain

Location

Investigational Site Number :7240006

Murcia, 30120, Spain

Location

Investigational Site Number :7240007

Valencia, 46026, Spain

Location

Investigational Site Number :7520001

Gothenburg, 413 45, Sweden

Location

Investigational Site Number :7520002

Stockholm, 113 65, Sweden

Location

Investigational Site Number :1580007

Hsinchu, 30059, Taiwan

Location

Investigational Site Number :1580005

Kaohsiung City, 833, Taiwan

Location

Investigational Site Number :1580003

Taichung, 402, Taiwan

Location

Investigational Site Number :1580002

Taipei, 112, Taiwan

Location

Investigational Site Number :1580006

Taoyuang, 333, Taiwan

Location

Investigational Site Number :7920005

Eskişehir, Turkey (Türkiye)

Location

Investigational Site Number :7920011

Hatay, Turkey (Türkiye)

Location

Investigational Site Number :7920002

Istanbul, 34098, Turkey (Türkiye)

Location

Investigational Site Number :7920009

Istanbul, 34688, Turkey (Türkiye)

Location

Investigational Site Number :7920007

Istanbul, 34785, Turkey (Türkiye)

Location

Investigational Site Number :7920003

Istanbul, Turkey (Türkiye)

Location

Investigational Site Number :7920008

Izmir, 35100, Turkey (Türkiye)

Location

Investigational Site Number :7920010

Izmir, Turkey (Türkiye)

Location

Investigational Site Number :7920001

Kocaeli, 41380, Turkey (Türkiye)

Location

Investigational Site Number :7920006

Mersin, 33070, Turkey (Türkiye)

Location

Investigational Site Number :8040011

Ivano-Frankivsk, 76493, Ukraine

Location

Investigational Site Number :8040016

Kharkiv, 61068, Ukraine

Location

Investigational Site Number :8040013

Kharkiv, 61103, Ukraine

Location

Investigational Site Number :8040008

Kherson, 73000, Ukraine

Location

Investigational Site Number :8040014

Kyiv, 03115, Ukraine

Location

Investigational Site Number :8040010

Lutsk, 43005, Ukraine

Location

Investigational Site Number :8040001

Lviv, 79010, Ukraine

Location

Investigational Site Number :8040009

Odesa, 65025, Ukraine

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

• EFC16033 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 30, 2020
• Primary Completion: July 15, 2024
• Study Completion: July 15, 2024
• Last Updated: July 2, 2025
• Results First Posted: June 18, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); RU (12); BE (2); DK (2); HK (1); ES (2); CA (4); BU (7); LI (4); FI (3); US (23); TU (10); ME (3); CZ (4); RO (8); CN (28); TW (5); IT (14); JP (14); DE (6); PL (8); SE (2); UA (8)