RMS Study of BTK Inhibitor SAR442168

  • STATUS
    Recruiting
  • End date
    Aug 31, 2024
  • participants needed
    900
  • sponsor
    Peking University Third Hospital
Updated on 21 July 2021

Summary

To access SAR442168 in the RMS populstion. Efficaty will be accessed by adjudicated relapse rate, disability progression, and MRI findings of disease activity.

Description

Despite a number of disease-modifying therapies (DMTs) approved for relapsing multiple sclerosis (RMS), there is still a need for additional efficacious treatments, especially treatments that target disease mechanisms in the central nervous system (CNS) behind a closed or partially closed blood-brain barrier. Current treatments cannot ensure long-term suppression of multiple sclerosis (MS) inflammatory activity including relapse and new magnetic resonance imaging (MRI) lesion control. Some medications delay RMS progression, but the disease may still not be completely controlled, and it affects life activities and wellbeing. Even the most recent high-efficacy DMTs mainly act on adaptive immunity in the periphery with only modest ability to slow neuroinflammatory and neurodegenerative processes, as demonstrated by recent studies in progressive MS. Therefore, development of MS treatments with new modes of action is of interest. In addition to the current focus on suppressing Bor T-cell mediated immunity in MS treatments, there is mounting evidence that innate immunity, including myeloid lineage bone-marrow-derived monocytes, macrophages, and CNS-resident microglial cells, is responsible for many of the neurodegenerative aspects of MS. Modulation of innate immunity could therefore provide additional benefit in treatment of MS. SAR442168 shows in vitro capacity to inhibit Bruton's tyrosine kinase (BTK), which is responsible for downstream signaling in macrophages and microglial cells and is expected to act on these targets in the brain due to its ability to penetrate the blood-brain barrier. Based on this knowledge of the mode of action of SAR442168, its ability to penetrate the blood-brain barrier, and available evidence from nonclinical and healthy volunteer studies, SAR442168 is expected to prove itself as a high-efficacy disease-modifying treatment for MS. The ability of SAR442168 to reduce formation of new, active brain lesions in MS was assessed in a Phase 2b dose-finding trial in participants with RMS (DRI15928). This radiographic outcome has been established as a highly reliable predictive biomarker for clinical efficacy in pivotal studies in MS including Phase 3 RMS studies. The dose selected on the basis of the SAR442168 effect on gadolinium-(Gd) enhancing T1-hyperintense lesions on MRI in the Phase 2b trial will be used for this and other Phase 3 trials with SAR442168 in MS. The goal of this Phase 3 study is to assess SAR442168 in the RMS population. Efficacy will be assessed by adjudicated relapse rate, disability progression, and MRI findings of disease activity VV-CLIN-0579239 1.0Amended Clinical Trial Protocol 01 07-May-2020 SAR442168-EFC16033 Version number: 1 Property of the Sanofi group - strictly confidential Page 12 (Gd-enhancing lesions and new/enlarging T2-hyperintense lesions). Together with evaluation of other secondary and exploratory endpoints, this study will provide a comprehensive evaluation of the efficacy and safety of SAR442168 in the RMS population.

Details
Condition Relapsing Multiple Sclerosis
Treatment SAR442168
Clinical Study IdentifierNCT04964791
SponsorPeking University Third Hospital
Last Modified on21 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply: Age I 01. 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. I 03. 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. Sex I 06. 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, as described in Appendix 4 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. 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. E 02. 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 participant has a lymphocyte count less than the lower limit of normal (LLN) at the Screening Visit. A history of diagnosis of progressive multifocal leukoencephalopathy (PML) or evidence of findings suggestive of PML on the screening MRI. A history of infection with human immunodeficiency virus (HIV). A history of active or latent tuberculosis (TB) (unless the participant has completed a full course of anti-tuberculosis therapy or it is documented by a specialist that the participant has been adequately treated and can begin treatment with an immunosuppressive agent); screening tuberculosis testing should be performed at screening and again during the study, if clinically indicated. Blood testing (eg, QuantiFERON TB Gold test) is preferred; skin testing (eg, tuberculin skin test) will be allowed if blood testing is not available or the blood test result is indeterminate. Persistent chronic or active recurring infection requiring treatment with antibiotics, antivirals, or antifungals. Fever within 4 weeks of the Screening Visit (38C; however, if due to brief and mild ear, nose, throat viral infection participant may be included based on the Investigator's judgment). 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. Serologies consistent with resolved infection or vaccination may not exclude potential participants from the trial. Any other active infections that would adversely affect participation or IMP administration in this study, as judged by the Investigator. E 03. 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. A documented history of attempted suicide over the 6 months prior to the Screening Visit, presents with suicidal ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) during the study, OR if in the Investigator's judgment, the participant is at risk for a suicide attempt. A history of alcohol or drug abuse within 1 year 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 E 05. 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/L at the Screening Visit The participant has had major surgery within 4 weeks prior to the Screening Visit, which could affect the participant's safety or affect immune response (as judged by the Investigator) or has planned any elective major surgery during the study. E 06. Conditions that would adversely affect participation in the study or make the primary efficacy endpoint non-evaluable: Sensitivity to any of the study interventions, or components thereof, or has a drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study. A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist. A history or presence of significant other concomitant illness according to the Investigator's judgment such as, but not limited to cardiovascular (including Stage III or IV cardiac failure according to New York Heart Association [NYHA] classification), or renal (ie, undergoing dialysis), neurological, endocrine, gastrointestinal, hepatic (ie, underlying hepatobiliary disease, screening ALT >3 X upper limit of normal (ULN), or albumin 2.5 g/dL [25 g/L]), metabolic, pulmonary, or lymphatic disease that would adversely affect participation in this study. 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. Any other 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. 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): Systemic corticosteroids, adrenocorticotropic hormone : 1 month prior to screening MRI scan. Dimethyl fumarate (DMF), siponimod :1 month prior to randomization. Intravenous immunoglobulin, fingolimod: 2 months prior to randomization. Teriflunomide (<3 months treatment), mildly to moderately immunosuppressive/chemotherapeutic medications such azathioprine and methotrexate, mycophenolate: 3 months prior to randomization (no time restriction if accelerated elimination procedure is done). Teriflunomide (3 months treatment), lymphoid irradiation, bone marrow transplantation, mitoxantrone (with evidence of cardiotoxicity following treatment, or cumulative lifetime dose >120 mg/m2), other strongly immunosuppressive treatments with very long-lasting effects: any time. Natalizumab: 6 months prior to randomization. B-cell-depleting therapies such as ocrelizumab and rituximab: 6 months prior to randomization or until return of B-cell counts to normal levels, whichever is longer. Highly immunosuppressive/chemotherapeutic medications: mitoxantrone up to 120 mg/m2 body surface area, cyclophosphamide, cladribine: 2 years prior to randomization. Alemtuzumab: 4 years prior to randomization. Other MS-disease modifying treatments: 5 half-lives or until end of pharmacodynamics activity, whichever is longer. 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) Heparin, including low molecular weight heparin (antithrombin agents) Dabigatran (direct thrombin inhibitor) Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors) Note: All above drugs need to be stopped at least 5 half-lives before study drug administration except for aspirin, which needs to be stopped at least 8 days before. E 10\. A history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in Aubagio (this includes anaphylaxis, angioedema, and serious skin reactions) Prior/concurrent clinical study experience E 11. The participant was previously exposed to any BTK inhibitor, including SAR442168. E 12. The participant has taken other investigational drugs within 3 months or 5 half-lives, whichever is longer, before the Screening Visit. Diagnostic assessments E 13. The participant has had a relapse in the 30 days prior to randomization. E 14. The participant has contraindication for MRI, ie, presence of pacemaker, metallic implants in high-risk areas (ie, artificial heart valves, aneurysm/vessel clips), presence of metallic material (eg, shrapnel) in high risk areas, known history of allergy to any contrast medium, or history of claustrophobia that would prevent completion of all protocol-scheduled MRI scans Note: People with a contraindication to Gd can be enrolled into the study but cannot receive Gd contrast dyes during their MRI scans. Other exclusions E 15. Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized. E 16. Any country-related specific regulation that would prevent the participant from entering the study. E 17. 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). E 18\. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 of the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Ordinance E6). E 19. Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals. E 20. Any other situation during study implementation/course that may raise ethics considerations. Note: a one-time retest at screening may be performed if an abnormal laboratory test value is considered temporary. 5.3 LIFESTYLE CONSIDERATIONS 5.3.1 Meals and dietary restrictions SAR442168 shall be taken with a meal. When possible, the meal (eg, breakfast, lunch, or dinner) should be consistent in terms of time of day throughout the study. The typical time of day at which IMP is administered will be collected at each visit. The participant must refrain from consumption of grapefruit or grapefruit juice from 5 days prior to intervention administration and throughout the treatment phase. 5.3.2 Caffeine, alcohol, and tobacco For each visit with PK/PD assessment, participants will abstain from ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 2 hours before the start of treatment until after collection of the final PK and/or PD sample later that day. For each visit with PK/PD assessment, participants will abstain from alcohol for 24 hours before the start of treatment until after collection of the final PK and/or PD sample later that day. During the entire study, the IMP should be used with caution in participants who consume substantial quantities of alcohol. 5.3.3 Activity No special restrictions. 5.4 SCREEN FAILURES Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently randomly assigned to the study intervention. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any SAE. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened up to 2 times. Rescreened individuals should be assigned a different participant number
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