Clinical trial NCT03889639: Dose-finding Study for SAR442168 in Relapsing Multiple Sclerosis
Official title: A Phase 2b Dose-finding Study for SAR442168, a Bruton's Tyrosine Kinase Inhibitor, in Participants With Relapsing Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsing Multiple Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2019-03-26
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To determine the dose-response relationship for SAR442168 to reduce the number of new active brain lesions.

Secondary Objectives:

* To evaluate efficacy of SAR442168 on disease activity as assessed by imaging measures.
* To evaluate the safety and tolerability of SAR442168.

Detailed description: The total study duration was 24 weeks which included a screening period of 4 weeks, a treatment period of 16 weeks, and a follow-up period of up to 4 weeks. Participants who completed the Week 16 visit were proposed to be enrolled in a long-term extension safety and efficacy study to assess safety, tolerability and efficacy of SAR442168.

Eligibility criteria: Inclusion criteria:

* Participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent.
* Participant was diagnosed with relapsing multiple sclerosis (RMS) according to the 2017 revision of the McDonald diagnostic criteria.
* Participant must had at least 1 documented relapse within the previous year, OR greater than or equal to (\>=) 2 documented relapses within the previous 2 years, OR \>=1 active Gadolinium (Gd) enhancing brain lesion on an MRI scan in the past 6 months and prior to screening.
* A female participant must had used a double contraception method including a highly effective method of birth control from inclusion and up to 2 months after the last study dose, except if she had undergone sterilization at least 3 months earlier or was postmenopausal. Menopause was defined as being amenorrheic for \>=12 months with serum follicle-stimulating hormone (FSH) level greater than (\>) 30 International Units per liters.
* Male participants, whose partners were of childbearing potential (including breastfeeding women), must had accepted to use, during sexual intercourse, a double contraceptive method according to the following algorithm: (condom) plus (intrauterine device or hormonal contraceptive) from inclusion up to 3 months after the last dose.
* Male participants whose partners were pregnant must had used, during sexual intercourse, a condom from inclusion up to 3 months after the last dose.
* Male participants had agreed not to donate sperm from the inclusion up to 3 months after the last dose.
* Participant had given written informed consent prior to undertaking any study-related procedure.

Exclusion criteria:

* The participant had been diagnosed with primary progressive multiple sclerosis according to the 2017 revision of the McDonald diagnostic criteria or with non relapsing secondary progressive multiple sclerosis.
* Requirement for concomitant treatment that could bias the primary evaluation.
* Contraindication for MRI.
* Contraindications to use MRI Gd contrast-enhancing preparations.
* History of infection with the human immunodeficiency virus (HIV).
* History of active or latent tuberculosis.
* Any other active infections that would adversely affect participation or investigational medicinal product administration in this study, as judged by the Investigator.
* Presence of any screening laboratory or electrocardiogram values outside normal limits that were considered in the Investigator's judgment to be clinically significant.
* Presence of liver injury.
* At screening, the participant was positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or was positive for hepatitis C antibody.
* Bleeding disorder or known platelet dysfunction at any time prior to screening visit.
* Participant had received any live (attenuated) vaccine (including but not limited to varicella zoster, oral polio, and nasal influenza) within 2 months before first treatment visit.
* Participant was receiving strong inducers or inhibitors of cytochrome P450 3A (CYP3A) or CYP2C8 hepatic enzymes.
* Participant was receiving anticoagulant/antiplatelet therapies.
* Participant had taken other investigational drugs within 3 months or 5 half lives, whichever was longer, before screening visit.
* Participant had an Expanded Disability Status Scale score \>5.5 at first screening visit.
* Participant had a relapse in the 30 days prior to randomization.
* Participant was pregnant or a breastfeeding woman.
* History or presence of significant other concomitant illness.
* The participant had received medications/treatments for multiple sclerosis within a specified time frame.

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

Primary outcomes:
measure: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New Gadolinium (Gd) Enhancing T1-hyperintense Lesions
timeFrame: After 12 weeks of SAR442168 treatment for SAR442168 reporting arms (i.e., at Week 12 for Cohort 1 participants, at Week 16 for Cohort 2 participants) and at Week 4 for Cohort 2 placebo
Secondary outcomes:
measure: Number of New or Enlarging T2 Lesions
timeFrame: After 12 weeks of SAR442168 treatment for SAR442168 reporting arms (i.e., at Week 12 for Cohort 1 participants, at Week 16 for Cohort 2 participants), and at Week 4 for Cohort 2 placebo
measure: Total Number of Gd-enhancing T1-hyperintense Lesions
timeFrame: After 12 weeks of SAR442168 treatment for SAR442168 reporting arms (i.e., at Week 12 for Cohort 1 participants, at Week 16 for Cohort 2 participants), and at Week 4 for Cohort 2 placebo
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Weeks 1-4 Period
timeFrame: From Baseline up to Week 4
measure: Number of Participants With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events: SAR442168 Treatment Period
timeFrame: Weeks 1 to 12 for Cohort 1 participants and Weeks 4 to 16 for Cohort 2 participants
measure: Number of Participants With Individual Clinically Relevant Abnormalities in Laboratory Tests (Hematology, Chemistry, Urinalysis), Vital Signs, and Electrocardiograms (ECG)
timeFrame: Baseline up to Week 12 for Cohort 1 participants; Baseline up to Week 4 for Cohort 2 Placebo and from Weeks 4 to 16 for Cohort 2 SAR442168 receiving participants
Other outcomes:
Locations:
city: Cullman
country: United States
facility: Investigational Site Number 8400005
state: Alabama
city: Maitland
country: United States
facility: Investigational Site Number 8400002
state: Florida
city: Sunrise
country: United States
facility: Investigational Site Number 8400004
state: Florida
city: Tampa
country: United States
facility: Investigational Site Number 8400009
state: Florida
city: Savannah
country: United States
facility: Investigational Site Number 8400007
state: Georgia
city: Northbrook
country: United States
facility: Investigational Site Number 8400001
state: Illinois
city: Dayton
country: United States
facility: Investigational Site Number 8400008
state: Ohio
city: Westerville
country: United States
facility: Investigational Site Number 8400006
state: Ohio
city: Knoxville
country: United States
facility: Investigational Site Number 8400003
state: Tennessee
city: Gatineau
country: Canada
facility: Investigational Site Number 1240002
city: Greenfield Park
country: Canada
facility: Investigational Site Number 1240001
city: Vancouver
country: Canada
facility: Investigational Site Number 1240003
city: Brno
country: Czechia
facility: Investigational Site Number 2030007
city: Hradec Kralove
country: Czechia
facility: Investigational Site Number 2030004
city: Jihlava
country: Czechia
facility: Investigational Site Number 2030003
city: Ostrava - Poruba
country: Czechia
facility: Investigational Site Number 2030005
city: Pardubice
country: Czechia
facility: Investigational Site Number 2030006
city: Praha 2
country: Czechia
facility: Investigational Site Number 2030001
city: Praha 5 - Motol
country: Czechia
facility: Investigational Site Number 2030002
city: Tallinn
country: Estonia
facility: Investigational Site Number 2330001
city: Nancy Cedex
country: France
facility: Investigational Site Number 2500004
city: Nantes Cedex 1
country: France
facility: Investigational Site Number 2500001
city: Strasbourg Cedex
country: France
facility: Investigational Site Number 2500002
city: Toulouse Cedex 9
country: France
facility: Investigational Site Number 2500003
city: Amsterdam
country: Netherlands
facility: Investigational Site Number 5280001
city: Sittard-Geleen
country: Netherlands
facility: Investigational Site Number 5280002
city: Kazan
country: Russian Federation
facility: Investigational Site Number 6430006
city: Moscow
country: Russian Federation
facility: Investigational Site Number 6430003
city: Moscow
country: Russian Federation
facility: Investigational Site Number 6430002
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number 6430001
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 6430005
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 6430004
city: Tyumen
country: Russian Federation
facility: Investigational Site Number 6430007
city: Bratislava
country: Slovakia
facility: Investigational Site Number 7030001
city: Martin
country: Slovakia
facility: Investigational Site Number 7030002
city: Barakaldo
country: Spain
facility: Investigational Site Number 7240006
city: Barcelona
country: Spain
facility: Investigational Site Number 7240002
city: Madrid
country: Spain
facility: Investigational Site Number 7240001
city: Murcia
country: Spain
facility: Investigational Site Number 7240004
city: Salt
country: Spain
facility: Investigational Site Number 7240005
city: Sevilla
country: Spain
facility: Investigational Site Number 7240003
city: Chernivtsi
country: Ukraine
facility: Investigational Site Number 8040002
city: Dnipro
country: Ukraine
facility: Investigational Site Number 8040005
city: Lviv
country: Ukraine
facility: Investigational Site Number 8040001
city: Lviv
country: Ukraine
facility: Investigational Site Number 8040006
city: Odesa
country: Ukraine
facility: Investigational Site Number 8040009
city: Vinnytsya
country: Ukraine
facility: Investigational Site Number 8040003
city: Zhytomyr
country: Ukraine
facility: Investigational Site Number 8040007
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Reich DS, Arnold DL, Vermersch P, Bar-Or A, Fox RJ, Matta A, Turner T, Wallstrom E, Zhang X, Mares M, Khabirov FA, Traboulsee A; Tolebrutinib Phase 2b Study Group. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021 Sep;20(9):729-738. doi: 10.1016/S1474-4422(21)00237-4.