Relapsing Forms of multiple sclerosis (RMS) study of Bruton's Tyrosine Kinase (BTK) inhibitor Tolebrutinib (SAR442168)

JRCT ID: jRCT2021200035

Registered date:24/12/2020

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Relapsing Multiple Sclerosis
• Date of first enrollment: 22/02/2021
• Target sample size: 900
• Countries of recruitment: Bulgaria,Japan,Canada,Japan,Czechia,Japan,Estonia,Japan,Spain,Japan,United States,Japan,Belarus,Japan,China,Japan,Finland,Japan,Germany,Japan,Italy,Japan,Lithuania,Japan,Poland,Japan,Romania,Japan,Russian Federation,Japan,Sweden,Japan,Taiwan,Japan,Turkey,Japan,Ukraine,Japan,Denmark,Japan,Austria,Japan,Mexico,Japan
• Study type: Interventional

Intervention(s)

Drug: SAR442168 (Tolebrutinib)
Pharmaceutical form: Tablet, Route of administration: Oral
Drug: Placebo to match SAR442168 (Tolebrutinib)
Pharmaceutical form: Tablet, Route of administration: Oral
Drug: Teriflunomide HMR1726
Pharmaceutical form: Tablet, Route of administration: Oral
Drug: Placebo to match Teriflunomide
Pharmaceutical form: Tablet, Route of administration: Oral

Outcome(s)

Primary Outcome

1. Annualized Adjudicated Relapse Rate : Number of confirmed adjudicated protocol defined relapses [ Time Frame: Up to approximately 36 months ]
Number of confirmed adjudicated protocol defined relapses

Secondary Outcome

1. Time to onset of confirmed disability worsening confirmed over at least 6 months [ Time Frame: Up to approximately 36 months ]
Time to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows:
- increase of >= 1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0 OR
- increase of >= 1.0 point from the baseline EDSS score when the baseline score is 0.5 to <= 5.5 OR
- increase of >= 0.5 point from the baseline EDSS score when the baseline score is >5.5 - 5.
2. Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 months [ Time Frame: Up to approximately 36 months ]
3. Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from Month 6 through the end of study (EOS) [ Time Frame: From 6 months up to approximately 36 months ]"
4. Total of Gd-enhancing T1 hyperintense lesions as detected by MRI from 6 months through the EOS [ Time Frame: From 6 months up to approximately 36 months ]
5. Change in cognitive function [ Time Frame: From Baseline up to approximately 36 months ]
Change in cognitive function from baseline to the end of study (EOS) as assessed by SDMT and by CVLT-II where available
6. Time to confirmed disability improvement [ Time Frame: From Baseline up to approximately 36 months ]
Time to confirmed disability improvement (CDI), defined as a >= 1.0 point decrease on the EDSS from the baseline EDSS score confirmed over at least 6 months
7. Percent Change in Brain volume loss (BVL) [ Time Frame: From 6 months up to approximately 36 months ]
Brain volume loss (BVL) rate as detected by brain MRI from Month 6 to the EOS
8. Change in Multiple Sclerosis Quality of Life [ Time Frame: From Baseline up to approximately 36 months ]
Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
9. Number of participants with adverse events A(Es) leading to permanent study intervention discontinuation, and adverse events of special interest (AESI) [ Time Frame: From screening until end of study approximately 36 months ]
10. Population Pharmacokinetics - Concentration SAR442168 and relevant metabolites at 6 months [ Time Frame: 6 Months ]
Plasma concentration of SAR442168 (population PK assessment) at 6 Months
11. Population Pharmacokinetics Concentration of SAR442168 and relevant metabolites at 9 Months [ Time Frame: 9 Months ]
Plasma concentration of SAR442168 (population PK assessment) at 9 Months
12. Population Pharmacokinetics - Concentration of SAR442168 and relevant metabolites at 12 Months [ Time Frame: 12 Months ]
Plasma concentration of SAR442168 (population PK assessment) at 12 Months
13. Change in plasma NfL [ Time Frame: From Baseline until end of study approximately 36 months ]
Change in plasma neurofilament light chain (NfL) levels at the EOS compared to baseline
14. Change in lymphocyte Phenotype [ Time Frame: From Baseline until end of study approximately 36 months ]
Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants.
15. Changes in serum Immunoglobulin levels [ Time Frame: From Baseline until end of study (up to 36 months) ]
Changes in serum immunoglobulin level at the EOS compared to baseline
16. Change in CHI3L1 levels [ Time Frame: From Baseline until end of study approximately 36 months ]
Change in serum Chi3L1 levels at the EOS compared to baseline

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: <= 55age old
• Gender: Both

Include 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:
a) >=1 documented relapse within the previous year OR
b) >=2 documented relapses within the previous 2 years, OR
c) >=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 Woman of child-bearing potential (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 24 hours 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.

Exclude criteria

Participants are excluded from the study if any of the following criteria apply:
- 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, 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

- 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/microL 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.

Related Information

• Primary Sponsor: Tanaka Tomoyuki
• Secondary ID(s): NCT04410978,2020-000637-41