Primary progressive multiple sclerosis (PPMS) Study of Bruton's tyrosine kinase (BTK) inhibitor SAR442168

JRCT ID: jRCT2021200028

Registered date:18/11/2020

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Primary Progressive Multiple Sclerosis
• Date of first enrollment: 21/01/2021
• Target sample size: 700
• Countries of recruitment: Bulgaria,Japan,Canada,Japan,Chile,Japan,Czechia,Japan,Estonia,Japan,France,Japan,India,Japan,Latvia,Japan,Poland,Japan,Romania,Japan,Russian Federation,Japan,Spain,Japan,Ukraine,Japan,United States,Japan,Argentina,Japan,Australia,Japan,Austria,Japan,Belarus,Japan,Belgium,Japan,China,Japan,Colombia,Japan,Croatia,Japan,Denmark,Japan,Germany,Japan,Greece,Japan,Hungary,Japan,Israel,Japan,Italy,Japan,Mexico,Japan,Netherlands,Japan,Norway,Japan,Peru,Japan,Portugal,Japan,Serbia,Japan,Sweden,Japan,Turkey,Japan,United Kingdom,Japan,Georgia,Japan,Singapore,Japan,South Africa,Japan
• Study type: Interventional

Intervention(s)

Drug: SAR442168 (Tolebrutininb)
Pharmaceutical form: Film-coated Tablet, Route of administration: Oral, Dose 1 of oral SAR442168 daily
Drug: Placebo
Pharmaceutical form: Film-coated Tablet, Route of administration: Oral, Placebo to match the SAR442168 daily

Outcome(s)

Primary Outcome

1. 3 month composite Confirmed Disability Progression (cCDP) [ Time Frame: Up to approximately 60 months ]
Time to onset of 3 month cCDP defined as follows:
Increase over at least 3 months of >=1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is <=5.5, or >=0.5 points when the baseline EDSS score is >5.5, or >=20% from the baseline T25-FW, or >=20% from the baseline 9-HPT

Secondary Outcome

1. 6-month Confirmed Disability Progression (CDP) [ Time Frame: Up to approximately 60 months ]
Time to onset of 6-month CDP as assessed by EDSS score
2. 6-month composite Confirmed Disability Progression (cCDP) [ Time Frame: Up to approximately 60 months ]
Time to onset of 6-month cCDP
3. Change in T2 hyperintense lesions by MRI [ Time Frame: From screening MRI to approximately 60 months ]
Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI after baseline up to and including the end of study (EOS)
4. Time to onset of confirmed disability improvement (CDI) [ Time Frame: Up to approximately 60 months ]
Time to onset of CDI defined as >=1.0-point decrease on the EDSS score from baseline confirmed over at least 6 months
5. Percent change in Brain volume (BV) [ Time Frame: From 6 months up to approximately 60 months ]
Percent change in brain volume (BV) as detected by brain MRI at the EOS compared to month 6
6. Change in cognitive function as assessed by SDMT [ Time Frame: From Baseline up to approximately 60 months ]
Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT)
7. Change in cognitive function as assessed by the CVLT-II [ Time Frame: From Baseline up to approximately 60 months ]
Change in cognitive function at the EOS compared to baseline as assessed by the California Verbal Learning Test II(CVLT-II) where available
8. Change in Multiple Sclerosis Quality of Life [ Time Frame: From Baseline up to approximately 60 months ]
Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) at the EOS compared to baseline
9. Safety and Tolerability [ Time Frame: From screening up to approximately 60 months ]
Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
10. Population pharmacokinetics [ Time Frame: Months 6, 9 and 12 ]
Plasma concentration of SAR442168 (population PK assessment) at Months 6, 9, and 12
11. Change in plasma neurofilament light chain (NfL) [ Time Frame: From Baseline up to approximately 60 months ]
Change in NfL levels from at the EOS compared to baseline
12. Change in lymphocyte phenotype subsets [ Time Frame: From Baseline up to approximately 60 months ]
Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants
13. Changes in serum Immunoglobulin level [ Time Frame: From Baseline up to approximately 60 months ]
Changes in serum Immunoglobulin level at the EOS compared to baseline
14. Change in serum chitinase-3 like protein 1 (Chi3L1) [ Time Frame: From Baseline up to approximately 60 months ]
Change in serum Chi3L1 at EOS compared to baseline

Key inclusion & exclusion criteria

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

Include criteria

- 18 to 55 years of age inclusive
- Diagnosis of PPMS according to the 2017 McDonald criteria
- Expanded disability status scale (EDSS) score between 2.0 to 6.5 points, at screening inclusive
- Positive cerebrospinal fluid oligoclonal bands and/or elevated Immunoglobulin G (IgG) index either during screening or documented previous history
- Contraceptive use consistent with local regulations for individuals participating in clinical studies
- Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of child bearing potential (WOCBP) or Is a WOCBP and agrees to use an acceptable contraceptive method
- The participant must not have access to ocrelizumab (eg, ocrelizumab not available on the national market or not reimbursed for the approved indication)
- The participant must have access to and be eligible to be treated with ocrelizumab but: 1) does not tolerate it due to side effects or safety reasons; and/or 2) has failed ocrelizumab treatment due to perceived lack of efficacy

Exclude criteria

- Participant has conditions that would adversely affect study participation such as short life expectancy.
- Evidence of infection with human immunodeficiency virus (HIV), transplantation, progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infection that would adversely affect study participation.
- Persistent chronic or active or recurring system infection that may adversely affect participation or IMP administration in this study as judged by the investigator.
- History of malignancy within 5 years prior to screening.
- History of alcohol or drug abuse within 1 year prior to Screening.
- Hospitalized for psychiatric disease within 2 years prior to Screening.
- Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.
- 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.
- A history of significant bleeding event within 6 months prior to screening, according to the Investigator's judgment such as, but not limited to cerebral or gastrointestinal.
- Lymphocyte count below the lower limit of normal at Screening.
- Recent live (attenuated) vaccine within 2 months before the first treatment visit.
- Recent major surgery (within 4 weeks of Screening) or planned major surgery during the study.
- The participant has received medications/treatments for MS within a specified time frame.
- Receiving potent and moderate inducers of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes.
- Receiving anticoagulant or antiplatelet therapy (such as aspirin >81mg/day, clopidogrel, warfarin).
- Contraindications to magnetic resonance imaging (MRI).

NOTE: Other Inclusion/Exclusion criteria may apply.

Related Information

• Primary Sponsor: Tanaka Tomoyuki
• Secondary ID(s): NCT04458051,2020-000645-14