A Study of Efficacy and Safety of M2951 in Participants With Relapsing Multiple Sclerosis

Relapsing-remitting Multiple Sclerosis Clinical Trial

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02975349
• Other study ID #: MS200527-0086
• Secondary ID: 2016-001448-21
• Status: Terminated
• Phase: Phase 2
• Start date: March 7, 2017
• Est. completion date: April 2, 2024

Study information

• Verified date: April 2024
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 267
• Est. completion date: April 2, 2024
• Est. primary completion date: January 24, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing-remitting Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Evobrutinib
Participants received Evobrutinib 75 milligrams (mg) orally, twice daily (BID) up to Week 48
• Evobrutinib
Participants received Evobrutinib 25 mg orally, once daily (QD) up to Week 48
• Evobrutinib
Participants received Evobrutinib 75 mg orally, QD up to Week 48
• Placebo
Placebo were administered for 24 weeks
• Tecfidera
Tecfidera; 120 mg hard capsule BID for 7 days then 240 mg hard capsule BID for duration of treatment (48 weeks).
• Evobrutinib
Following Placebo for 24 weeks, participants received Evobrutinib 25 milligram (mg) orally, once daily (QD) from Week 24 to 48 weeks.

Locations

Country	Name	City	State
Bulgaria	Research Site	Blagoevgrad
Bulgaria	Research Site	Dupnitsa
Bulgaria	Research Site 1	Pleven
Bulgaria	Research Site 2	Pleven
Bulgaria	Research Site	Ruse
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Czechia	Research Site	Brno
Czechia	Research Site	Hradec Kralove
Czechia	Research Site	Hradec Kralove
Czechia	Research Site	Jihlava
Czechia	Research Site	Prague 5
Czechia	Research Site	Teplice
Poland	Research Site	Bydgoszcz
Poland	Research Site	Katowice
Poland	Research Site	Katowice
Poland	Research Site	Lodz
Poland	Research Site	Lublin
Poland	Research Site	Oswiecim
Poland	Research Site	Plewiska
Poland	Research Site	Poznan
Poland	Research Site	Rzeszow
Poland	Research Site	Warszawa
Russian Federation	Research Site	Kazan
Russian Federation	Research Site	Krasnoyarsk
Russian Federation	Research Site	Krasnoyarsk
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Perm
Russian Federation	Research Site	Saransk
Serbia	Research Site	Belgrade
Serbia	Research Site	Kragujevac
Serbia	Research Site	Nis
Serbia	Research Site	Uzice
Slovakia	Research Site	Banska Bystrica
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Dubnica nad Vahom
Spain	Research Site	A Coruña
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Ukraine	Research Site	Chernivtsi
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lviv
Ukraine	Research Site	Poltava
Ukraine	Research Site	Zaporizhzhia
Ukraine	Research Site	Zaporizhzhia

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.	Merck KGaA, Darmstadt, Germany

Countries where clinical trial is conducted

Bulgaria,  Czechia,  Poland,  Russian Federation,  Serbia,  Slovakia,  Spain,  Ukraine, 

References & Publications (1)

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; — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Annualized Relapse Rate (ARR) at Week 24	A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.	Week 24
Secondary	Qualified Relapse-Free Status at Week 24	A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status at week 24 were reported. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.	Week 24
Secondary	Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24	The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis [MS]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS). As per planned analysis, Tecfidera treatment group was not included in inferential analysis.	Baseline, Week 24
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death	An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the date of first dose and within 28 days after the date of last dose in the study. TEAEs include both Serious TEAEs and non-serious TEAEs.	Baseline up to Safety Follow-up (Week 52)
Secondary	Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)	Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in vital signs and ECG were reported. Clinical Significance was decided by the investigator.	Baseline up to Safety Follow-up (Week 52)
Secondary	Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values	Hematology, biochemistry, and urinalysis values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). For the hematology and biochemistry parameters, participants with a value grade 3 or higher were reported. For the urinalysis parameters, participants with a value grade 3 or higher, or a value >= 2 upper limit of normal (ULN), or a value classified as ++ Increasing were reported.	Baseline up to Safety Follow-up (Week 52)
Secondary	Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)	Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.	Baseline (Day 1), Weeks 4, 16, and 24
Secondary	Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)	Absolute Concentrations serum levels of IgG, IgA, IgM were to be assessed.	Weeks 48
Secondary	Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period)	Change in the serum levels of IgG, IgA, IgM were assessed.	Baseline (Day 1), Weeks 4, 16, and 24
Secondary	Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period)	Change in the serum levels of IgG, IgA, IgM were to be assessed.	Baseline (Day 1), Week 48
Secondary	Absolute Numbers of B Cells (Active Treatment Period)	Absolute Numbers of B Cells are reported.	Baseline (Day 1), Weeks 4, and 24
Secondary	Absolute Numbers of B Cells (Blinded Extension Period)	Absolute Numbers of B Cells to be reported.	Weeks 48 and 52
Secondary	Change From Baseline in Absolute B Cells (Active Treatment Period)	Change from baseline in absolute B cells are reported.	Baseline (Day 1), Weeks 4, and 24
Secondary	Change From Baseline in Absolute B Cells (Blinded Extension Period)	Change from baseline in absolute B cells to be reported.	Weeks 48 and 52
Secondary	Total Number of New Gadolinium-positive (Gd+) T1 Lesions	Analysis of Gadolinium-positive T1 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 24
Secondary	Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions	Analysis of Gadolinium-positive T1 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	Total Number of New or Enlarging T2 Lesions	Analysis of New or Enlarging T2 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	Change From Baseline in Volume of T2 Lesions at Week 24	Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. Tecfidera treatment group was not included in inferential analysis.	Baseline, Week 24
Secondary	Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24	Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis.	Baseline, Week 24
Secondary	Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48	Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.	Week 48
Secondary	Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48	Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.	Week 48
Secondary	Annualized Relapse Rate (ARR)	A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days.	Week 0 to Week 48
Secondary	Qualified Relapse-free Status	A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status were reported.	Week 25 to Week 48
Secondary	Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48	The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis [MS]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS).	Week 24, Week 48
Secondary	Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24	Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans.	Week 24 to Week 48
Secondary	Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48	Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.	Week 24, Week 48
Secondary	Change From Week 24 in Volume of T2 Lesions at Week 48	Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans.	Week 24, Week 48

External Links

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