Relapsing forms of multiple sclerosis (RMS) study of BTK inhibitor SAR442168 (GEMINI 2)

Phase 3

Completed

• Conditions: Multiple sclerosis,

• Registration Number: CTRI/2020/11/029237
• Lead Sponsor: Sanofi Healthcare India Private Limited

Brief Summary

SAR442168 is expected to reduce MS relapse rate,disability progression, and underlying central nervous system (CNS) damagethrough its dual action on adaptive immunity in the periphery and innateimmunity and the inflammation process in the CNS. The results from the Phase 2btrial (DRI15928) demonstrated a dose–responserelationship for SAR442168 as evidenced by a reduction in the number of newGd-enhancing T1-hyperintense brain lesions detected by brain MRI after 12 weeksof treatment. There was an 85% relative reduction in lesions at 12 weeks in the60 mg dose group as compared with placebo. This was obtained from the negativebinomial regression model adjusted for baseline Gd-enhancing T1-hyperintenselesion activity Approximately 80 to 85 percentof MS patients are initially diagnosed with relapsing remitting multiplesclerosis (RRMS). The current DMTs cannot ensure long-term suppression ofmultiple sclerosis (MS) inflammatory activity including relapse and newmagnetic resonance imaging (MRI) lesion control. Therefore, there is still anunmet need for additional efficacious treatments, especially treatments thattarget disease mechanisms CNS behind a closed or partially closed blood-brainbarrier. In addition, there is still a significant unmet need for therapiesthat target neuroinflammation in the CNS with a goal of halting long-termdisability and neurodegeneration in all diagnostic categories of MS (i.e. RMSas well as progressive forms of the disease, primary progressive MS [PPMS] andsecondary progressive MS [SPMS]). 6 In spite of the effectiveness ofapproved DMTs in preventing acute relapses, abundantevidence suggests that innate immunity, and specifically CNS resident microglialcell activity, is a significant driver of neurodegeneration and disabilityaccumulation in all forms of MS. 1,2  Even the most recent high-efficacy DMTs mainlyact on adaptive immunity in the periphery with only modest ability to slowneuroinflammatory and neurodegenerative processes, as demonstrated by recentstudies in progressive MS. 4,5 The modulation of innate immunity hasthe potential to curtail smoldering neuroinflammation and other manifestationsof disease progression that remain unaddressed by current, approved therapiesand therefore, MS treatments targeting innate immunity with new modes of actionis of interest. This is particularly important for RRMS constituting the majorsubgroup of all MS phenotypes

Detailed Description

Not available

Study Timeline

• Study Start: 2020-01-12
• Last Update Posted: 2023-08-16

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 900

Inclusion Criteria

• The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent.
• Type of participant and disease characteristics I 02.
• The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria (16).
• The participant has an EDSS score ≤5.5 at the first Screening Visit I 04.
• 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 brain lesion on an MRI scan within the previous year.
• Note: The initial clinical demyelinating episode of MS should be counted as a relapse for the first 2 criteria Weight I 05.
• Not applicable.
• Male or Female 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 wishing to conceive a child and female participants becoming pregnant or wishing to become pregnant must permanently discontinue the study intervention and follow the local teriflunomide label recommendation A) Male participants Male participants are eligible to participate if they agree to the following during the intervention period and until the accelerated elimination procedure is performed.
• 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 method 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 B) Female participants 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), with low user dependency, during the intervention period and until the accelerated elimination procedure is completed after the last dose of study intervention A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) 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.
• Additional requirements for pregnancy testing during the study and after study intervention are located in the schedule of activities (SoA) 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, if allowed by local regulations.
• See protocol for country-specific contraception requirements Informed Consent I 07.
• 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

• Participants are excluded from the study if any of the following criteria apply: Medical conditions E 01.
• The participant has been diagnosed with PPMS according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing SPMS.
• The participant has a history of infection or may be at risk for infection: A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solid organ, stem cell, and bone marrow transplantation) and/or antirejection therapy The participant has received any live (attenuated) vaccine (including but not limited to varicella zoster, oral polio, and nasal influenza) within 2 months before the first treatment visit.
• The presence of psychiatric disturbance or substance abuse as evidenced by: A history of any psychiatric disease, behavioral condition, or depression requiring hospitalization within 2 years prior to the Screening Visit E 04.
• The following findings obtained during the screening visit considered in the Investigator’s judgment to be clinically significant: Any screening laboratory values outside normal limits.
• Abnormal ECG.
• Conditions that may predispose the participant to excessive bleeding: 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.
• Conditions that would adversely affect participation in the study or make the primary efficacy endpoint non-evaluable: Any malignancy within 5 years prior to the Screening visit (except for effectively treated carcinoma in situ of the cervix or adequately treated non-metastatic squamous or basal cell carcinoma of the skin) will also be exclusionary.
• Prior/concomitant therapy E 07.
• The participant has received any of the following medications/treatments within the specified time frame before any baseline assessment (no washout is required for interferon beta or glatiramer acetate treatments): E 08.
• The participant is receiving strong inducers or inhibitors of cytochrome P450 (CYP) 3A or CYP2C8 hepatic enzymes as listed in Appendix 8A E 09.
• The participant is receiving anticoagulant/antiplatelet therapies, including: Acetylsalicylic acid (aspirin) Antiplatelet drugs (eg, clopidogrel) Warfarin (vitamin K antagonist) Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors) Prior/concurrent clinical study experience E 10.
• The participant was previously exposed to any BTK inhibitor, including SAR442168.
• The participant has taken other investigational drugs within 3 months or 5 half-lives, whichever is longer, before the Screening Visit.
• Diagnostic assessments E 12.
• The participant has had a relapse in the 30 days prior to randomization.
• Other exclusions E 13.
• Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.
• Any country-related specific regulation that would prevent the participant from entering the study.
• Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures or not able to follow the schedule of protocol assessments due to other reasons (exception: participants who are not able to complete electronic clinical outcome assessments may be given paper clinical outcome assessments to complete).

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Annualized adjudicated relapse rate (ARR) during the study period assessed by confirmed protocol-defined adjudicated relapses	Study will continue until 162 events are projected to have occurred in the pooled data, to ensure approximately 90% power to detect a 40% risk reduction in 6-month CDW with SAR442168 compared to teriflunomide, based on an assumed 24-month event rate of 12% in the teriflunomide arm.

Secondary Outcome Measures

Name	Time	Method
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
Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 months

Trial Locations

Locations (6)

Artemis Hospital; 🇮🇳 Gurgaon, HARYANA, India

Fortis Hospital; 🇮🇳 Gurgaon, HARYANA, India

Government medical college; 🇮🇳 Thiruvananthapuram, KERALA, India

NIMHANS; 🇮🇳 Bangalore, KARNATAKA, India

Postgraduate Institute of Medical Education and Research; 🇮🇳 Chandigarh, CHANDIGARH, India

Sir Gangaram Hospital; 🇮🇳 Central, DELHI, India

Artemis Hospital

🇮🇳Gurgaon, HARYANA, India

Dr Manish Mahajan

Principal investigator

8557873567

drmanishneurology@gmail.com