Clinical trial NCT04410978: Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1)
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: 974
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 population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168

Detailed description: This was an event-driven (6-month confirmed disability worsening \[CDW\]) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 48 months).

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)
* A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24hours before the first dose of study intervention.
* If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
* The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
* The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant's legally authorized representative

Exclusion criteria:

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

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

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

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

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 Treatment-emergent 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: Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite
timeFrame: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite
timeFrame: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
measure: Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite
timeFrame: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
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 Cluster of Differentiation (CD)19+ B Cells 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: Birmingham
country: United States
facility: University of Alabama MS Center-Site Number:8400013
state: Alabama
city: San Francisco
country: United States
facility: University of San Francisco, Sandler Neurosciences Center-Site Number:8400137
state: California
city: Aurora
country: United States
facility: University of Colorado-Site Number:8400012
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center-Site Number:8400119
state: District of Columbia
city: Fort Myers
country: United States
facility: Beth Israel Deaconess Medical Center-Site Number:8400064
state: Florida
city: Tampa
country: United States
facility: Axiom Clinical Research of Florida-Site Number:8400001
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: Boston
country: United States
facility: Tufts Medical Center-Site Number:8400072
state: Massachusetts
city: Farmington Hills
country: United States
facility: Michigan Institute For Neurological Disorders-Site Number:8400058
state: Michigan
city: Owosso
country: United States
facility: The Memorial Hospital-Site Number:8400033
state: Michigan
city: Ozark
country: United States
facility: Sharlin Health & Neurology-Site Number:8400093
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center-Site Number:8400019
state: Missouri
city: Raleigh
country: United States
facility: Meridian Clinical Research, LLC-Site Number:8400005
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center-Site Number:8400116
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center-Site Number:8400150
state: Ohio
city: Columbus
country: United States
facility: Optimed Research, LTD-Site Number:8400147
state: Ohio
city: Westerville
country: United States
facility: Columbus Neuroscience-Site Number:8400010
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Medical Research Foundation-Site Number:8400018
state: Oklahoma
city: Portland
country: United States
facility: Providence Multiple Sclerosis Center-Site Number:8400020
state: Oregon
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center-Site Number:8400077
state: Texas
city: Seattle
country: United States
facility: Multiple Sclerosis Center, Swedish Neuroscience Institute-Site Number:8400121
state: Washington
city: Linz
country: Austria
facility: Investigational Site Number :0400004
city: Vitebsk
country: Belarus
facility: Investigational Site Number :1120005
city: Vitebsk
country: Belarus
facility: Investigational Site Number :1120004
city: Pleven
country: Bulgaria
facility: Investigational Site Number :1000002
city: Plovdiv
country: Bulgaria
facility: Investigational Site Number :1000005
city: Sofia
country: Bulgaria
facility: Investigational Site Number :1000004
city: Sofia
country: Bulgaria
facility: Investigational Site Number :1000008
city: Sofia
country: Bulgaria
facility: Investigational Site Number :1000001
city: Sofia
country: Bulgaria
facility: Investigational Site Number :1000006
city: Sofia
country: Bulgaria
facility: Investigational Site Number :1000009
city: Vancouver
country: Canada
facility: Investigational Site Number :1240016
state: British Columbia
city: Ottawa
country: Canada
facility: Investigational Site Number :1240003
state: Ontario
city: Toronto
country: Canada
facility: Investigational Site Number :1240013
state: Ontario
city: Gatineau
country: Canada
facility: Investigational Site Number :1240006
state: Quebec
city: Baotou
country: China
facility: Investigational Site Number :1560022
city: Beijing
country: China
facility: Investigational Site Number :1560006
city: Beijing
country: China
facility: Investigational Site Number :1560010
city: Beijing
country: China
facility: Investigational Site Number :1560012
city: Beijing
country: China
facility: Investigational Site Number :1560023
city: Beijing
country: China
facility: Investigational Site Number :1560001
city: Beijing
country: China
facility: Investigational Site Number :1560009
city: Beijing
country: China
facility: Investigational Site Number :1560025
city: Beijing
country: China
facility: Investigational Site Number :1560021
city: Changchun
country: China
facility: Investigational Site Number :1560004
city: Changsha
country: China
facility: Investigational Site Number :1560015
city: Chengdu
country: China
facility: Investigational Site Number :1560005
city: Chongqing
country: China
facility: Investigational Site Number :1560019
city: Fuzhou
country: China
facility: Investigational Site Number :1560035
city: Guangzhou
country: China
facility: Investigational Site Number :1560016
city: Guangzhou
country: China
facility: Investigational Site Number :1560028
city: Guangzhou
country: China
facility: Investigational Site Number :1560002
city: Hohhot
country: China
facility: Investigational Site Number :1560027
city: Nanjing
country: China
facility: Investigational Site Number :1560044
city: Nanjing
country: China
facility: Investigational Site Number :1560042
city: Shanghai
country: China
facility: Investigational Site Number :1560003
city: Shenyang
country: China
facility: Investigational Site Number :1560018
city: Shijiazhuang
country: China
facility: Investigational Site Number :1560014
city: Taiyuan
country: China
facility: Investigational Site Number :1560008
city: Tianjin
country: China
facility: Investigational Site Number :1560020
city: Wuhan
country: China
facility: Investigational Site Number :1560011
city: Xi'an
country: China
facility: Investigational Site Number :1560017
city: Yinchuan
country: China
facility: Investigational Site Number :1560033
city: Hradec Kralove
country: Czechia
facility: Investigational Site Number :2030004
city: Pardubice
country: Czechia
facility: Investigational Site Number :2030009
city: Teplice
country: Czechia
facility: Investigational Site Number :2030003
city: Zlin
country: Czechia
facility: Investigational Site Number :2030007
city: Esbjerg
country: Denmark
facility: Investigational Site Number :2080001
city: Holstebro
country: Denmark
facility: Investigational Site Number :2080005
city: Tallinn
country: Estonia
facility: Investigational Site Number :2330001
city: Tartu
country: Estonia
facility: Investigational Site Number :2330002
city: Helsinki
country: Finland
facility: Investigational Site Number :2460003
city: Tampere
country: Finland
facility: Investigational Site Number :2460001
city: Turku
country: Finland
facility: Investigational Site Number :2460002
city: Dresden
country: Germany
facility: Investigational Site Number :2760001
city: Düsseldorf
country: Germany
facility: Investigational Site Number :2760019
city: Hamburg
country: Germany
facility: Investigational Site Number :2760016
city: Münster
country: Germany
facility: Investigational Site Number :2760008
city: Rostock
country: Germany
facility: Investigational Site Number :2760004
city: Ulm
country: Germany
facility: Investigational Site Number :2760011
city: Shatin, NT
country: Hong Kong
facility: Investigational Site Number : 3440001
city: Pozzilli
country: Italy
facility: Investigational Site Number :3800002
state: Isernia
city: Orbassano
country: Italy
facility: Investigational Site Number :3800007
state: Torino
city: Bergamo
country: Italy
facility: Investigational Site Number :3800011
city: Catania
country: Italy
facility: Investigational Site Number :3800015
city: Firenze
country: Italy
facility: Investigational Site Number :3800012
city: Genova
country: Italy
facility: Investigational Site Number :3800014
city: Milano
country: Italy
facility: Investigational Site Number :3800001
city: Milano
country: Italy
facility: Investigational Site Number :3800010
city: Napoli
country: Italy
facility: Investigational Site Number :3800003
city: Napoli
country: Italy
facility: Investigational Site Number :3800006
city: Pavia
country: Italy
facility: Investigational Site Number :3800008
city: Roma
country: Italy
facility: Investigational Site Number :3800005
city: Roma
country: Italy
facility: Investigational Site Number :3800009
city: Roma
country: Italy
facility: Investigational Site Number :3800013
city: Chiba-shi
country: Japan
facility: Investigational Site Number :3920016
state: Chiba
city: Koriyama-shi
country: Japan
facility: Investigational Site Number :3920008
state: Fukushima
city: Tsukuba-shi
country: Japan
facility: Investigational Site Number :3920012
state: Ibaraki
city: Morioka-shi
country: Japan
facility: Investigational Site Number :3920022
state: Iwate
city: Niigata-shi
country: Japan
facility: Investigational Site Number :3920005
state: Niigata
city: Moriguchi-shi
country: Japan
facility: Investigational Site Number :3920004
state: Osaka
city: Osaka-shi
country: Japan
facility: Investigational Site Number :3920001
state: Osaka
city: Kawagoe-shi
country: Japan
facility: Investigational Site Number :3920018
state: Saitama
city: Bunkyo-ku
country: Japan
facility: Investigational Site Number :3920014
state: Tokyo
city: Kodaira-shi
country: Japan
facility: Investigational Site Number :3920003
state: Tokyo
city: Ota-ku
country: Japan
facility: Investigational Site Number :3920010
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Investigational Site Number :3920013
state: Tokyo
city: Ube-shi
country: Japan
facility: Investigational Site Number :3920009
state: Yamaguchi
city: Sagamihara-shi
country: Japan
facility: Investigational Site Number :3920023
city: Kaunas
country: Lithuania
facility: Investigational Site Number :4400003
city: Klaipeda
country: Lithuania
facility: Investigational Site Number :4400002
city: Siauliai
country: Lithuania
facility: Investigational Site Number :4400004
city: Vilnius
country: Lithuania
facility: Investigational Site Number :4400001
city: Mexico
country: Mexico
facility: Investigational Site Number :4840002
city: Mexico
country: Mexico
facility: Investigational Site Number :4840001
city: Veracruz
country: Mexico
facility: Investigational Site Number :4840003
city: Bydgoszcz
country: Poland
facility: Investigational Site Number :6160003
state: Kujawsko-pomorskie
city: Warszawa
country: Poland
facility: Investigational Site Number :6160005
state: Mazowieckie
city: Warszawa
country: Poland
facility: Investigational Site Number :6160006
state: Mazowieckie
city: Glogow Mlp.
country: Poland
facility: Investigational Site Number :6160009
state: Podkarpackie
city: Katowice
country: Poland
facility: Investigational Site Number :6160002
state: Slaskie
city: Katowice
country: Poland
facility: Investigational Site Number :6160004
state: Slaskie
city: Plewiska
country: Poland
facility: Investigational Site Number :6160008
state: Wielkopolskie
city: Lodz
country: Poland
facility: Investigational Site Number :6160001
city: Brasov
country: Romania
facility: Investigational Site Number :6420015
city: Bucuresti
country: Romania
facility: Investigational Site Number :6420008
city: Campulung
country: Romania
facility: Investigational Site Number :6420004
city: Constanta
country: Romania
facility: Investigational Site Number :6420003
city: Oradea
country: Romania
facility: Investigational Site Number :6420010
city: Sibiu
country: Romania
facility: Investigational Site Number :6420005
city: Targu Mures
country: Romania
facility: Investigational Site Number :6420001
city: Timisoara
country: Romania
facility: Investigational Site Number :6420002
city: Krasnoyarsk
country: Russian Federation
facility: Investigational Site Number :6430014
city: Moscow
country: Russian Federation
facility: Investigational Site Number :6430002
city: Moscow
country: Russian Federation
facility: Investigational Site Number :6430008
city: Nizhny Novgorod
country: Russian Federation
facility: Investigational Site Number :6430011
city: Nizhny Novgorod
country: Russian Federation
facility: Investigational Site Number :6430003
city: Pyatigorsk
country: Russian Federation
facility: Investigational Site Number :6430007
city: Rostov-on-Don
country: Russian Federation
facility: Investigational Site Number :6430012
city: Samara
country: Russian Federation
facility: Investigational Site Number :6430005
city: Smolensk
country: Russian Federation
facility: Investigational Site Number :6430009
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number :6430001
city: Tyumen
country: Russian Federation
facility: Investigational Site Number :6430006
city: Ufa
country: Russian Federation
facility: Investigational Site Number :6430004
city: Sevilla
country: Spain
facility: Investigational Site Number :7240003
state: Andalucia
city: Barcelona
country: Spain
facility: Investigational Site Number :7240009
state: Barcelona [Barcelona]
city: Pozuelo De Alarcón
country: Spain
facility: Investigational Site Number :7240001
state: Madrid
city: Donostia
country: Spain
facility: Investigational Site Number :7240008
state: Pais Vasco
city: Córdoba
country: Spain
facility: Investigational Site Number :7240004
city: Murcia
country: Spain
facility: Investigational Site Number :7240006
city: Málaga
country: Spain
facility: Investigational Site Number :7240005
city: Valencia
country: Spain
facility: Investigational Site Number :7240007
city: Göteborg
country: Sweden
facility: Investigational Site Number :7520001
city: Stockholm
country: Sweden
facility: Investigational Site Number :7520002
city: Hsinchu City
country: Taiwan
facility: Investigational Site Number :1580007
city: Kaohsiung
country: Taiwan
facility: Investigational Site Number :1580005
city: Taichung
country: Taiwan
facility: Investigational Site Number :1580003
city: Taipei
country: Taiwan
facility: Investigational Site Number :1580002
city: Taoyuang
country: Taiwan
facility: Investigational Site Number :1580006
city: Eskisehir
country: Turkey
facility: Investigational Site Number :7920005
city: Hatay
country: Turkey
facility: Investigational Site Number :7920011
city: Istanbul
country: Turkey
facility: Investigational Site Number :7920002
city: Istanbul
country: Turkey
facility: Investigational Site Number :7920009
city: Istanbul
country: Turkey
facility: Investigational Site Number :7920007
city: Istanbul
country: Turkey
facility: Investigational Site Number :7920003
city: Izmir
country: Turkey
facility: Investigational Site Number :7920008
city: Izmir
country: Turkey
facility: Investigational Site Number :7920010
city: Kocaeli
country: Turkey
facility: Investigational Site Number :7920001
city: Mersin
country: Turkey
facility: Investigational Site Number :7920006
city: Ivano-Frankivsk
country: Ukraine
facility: Investigational Site Number :8040011
city: Kharkiv
country: Ukraine
facility: Investigational Site Number :8040016
city: Kharkiv
country: Ukraine
facility: Investigational Site Number :8040013
city: Kherson
country: Ukraine
facility: Investigational Site Number :8040008
city: Kyiv
country: Ukraine
facility: Investigational Site Number :8040014
city: Lutsk
country: Ukraine
facility: Investigational Site Number :8040010
city: Lviv
country: Ukraine
facility: Investigational Site Number :8040001
city: Odesa
country: Ukraine
facility: Investigational Site Number :8040009
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: