Study Stopped
Results from the EVOLUTION clinical trials showed evobrutinib did not meet its primary endpoint of annualized relapse rate for up to 156 weeks compared to oral teriflunomide in both studies.
A Study of Efficacy and Safety of M2951 in Participants With Relapsing Multiple Sclerosis
A Randomized, Double-Blind, Placebo-Controlled Phase II Study of M2951 With a Parallel, Open-Label, Active Control Group (Tecfidera), in Patients With Relapsing Multiple Sclerosis to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics, and Biological Activity.
2 other identifiers
interventional
267
8 countries
56
Brief Summary
The aim of this protocol is to find out about the safety and effectiveness of M2951 in participants with relapsing multiple sclerosis. Participants were placed into 1 of 3 groups to receive M2951, placebo or tecfidera for 24 weeks. After 24 weeks, the participants on placebo were given M2951.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Mar 2017
Longer than P75 for phase_2
56 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 23, 2016
CompletedFirst Posted
Study publicly available on registry
November 29, 2016
CompletedStudy Start
First participant enrolled
March 7, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 24, 2018
CompletedResults Posted
Study results publicly available
February 5, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
April 2, 2024
CompletedMay 14, 2025
May 1, 2025
11 months
November 23, 2016
January 13, 2021
May 13, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Total Number of Gadolinium-Enhancing T1 Lesions
Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.
Week 12 to Week 24
Secondary Outcomes (37)
Annualized Relapse Rate (ARR) at Week 24
Week 24
Qualified Relapse-Free Status at Week 24
Week 24
Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24
Baseline, Week 24
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death
Baseline up to Safety Follow-up (Week 52)
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)
Baseline up to Safety Follow-up (Week 52)
- +32 more secondary outcomes
Study Arms (7)
Placebo then Evobrutinib 25 mg QD (Period 2)
EXPERIMENTALParticipants who received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1 received Evobrutinib 25 milligram (mg) orally, once daily (QD) in blinded extension (BE) period from week 25 to week 48.
Evobrutinib 25 mg QD (Period 1, 2 and 3)
EXPERIMENTALParticipants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 25 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Evobrutinib 75 mg QD (Period 1, 2 and 3)
EXPERIMENTALParticipants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Evobrutinib 75 mg BID (Period 1, 2 and 3)
EXPERIMENTALParticipants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Tecfidera (Period 1, 2 and 3)
ACTIVE COMPARATORParticipants received Tecfidera 120 mg twice daily (BID) for first 7 days followed by 240 mg orally, BID up to Week 48 in active treatment period 1 and BE period received Tecfidera 120 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Placebo
PLACEBO COMPARATORParticipants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1.
Placebo + Evobrutinib 25 mg QD (Period 3)
EXPERIMENTALParticipants who received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1 received Evobrutinib 25 mg orally, QD from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Interventions
Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Participants received Tecfidera 120 mg twice daily (BID) for first 7 days followed by 240 mg orally, BID up to Week 48 in active treatment period 1 and BE period received Tecfidera 120 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.
Eligibility Criteria
You may qualify if:
- Participants with a diagnosis of relapsing multiple sclerosis (may include participants with Secondary Progressive Multiple Sclerosis (SPMS) with superimposed relapses provided they meet the other criteria) in accordance with revised McDonald criteria for MS and Lublin and Reingold
- Male or female aged 18 to 65 years
- 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-positive (Gd+) T1 lesion within 6 months prior to randomization would make the patient eligible.
- Expanded Disability Status Scale score of 0 to 6 at Baseline
- Women of childbearing potential must use a supplementary barrier method together with a highly effective method of contraception (according to International Council for Harmonisation \[ICH\] guidance M3\[R2\]) for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP.
- Signed and dated informed consent (participant must be able to understand the informed consent) indicating that the participant has been informed of all the pertinent aspects of the trial prior to enrolment and will comply with the requirements of the protocol.
You may not qualify if:
- Progressive MS
- Disease duration \> 15 years in participants with EDSS of 2 or less
- Use of the following, as determined in the protocol ; rituximab, ocrelizumab, mitoxantrone, or lymphocyte-depleting therapies, lymphocyte trafficking blockers (eg, natalizumab, fingolimod), intravenous (IV) immunoglobulins (Ig), plasmapheresis, immunosuppressive treatments, B-interferons or glatiramer acetate, Systemic glucocorticoids, teriflunomide
- Exposure to Tecfidera within 6 months prior to randomization
- Any allergy, contraindication, or inability to tolerate Tecfidera
- Treatment with dalfampridine (fampridine, Ampyra) unless on a stable dose for ≥ 30 days prior to randomization
- Inability to comply with MRI scanning
- Immunologic disorder other than MS, with the exception of secondary well-controlled diabetes or thyroid disorder, or any other condition requiring oral, IV, intramuscular, or intra-articular corticosteroid therapy
- Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
- Severe drug allergy or history of anaphylaxis, or allergy to the IMP or any of its incipients
- History of or positive testing for human immunodeficiency virus (HIV), hepatitis C (HCV) antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B core total, and/or immunoglobulin M (IgM) antibody (+) at Screening.
- The participant: • Has a history of or current diagnosis of active tuberculosis (TB) or • Is currently undergoing treatment for latent TB infection (LTBI) or • Has an untreated LTBI or • Has a positive QuantiFERON®-TB test at Screening.
- Indeterminate QuantiFERON®
- Participants with current household contacts with active TB will also be excluded
- History of splenectomy or any major surgery within 2 months prior to Screening
- +11 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (56)
Research Site
Blagoevgrad, 2700, Bulgaria
Research Site
Dupnitsa, 2600, Bulgaria
Research Site 1
Pleven, 5800, Bulgaria
Research Site 2
Pleven, 5800, Bulgaria
Research Site
Rousse, 7002, Bulgaria
Research Site
Sofia, 1142, Bulgaria
Research Site
Sofia, 1309, Bulgaria
Research Site
Sofia, 1336, Bulgaria
Research Site
Sofia, 1407, Bulgaria
Research Site
Sofia, 1431, Bulgaria
Research Site
Sofia, 1606, Bulgaria
Research Site
Sofia, 1797, Bulgaria
Research Site
Brno, 656 91, Czechia
Research Site
Hradec Králové, 500 05, Czechia
Research Site
Hradec Králové, 50003, Czechia
Research Site
Jihlava, 58633, Czechia
Research Site
Prague, 150 06, Czechia
Research Site
Teplice, 41529, Czechia
Research Site
Bydgoszcz, 85-654, Poland
Research Site
Katowice, 40-595, Poland
Research Site
Katowice, 40-650, Poland
Research Site
Lodz, 90-324, Poland
Research Site
Lublin, 20-605, Poland
Research Site
Oświęcim, 32-600, Poland
Research Site
Plewiska, 62-064, Poland
Research Site
Poznan, 61-853, Poland
Research Site
Rzeszów, 35-055, Poland
Research Site
Warsaw, 01-697, Poland
Research Site
Kazan', 420021, Russia
Research Site
Krasnoyarsk, 660037, Russia
Research Site
Krasnoyarsk, 660049, Russia
Research Site
Moscow, 129128, Russia
Research Site
Novosibirsk, 630102, Russia
Research Site
Perm, 614000, Russia
Research Site
Saransk, 430032, Russia
Research Site
Belgrade, 11000, Serbia
Research Site
Kragujevac, 34000, Serbia
Research Site
Niš, 18000, Serbia
Research Site
Užice, 31000, Serbia
Research Site
Banská Bystrica, 97404, Slovakia
Research Site
Bratislava, 85101, Slovakia
Research Site
Dubnica nad Váhom, 01841, Slovakia
Research Site
A Coruña, 15006, Spain
Research Site
Barcelona, 08003, Spain
Research Site
Barcelona, 08035, Spain
Research Site
Chernivtsi, 58018, Ukraine
Research Site
Ivano-Frankivsk, 76008, Ukraine
Research Site
Kharkiv, 61058, Ukraine
Research Site
Kharkiv, 61068, Ukraine
Research Site
Kharkiv, 61103, Ukraine
Research Site
Kyiv, 01601, Ukraine
Research Site
Kyiv, 03110, Ukraine
Research Site
Lviv, 79010, Ukraine
Research Site
Poltava, 36011, Ukraine
Research Site
Zaporizhzhia, 69035, Ukraine
Research Site
Zaporizhzhia, 69600, Ukraine
Related Publications (6)
Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, Martin EC, Dangond F, Syed S, Wolinsky JS; Evobrutinib Phase 2 Study Group. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019 Jun 20;380(25):2406-2417. doi: 10.1056/NEJMoa1901981. Epub 2019 May 10.
PMID: 31075187RESULTArnold DL, Elliott C, Martin EC, Hyvert Y, Tomic D, Montalban X. Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial. Neurology. 2024 Mar 12;102(5):e208058. doi: 10.1212/WNL.0000000000208058. Epub 2024 Feb 9.
PMID: 38335474RESULTPapasouliotis O, Mitchell D, Girard P, Dangond F, Dyroff M. Determination of a clinically effective evobrutinib dose: Exposure-response analyses of a phase II relapsing multiple sclerosis study. Clin Transl Sci. 2022 Dec;15(12):2888-2898. doi: 10.1111/cts.13407. Epub 2022 Sep 30.
PMID: 36126241RESULTMontalban X, Wallace D, Genovese MC, Tomic D, Parsons-Rich D, Le Bolay C, Kao AH, Guehring H. Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis. J Neurol Neurosurg Psychiatry. 2023 Jan;94(1):1-9. doi: 10.1136/jnnp-2022-328799. Epub 2022 Nov 23.
PMID: 36418156RESULTBar-Or A, Cross AH, Cunningham AL, Hyvert Y, Seitzinger A, Guhring H, Drouin EE, Alexandri N, Tomic D, Montalban X. Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton's tyrosine kinase inhibitor. Mult Scler. 2023 Oct;29(11-12):1471-1481. doi: 10.1177/13524585231192460. Epub 2023 Aug 25.
PMID: 37626477RESULTMontalban X, Wallace D, Genovese MC, Tomic D, Parsons-Rich D, Bolay CL, Kao AH, Guehring H. A plain language summary of what clinical studies can tell us about the safety of evobrutinib - a potential treatment for multiple sclerosis. Neurodegener Dis Manag. 2023 Aug;13(4):207-213. doi: 10.2217/nmt-2023-0003. Epub 2023 Jun 22.
PMID: 37345645DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Limitations and Caveats
Reported p values are not adjusted for multiple testing.
Results Point of Contact
- Title
- Communication Center
- Organization
- Merck KGaA, Darmstadt, Germany
Study Officials
- STUDY DIRECTOR
Medical Responsible
EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
November 23, 2016
First Posted
November 29, 2016
Study Start
March 7, 2017
Primary Completion
January 24, 2018
Study Completion
April 2, 2024
Last Updated
May 14, 2025
Results First Posted
February 5, 2021
Record last verified: 2025-05
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
- Time Frame
- Within six months after the occurrence of an approval of a new product or a new indication for an approved product in both the European Union and the United States after January 1, 2014 If approval of a product is not sought, Merck shall make publicly available such data within eighteen months after the trial completion date. Data will not be shared for products and indications approved prior to January 1, 2014
- Access Criteria
- Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researcher qualifications and legitimacy of the research purpose.
Per company policy and with respect to the principles set forth by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), the European Federation of Pharmaceutical Industries and Associations (EFPIA), the Pharmaceutical Research and Manufacturers of America (PhRMA), the Declaration of Helsinki, and applicable laws and regulations , we inform the public about the designs and results of our clinical trials in a timely and balanced manner, regardless of the outcome. We are committed to enhancing public health through responsible sharing of clinical trial data in a manner that is consistent with: safeguarding the privacy of patients; respecting the integrity of national regulatory systems; and maintaining incentives for investment in biomedical research.