Clinical trial NCT04410991: Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2)
Official title: A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsing Multiple Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2020-06-01
Enrollment: 899
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses
timeFrame: Baseline (Day 1) to approximately 48 months
Secondary outcomes:
measure: Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
timeFrame: Baseline (Day 1) to approximately 48 months
measure: Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
timeFrame: Baseline (Day 1) to approximately 48 months
measure: Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year
timeFrame: Baseline (Day 1) to approximately 48 months
measure: Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan
timeFrame: Baseline (Day 1) to approximately 48 months
measure: Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS
timeFrame: Baseline (Day 1) to EOS (up to approximately 48 months)
measure: Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS
timeFrame: Baseline (Day 1) to EOS (up to approximately 48 months)
measure: Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale
timeFrame: Baseline (Day 1) to approximately 48 months
measure: Percent Change in Brain Volume Loss at EOS Compared to Month 6
timeFrame: Month 6 to EOS (up to approximately 48 months)
measure: Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS
timeFrame: Baseline (Day 1) to EOS (up to approximately 48 months)
measure: 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)
timeFrame: 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
measure: Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS
timeFrame: Baseline (Day 1) to EOS (up to approximately 48 months)
measure: Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS
timeFrame: Baseline (Day 1) to EOS (up to approximately 48 months)
Other outcomes:
Locations:
city: Cullman
country: United States
facility: North Central Neurology Associates, PC-Site Number:8400009
state: Alabama
city: Phoenix
country: United States
facility: Center for Neurology and Spine-Site Number:8400089
state: Arizona
city: Arcadia
country: United States
facility: Arcadia Neurology Center-Site Number:8400070
state: California
city: Newport Beach
country: United States
facility: Multiple Sclerosis Center of California-Site Number:8400135
state: California
city: Torrance
country: United States
facility: Harbor UCLA-Site Number:8400088
state: California
city: Basalt
country: United States
facility: Mountain Neurological Research Center, Inc.-Site Number:8400128
state: Colorado
city: Fort Collins
country: United States
facility: Advanced Neurosciences Research-Site Number:8400025
state: Colorado
city: Boca Raton
country: United States
facility: South Florida Neurology Associates-Site Number:8400029
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health-Site Number:8400159
state: Florida
city: Maitland
country: United States
facility: Neurology Associates, PA-Site Number:8400004
state: Florida
city: Miami
country: United States
facility: University of Miami-Site Number:8400063
state: Florida
city: Sunrise
country: United States
facility: Infinity Clinical Research-Site Number:8400008
state: Florida
city: Tampa
country: United States
facility: University of South Florida-Site Number:8400006
state: Florida
city: Savannah
country: United States
facility: Meridian Clinical Research-Site Number:8400003
state: Georgia
city: Northbrook
country: United States
facility: Consultants In Neurology-Site Number:8400011
state: Illinois
city: Springfield
country: United States
facility: Prairie Education and Research Cooperative-Site Number:8400071
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Neurological Center-Site Number:8400039
state: Indiana
city: Lexington
country: United States
facility: CHI Saint Joseph Medical Group Neurology-Site Number:8400110
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky-Site Number:8400106
state: Kentucky
city: Louisville
country: United States
facility: Norton Neurology MS Services-Site Number:8400127
state: Kentucky
city: Baton Rouge
country: United States
facility: The NeuroMedical Center-Site Number:8400057
state: Louisiana
city: Lutherville-Timonium
country: United States
facility: International Neurorehabilitation Institute-Site Number:8400034
state: Maryland
city: Detroit
country: United States
facility: Wayne State University-Site Number:8400046
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis Clinic of Neurology-Site Number:8400051
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital-Site Number:8400153
state: Missouri
city: Omaha
country: United States
facility: West Omaha Family Physicians-Site Number:8400139
state: Nebraska
city: Omaha
country: United States
facility: University Of Nebraska-Site Number:8400129
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Hospital-Site Number:8400047
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico-Site Number:8400032
state: New Mexico
city: Patchogue
country: United States
facility: South Shore Neurologic Associates-Site Number:8400100
state: New York
city: Charlotte
country: United States
facility: Novant Health Multiple Sclerosis Care Center - South Park-Site Number:8400120
state: North Carolina
city: Raleigh
country: United States
facility: Meridian Clinical Research, LLC-Site Number:8400005
state: North Carolina
city: Fargo
country: United States
facility: Sanford Brain & Spine Center-Site Number:8400126
state: North Dakota
city: Centerville
country: United States
facility: Dayton Center for Neurological Disorders-Site Number:8400081
state: Ohio
city: Philadelphia
country: United States
facility: Jefferson Neurology Associates-Site Number:8400016
state: Pennsylvania
city: Greer
country: United States
facility: Premier Neurology-Site Number:8400069
state: South Carolina
city: Franklin
country: United States
facility: Advanced Neuroscience Center-Site Number:8400035
state: Tennessee
city: Knoxville
country: United States
facility: Sibyl Wray, MD, Neurology, PC-Site Number:8400007
state: Tennessee
city: Katy
country: United States
facility: Mt Olympus Medical Research-Site Number:8400163
state: Texas
city: San Antonio
country: United States
facility: Neurology Center of San Antonio-Site Number:8400036
state: Texas
city: Sherman
country: United States
facility: Texas Institute for Neuroogical Disorders-Sherman-Site Number:8400151
state: Texas
city: Richmond
country: United States
facility: Neurological Associates-Site Number:8400097
state: Virginia
city: Milwaukee
country: United States
facility: Wheaton Franciscan Healthcare-Site Number:8400022
state: Wisconsin
city: Caba
country: Argentina
facility: Investigational Site Number :0320004
state: Buenos Aires
city: Capital Federal
country: Argentina
facility: Investigational Site Number :0320002
state: Buenos Aires
city: Caba
country: Argentina
facility: Investigational Site Number :0320001
state: Ciudad De Buenos Aires
city: Rosario
country: Argentina
facility: Investigational Site Number :0320003
state: Santa Fe
city: San Miguel de Tucuman
country: Argentina
facility: Investigational Site Number :0320005
city: Brugge
country: Belgium
facility: Investigational Site Number :0560005
city: Gent
country: Belgium
facility: Investigational Site Number :0560004
city: Mons
country: Belgium
facility: Investigational Site Number :0560002
city: Pelt
country: Belgium
facility: Investigational Site Number :0560001
city: Porto Alegre
country: Brazil
facility: Investigational Site Number :0760001
state: Rio Grande Do Sul
city: Curitiba
country: Brazil
facility: Investigational Site Number :0760002
city: Sao Paulo
country: Brazil
facility: Investigational Site Number :0760007
city: Edmonton
country: Canada
facility: Investigational Site Number :1240002
state: Alberta
city: Hamilton
country: Canada
facility: Investigational Site Number : 1240012
state: Ontario
city: London
country: Canada
facility: Investigational Site Number :1240014
state: Ontario
city: Greenfield Park
country: Canada
facility: Investigational Site Number :1240005
state: Quebec
city: Gatineau
country: Canada
facility: Investigational Site Number :1240006
city: Quebec
country: Canada
facility: Investigational Site Number :1240021
city: Santiago
country: Chile
facility: Investigational Site Number :1520002
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number :1520005
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number :1520001
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number :1520003
state: Reg Metropolitana De Santiago
city: Concepción
country: Chile
facility: Investigational Site Number :1520006
city: Valdivia
country: Chile
facility: Investigational Site Number :1520004
city: Zagreb
country: Croatia
facility: Investigational Site Number :1910001
city: Zagreb
country: Croatia
facility: Investigational Site Number :1910002
city: Zagreb
country: Croatia
facility: Investigational Site Number :1910003
city: Brno
country: Czechia
facility: Investigational Site Number :2030002
city: Hradec Kralove
country: Czechia
facility: Investigational Site Number :2030011
city: Jihlava
country: Czechia
facility: Investigational Site Number :2030001
city: Praha 10
country: Czechia
facility: Investigational Site Number :2030008
city: Praha 5 - Motol
country: Czechia
facility: Investigational Site Number :2030005
city: Besancon
country: France
facility: Investigational Site Number :2500019
city: Bordeaux
country: France
facility: Investigational Site Number :2500018
city: Bron
country: France
facility: Investigational Site Number :2500011
city: Clermont Ferrand
country: France
facility: Investigational Site Number :2500005
city: Montpellier
country: France
facility: Investigational Site Number :2500006
city: Nantes
country: France
facility: Investigational Site Number :2500010
city: Nice
country: France
facility: Investigational Site Number :2500002
city: Nimes
country: France
facility: Investigational Site Number :2500017
city: Paris
country: France
facility: Investigational Site Number :2500007
city: Poissy
country: France
facility: Investigational Site Number :2500004
city: Rennes
country: France
facility: Investigational Site Number :2500003
city: Strasbourg
country: France
facility: Investigational Site Number :2500001
city: Bayreuth
country: Germany
facility: Investigational Site Number :2760005
city: Berlin
country: Germany
facility: Investigational Site Number :2760015
city: Berlin
country: Germany
facility: Investigational Site Number :2760014
city: Bochum
country: Germany
facility: Investigational Site Number :2760020
city: Essen
country: Germany
facility: Investigational Site Number :2760012
city: Würzburg
country: Germany
facility: Investigational Site Number :2760003
city: Athens
country: Greece
facility: Investigational Site Number :3000001
city: Athens
country: Greece
facility: Investigational Site Number :3000006
city: Athens
country: Greece
facility: Investigational Site Number :3000002
city: Athens
country: Greece
facility: Investigational Site Number :3000007
city: Athens
country: Greece
facility: Investigational Site Number :3000009
city: Larissa
country: Greece
facility: Investigational Site Number :3000004
city: Thessaloniki
country: Greece
facility: Investigational Site Number :3000003
city: Budapest
country: Hungary
facility: Investigational Site Number :3480105
city: Budapest
country: Hungary
facility: Investigational Site Number :3480102
city: Kaposvár
country: Hungary
facility: Investigational Site Number :3480106
city: Tatabánya
country: Hungary
facility: Investigational Site Number :3480103
city: Chandigarh
country: India
facility: Investigational Site Number :3560005
city: Gurgaon
country: India
facility: Investigational Site Number :3560007
city: Gurgaon
country: India
facility: Investigational Site Number :3560008
city: New Delhi
country: India
facility: Investigational Site Number :3560002
city: Thiruvananthapuram
country: India
facility: Investigational Site Number :3560004
city: Ashkelon
country: Israel
facility: Investigational Site Number :3760002
city: Haifa
country: Israel
facility: Investigational Site Number :3760003
city: Rehovot
country: Israel
facility: Investigational Site Number :3760006
city: Safed
country: Israel
facility: Investigational Site Number :3760004
city: Tel HaShomer
country: Israel
facility: Investigational Site Number :3760001
city: Goyang-si
country: Korea, Republic of
facility: Investigational Site Number :4100001
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number :4100003
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number :4100006
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number :4100002
state: Seoul-teukbyeolsi
city: Riga
country: Latvia
facility: Investigational Site Number :4280002
city: Riga
country: Latvia
facility: Investigational Site Number :4280003
city: Amsterdam
country: Netherlands
facility: Investigational Site Number :5280001
city: Namsos
country: Norway
facility: Investigational Site Number :5780002
city: Oslo
country: Norway
facility: Investigational Site Number :5780001
city: Braga
country: Portugal
facility: Investigational Site Number :6200001
city: Coimbra
country: Portugal
facility: Investigational Site Number :6200005
city: Lisboa
country: Portugal
facility: Investigational Site Number :6200011
city: Lisboa
country: Portugal
facility: Investigational Site Number :6200006
city: Matosinhos
country: Portugal
facility: Investigational Site Number :6200002
city: Porto
country: Portugal
facility: Investigational Site Number :6200010
city: Santa Maria da Feira
country: Portugal
facility: Investigational Site Number :6200004
city: Guaynabo
country: Puerto Rico
facility: San Juan MS Center-Site Number:8400015
city: Barnaul
country: Russian Federation
facility: Investigational Site Number :6430006
city: Bryansk
country: Russian Federation
facility: Investigational Site Number :6430013
city: Ekaterinburg
country: Russian Federation
facility: Investigational Site Number :6430012
city: Kazan
country: Russian Federation
facility: Investigational Site Number :6430001
city: Kirov
country: Russian Federation
facility: Investigational Site Number :6430010
city: Moscow
country: Russian Federation
facility: Investigational Site Number :6430007
city: Moscow
country: Russian Federation
facility: Investigational Site Number :6430005
city: Novosibirsk
country: Russian Federation
facility: Investigational Site Number :6430003
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number :6430014
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number :6430002
city: Saransk
country: Russian Federation
facility: Investigational Site Number :6430011
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number :6430004
city: Belgrade
country: Serbia
facility: Investigational Site Number :6880001
city: Belgrade
country: Serbia
facility: Investigational Site Number :6880003
city: Belgrade
country: Serbia
facility: Investigational Site Number :6880006
city: Kragujevac
country: Serbia
facility: Investigational Site Number :6880002
city: Nis
country: Serbia
facility: Investigational Site Number :6880004
city: Novi Sad
country: Serbia
facility: Investigational Site Number :6880005
city: Bratislava
country: Slovakia
facility: Investigational Site Number :7030001
city: Martin
country: Slovakia
facility: Investigational Site Number :7030002
city: Nitra
country: Slovakia
facility: Investigational Site Number :7030004
city: Sevilla
country: Spain
facility: Investigational Site Number :7240011
state: Andalucia
city: Barcelona
country: Spain
facility: Investigational Site Number :7240006
state: Barcelona [Barcelona]
city: Barakaldo
country: Spain
facility: Investigational Site Number :7240009
state: Bizkaia
city: Salt
country: Spain
facility: Investigational Site Number :7240004
state: Girona [Gerona]
city: Las Palmas de Gran Canaria
country: Spain
facility: Investigational Site Number :7240013
state: Las Palmas
city: Hospitalet de Llobregat
country: Spain
facility: Investigational Site Number :7240007
city: La Coruña
country: Spain
facility: Investigational Site Number :7240008
city: Lleida
country: Spain
facility: Investigational Site Number :7240005
city: Madrid
country: Spain
facility: Investigational Site Number :7240003
city: Madrid
country: Spain
facility: Investigational Site Number :7240001
city: Madrid
country: Spain
facility: Investigational Site Number :7240002
city: Málaga
country: Spain
facility: Investigational Site Number :7240010
city: Pozuelo De Alarcón
country: Spain
facility: Investigational Site Number :7240012
city: Aarau
country: Switzerland
facility: Investigational Site Number :7560003
city: Bern
country: Switzerland
facility: Investigational Site Number :7560002
city: Lugano
country: Switzerland
facility: Investigational Site Number :7560004
city: Ankara
country: Turkey
facility: Investigational Site Number :7920002
city: Besevler / Ankara
country: Turkey
facility: Investigational Site Number :7920005
city: Istanbul
country: Turkey
facility: Investigational Site Number :7920006
city: Kuttahta
country: Turkey
facility: Investigational Site Number :7920004
city: Samsun
country: Turkey
facility: Investigational Site Number :7920001
city: Trabzon
country: Turkey
facility: Investigational Site Number :7920003
city: Chernihiv
country: Ukraine
facility: Investigational Site Number :8040020
city: Chernivtsi
country: Ukraine
facility: Investigational Site Number :8040002
city: Chernivtsi
country: Ukraine
facility: Investigational Site Number :8040019
city: Dnipro
country: Ukraine
facility: Investigational Site Number :8040005
city: Kharkiv
country: Ukraine
facility: Investigational Site Number :8040022
city: Kharkiv
country: Ukraine
facility: Investigational Site Number :8040018
city: Kyiv
country: Ukraine
facility: Investigational Site Number :8040007
city: Lviv
country: Ukraine
facility: Investigational Site Number :8040006
city: Vinnytsia
country: Ukraine
facility: Investigational Site Number :8040003
city: Exeter
country: United Kingdom
facility: Investigational Site Number :8260003
state: Devon
city: Canterbury
country: United Kingdom
facility: Investigational Site Number :8260016
state: Kent
city: Bristol
country: United Kingdom
facility: Investigational Site Number :8260009
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: