Clinical trial NCT02975349: A Study of Efficacy and Safety of M2951 in Participants With Relapsing Multiple Sclerosis
Official title: 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Relapsing-remitting Multiple Sclerosis
Keywords: M2951
Relapsing Multiple Sclerosis
Bruton's Tyrosine Kinase inhibitor
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2016-11-29
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
* Active, clinically significant viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of Screening, or completion of oral anti-infectives within 2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary.
* 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
* History of myocardial infarction or cerebrovascular event as per the protocol
* History of attempted suicide within 6 months prior to Screening or a positive response to items 4 or 5 of Columbia-Suicide Severity Rating Scale (C-SSRS)
* An episode of major depression within the last 6 months prior to Screening
* On anticoagulation, fish oil supplements, or antiplatelet therapy other than daily aspirin for cardioprotection and treatment of Tecfidera induced flushing
* History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin
* Breastfeeding/lactating or pregnant women
* Participation in any investigational drug trial within 1 month or 5 half-lives of the investigational drug, whichever is longest, prior to Screening
* Participants currently receiving (or unable to stop using prior to receiving the first dose of IMP) medications or herbal supplements known to be potent inhibitors of cytochrome P450 3A (CYP3A)
* History of or current alcohol or substance abuse
* Clinically significant abnormality on electrocardiogram or screening chest X-ray
* Clinically significant laboratory abnormality

Primary outcomes:
measure: Total Number of Gadolinium-Enhancing T1 Lesions
timeFrame: Week 12 to Week 24
Secondary outcomes:
measure: Annualized Relapse Rate (ARR) at Week 24
timeFrame: Week 24
measure: Qualified Relapse-Free Status at Week 24
timeFrame: Week 24
measure: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death
timeFrame: Baseline up to Safety Follow-up (Week 52)
measure: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)
timeFrame: Baseline up to Safety Follow-up (Week 52)
measure: Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values
timeFrame: Baseline up to Safety Follow-up (Week 52)
measure: Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)
timeFrame: Baseline (Day 1), Weeks 4, 16, and 24
measure: Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)
timeFrame: Week 48
measure: Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period)
timeFrame: Baseline (Day 1), Weeks 4, 16, and 24
measure: Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period)
timeFrame: Baseline (Week 25), Week 48
measure: Absolute Concentration of B Cells (Active Treatment Period)
timeFrame: Baseline (Day 1), Weeks 4, and 24
measure: Absolute Concentration of B Cells (Blinded Extension Period)
timeFrame: Weeks 48 and 52
measure: Change From Baseline in Absolute B Cells (Active Treatment Period)
timeFrame: Baseline (Day 1), Weeks 4 and 24
measure: Change From Baseline in Absolute B Cells (Blinded Extension Period)
timeFrame: Baseline (Week 25), Weeks 48 and 52
measure: Total Number of New Gadolinium-positive (Gd+) T1 Lesions
timeFrame: Week 12 to 24
measure: Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions
timeFrame: Week 12 to Week 24
measure: Total Number of New or Enlarging T2 Lesions
timeFrame: Week 12 to Week 24
measure: Change From Baseline in Volume of T2 Lesions at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24
timeFrame: Baseline, Week 24
measure: Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48
timeFrame: Week 48
measure: Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48
timeFrame: Week 48
measure: Annualized Relapse Rate (ARR)
timeFrame: Week 0 to Week 48
measure: Qualified Relapse-free Status
timeFrame: Week 25 to Week 48
measure: Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48
timeFrame: Week 24, Week 48
measure: Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24
timeFrame: Week 24 to Week 48
measure: Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48
timeFrame: Week 24, Week 48
measure: Change From Week 24 in Volume of T2 Lesions at Week 48
timeFrame: Week 24, Week 48
measure: OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions
timeFrame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
measure: OLE Period: Annualized Relapse Rate (ARR)
timeFrame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
measure: OLE Period: Percentage of Participants With Qualified Relapse-Free Status
timeFrame: OLE Baseline (BE period Week 48) up to OLE Week 336
measure: OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336
timeFrame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
measure: OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: OLE Baseline (BE period Week 48) up to OLE Week 336
measure: OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
timeFrame: OLE Baseline (BE period Week 48) up to OLE Week 336
measure: OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
timeFrame: OLE Baseline (BE period Week 48) up to OLE Week 336
measure: OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs)
timeFrame: OLE Baseline (BE period Week 48) up to OLE Week 336
measure: OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels
timeFrame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288
measure: OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels
timeFrame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288
Other outcomes:
Locations:
city: Blagoevgrad
country: Bulgaria
facility: Research Site
city: Dupnitsa
country: Bulgaria
facility: Research Site
city: Pleven
country: Bulgaria
facility: Research Site 1
city: Pleven
country: Bulgaria
facility: Research Site 2
city: Ruse
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Jihlava
country: Czechia
facility: Research Site
city: Prague 5
country: Czechia
facility: Research Site
city: Teplice
country: Czechia
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Lodz
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Oswiecim
country: Poland
facility: Research Site
city: Plewiska
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Rzeszow
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Krasnoyarsk
country: Russian Federation
facility: Research Site
city: Krasnoyarsk
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Perm
country: Russian Federation
facility: Research Site
city: Saransk
country: Russian Federation
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Kragujevac
country: Serbia
facility: Research Site
city: Nis
country: Serbia
facility: Research Site
city: Uzice
country: Serbia
facility: Research Site
city: Banska Bystrica
country: Slovakia
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Dubnica nad Vahom
country: Slovakia
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Chernivtsi
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Poltava
country: Ukraine
facility: Research Site
city: Zaporizhzhia
country: Ukraine
facility: Research Site
city: Zaporizhzhia
country: Ukraine
facility: Research Site
Study officials:
affiliation: EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Arnold 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.
citation: Papasouliotis 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.
citation: Montalban 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.
citation: Bar-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.