E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing Multiple Sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Relapsing Multiple Sclerosis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10048393 |
E.1.2 | Term | Multiple sclerosis relapse |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
For the Double-blind Treatment Period (DBTP): To demonstrate superior efficacy with evobrutinib compared to Teriflunomide in terms of Annualized Relapse Rate (ARR). For the Open Label Extension (OLE) Period: To evaluate the long-term safety and tolerability of evobrutinib 45 mg twice daily (BID) in participants with Relapsing Multiple Sclerosis (RMS) over time. |
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E.2.2 | Secondary objectives of the trial |
For the DBTP-to demonstrate:a. the efficacy of evobrutinib relative to that of Teriflunomide on disability progression; b. the efficacy of evobrutinib relative to that of teriflunomide on disability improvement; c. the efficacy of evobrutinib relative to that of Teriflunomide on patient reported symptoms and functional status; d. the efficacy of evobrutinib relative to that of Teriflunomideon magnetic resonance imaging (MRI) lesion parameters e. the efficacy of evobrutinib relative to that of teriflunomide by evaluating response on Neurofilament light chain (NfL) concentrations in serum; f. To characterize the safety and tolerability of evobrutinib For the OLE Period-to evaluate:a. the long-term efficacy of evobrutinib 45mg BID in participants with RMS; b. the long-term effect of evobrutinib 45mg BID in participants with RMS on patient reported symptoms and functional status; c. further the long-term safety and tolerability of evobrutinib 45mg BID in participants with RMS over time
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic (PK) and Pharmacodynamic (PD) substudies will be performed in selected sites as part of the main protocol. The objective of PK study is to characterize the PK profile of evobrutinib in participants with MS and to describe the exposure-response relationship between evobrutinib and efficacy endpoints and safety endpoints. The objective of PD sub-study is to describe the exposure-response relationship between evobrutinib and PD biomarkers OLE period - secondary - MRI Substudy: To evaluate the long-term efficacy of evobrutinib 45 mg BID in participants with RMS on MRI parameters. OLE Period – exploratory - Biomarker Substudy: To further explore the long-term efficacy of evobrutinib 45 mg BID in participants with RMS by evaluating responses to biomarkers of disease (e.g., NfL) |
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E.3 | Principal inclusion criteria |
For DBTP: - 18 years to 55 years female and male participants - Participants are diagnosed with RMS (relapsing-remitting multiple sclerosis [RRMS] or secondary progressive multiple sclerosis [SPMS] with relapses) in accordance with 2017 Revised McDonald criteria (Thompson 2018) - Participants with one or more documented relapses within the 2 years before Screening with either: a. one relapse which occurred within the last year prior to randomization, OR b. the presence of at least 1 gadolinium-enhancing (Gd+) T1 lesion within 6 months prior to randomization - Participants have Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at Screening and Baseline (Day 1). Participants with an EDSS score <= 2 at Screening and Baseline (Day 1) are only eligible for participation if their disease duration (time since onset of symptoms) is no more than 10 years - Participants are neurologically stable for >= 30 days prior to both screening and baseline - Female participants must be neither pregnant nor breast-feeding or must lack child-bearing potential (as defined by either: post-menopausal or surgically sterile), or use an effective method of contraception for the duration of the study and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure - Male participants must refrain from donating sperm and/or abstain from intercourse with women of child-bearing potential or use an effective method of contraception for the duration of the study and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure - Participants have given written informed consent prior to any study-related procedure - Other protocol defined inclusion criteria could apply. For OLE period: - participants have completed the double blind, double dummy Treatment Period, or are still under study treatment when the PA is triggered, and who, in the opinion of the Investigator, may benefit from treatment with evobrutinib. - participants are able and willing to provide written informed consent for the OLE Phase (e.g., before the first OLE procedure on OLE Day 1) and to comply with the study protocol. - participants have documentation of completed AEP (confirmed bloodconcentration level of < 0.02 mcg/mL of teriflunomide as defined in protocol) before Day 1/Baseline visit. - Women of childbearing potential are willing to continue to use the contraceptive methods as described in protocol |
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E.4 | Principal exclusion criteria |
For DBTP: - Participants diagnosed with Progressive MS, in accordance with the 2017 Revised McDonald criteria as follows: a). Participants with Primary Progressive MS. b) Participants with secondary progressive MS without evidence of relapse. - Disease duration more than (>) 10 years in participants with an EDSS =< 2.0 at screening. - Immunologic disorder other than MS, or any other condition requiring oral, intravenous (IV) , intramuscular, or intra-articular corticosteroid therapy, with the exception of well-controlled Type 2 diabetes mellitus or well controlled thyroid disease. -Other protocol defined exclusion criteria could apply. For OLE period: - Participants who did not complete study intervention in DBTP or in the case of an event-driven PA, had discontinued blinded treatment prior to the PA trigger. - Treatment with injectable (e.g., IV, intramuscular, intra-articular) or oral glucocorticoids, or ACTH (e.g., Acthar gel) within 30 days before OLE Day 1, with the exception of rescue treatment for MS relapse specified by the study protocol. - History of suicidal ideation or an episode of clinically severe depression (as determined by the Investigator) within 12 weeks prior to OLE Day 1. - History of abnormal laboratory results that, in the opinion of the Investigator, are indicative of a significant cardiac, endocrine, hematologic, immunologic, metabolic urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurologic (other than MS), and/or other major diseases. - Any of the following abnormal blood tests during the Treatment Period requiring discontinuation of study intervention, and/or at End of Treatment visit or at OLE Day 1: ALT/serum glutamate pyruvate transaminase, AST/serum glutamic oxaloacetic transaminase, amylase, or lipase, eGFR. - Female participants who have a positive pregnancy test result, are pregnant, or are currently breast feeding. - Inability to comply with study requirements.
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E.5 End points |
E.5.1 | Primary end point(s) |
For DBTP: ARR based on qualified relapses up to 156 weeks in participants with RMS For OLE period: Occurrence of AEs and SAEs |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For DBTP: up to 156 weeks For OLE period: Entire OLE duration |
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E.5.2 | Secondary end point(s) |
For DBTP: a. Time to first occurrence of 12-week confirmed disability progression (CDP) as measured by the Expanded Disability Status Scale (EDSS) up to 156 weeks b.Time to first occurrence of 24-week CDP as measured by EDSS up to 156 weeks c. Time to first occurence of 24-week Confirmed Disability Improvement (CDI) as measured by the EDSS up to 156 weeks d.Change from Baseline (CFB) in Patient Reported Outcomes Measurement Information System [PROMIS] PF score over 96 weeks e.CFB in PROMIS Fatigue score over 96 weeks f.Total number of T1 Gd+ lesions based on all available MRI scans. g. Number of new or enlarging T2 lesions based on the last available MRI scan relative to the baseline MRI scan h. NfL concentration at 12 weeks i.Safety as assessed by the nature, severity, and occurrence of adverse events (AEs) and adverse events of special interest (AESIs); vital signs; electrocardiograms (ECGs); absolute concentrations and change from Baseline in immunoglobulin (Ig) levels; and clinical laboratory safety parameters up to the end of the safety follow-up period For OLE period: a. ARR based on protocol defined qualified relapses b. Time to first occurrence of 24-week CDP as measured by EDSS c. Time to first occurrence of 24-week CDI as measured by EDSS d. SDMT over time e. PROMISnq PF (MS) 15a score change over time f. PROMIS Fatigue (MS) 8a score change over time g. Safety Laboratory Parameters including Blood Chemistry, Hematology, Coagulation, Vitals, ECGs |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For DBTP: a. 12 week up to 156 weeks b.c. 24-week up to 156 weeks d, e: over 96 weeks f. Total number of T1 Gd+ lesions based on all available MRI scans g. Number of new or enlarging T2 lesions on the last available MRI scan relative to the baseline MRI scan h. at 12 weeks i. up to the end of the safety follow-up period For OLE period: a., d., e., f., g. for up to 96 weeks b., c. 24-weeks |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Active comparator (Aubagio), double-dummy |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 127 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Canada |
Chile |
Colombia |
Hong Kong |
India |
Israel |
Korea, Republic of |
Mexico |
Peru |
Taiwan |
United States |
Austria |
Estonia |
Finland |
France |
Poland |
Bulgaria |
Netherlands |
Spain |
Czechia |
Germany |
Italy |
Belgium |
Bosnia and Herzegovina |
Croatia |
Denmark |
Georgia |
Hungary |
Russian Federation |
Ukraine |
United Kingdom |
Serbia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 4 |