A Study of Efficacy and Safety of M2951 in Participants With Relapsing Multiple Sclerosis
- Conditions
- Relapsing-remitting Multiple Sclerosis
- Interventions
- Registration Number
- NCT02975349
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 267
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo then Evobrutinib 25 mg QD (Period 2) Evobrutinib Participants 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) Evobrutinib Participants 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) Evobrutinib 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. Evobrutinib 75 mg BID (Period 1, 2 and 3) Evobrutinib Participants 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) Tecfidera 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. Placebo Placebo Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Placebo + Evobrutinib 25 mg QD (Period 3) Evobrutinib Participants 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.
- Primary Outcome Measures
Name Time Method Total Number of Gadolinium-Enhancing T1 Lesions Week 12 to Week 24 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.
- Secondary Outcome Measures
Name Time Method Total Number of New Gadolinium-positive (Gd+) T1 Lesions Week 12 to 24 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.
Total Number of New or Enlarging T2 Lesions Week 12 to Week 24 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.
Change From Baseline in Volume of T2 Lesions at Week 24 Baseline, 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.
Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 Baseline, 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.
Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 Week 48 Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Change From Baseline in Absolute B Cells (Active Treatment Period) Baseline (Day 1), Weeks 4 and 24 Change from baseline in absolute B cells are reported.
Change From Baseline in Absolute B Cells (Blinded Extension Period) Baseline (Week 25), Weeks 48 and 52 Change from baseline in absolute B cells are reported.
Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions Week 12 to Week 24 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.
Annualized Relapse Rate (ARR) Week 0 to Week 48 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.
Qualified Relapse-free Status Week 25 to Week 48 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.
Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 Week 24, 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).
Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 Week 24 to Week 48 Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans.
Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 Week 24, Week 48 Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Change From Week 24 in Volume of T2 Lesions at Week 48 Week 24, Week 48 Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans.
OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336 Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans.
Annualized Relapse Rate (ARR) at Week 24 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.
Qualified Relapse-Free Status at Week 24 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.
Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 Baseline, 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.
OLE Period: Annualized Relapse Rate (ARR) OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336 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.
OLE Period: Percentage of Participants With Qualified Relapse-Free Status OLE Baseline (BE period Week 48) up to OLE Week 336 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 from OLE Baseline (BE period Week 48) up to Week 336 were reported.
OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336 OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336 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).
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death Baseline up to Safety Follow-up (Week 52) 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.
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) Baseline up to Safety Follow-up (Week 52) 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.
Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values Baseline up to Safety Follow-up (Week 52) 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.
Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) Baseline (Day 1), Weeks 4, 16, and 24 Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) Week 48 Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) Baseline (Day 1), Weeks 4, 16, and 24 Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) Baseline (Week 25), Week 48 Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
Absolute Concentration of B Cells (Active Treatment Period) Baseline (Day 1), Weeks 4, and 24 Absolute concentration of B Cells are reported.
Absolute Concentration of B Cells (Blinded Extension Period) Weeks 48 and 52 Absolute concentration of B Cells were reported.
Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 Week 48 Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) OLE Baseline (BE period Week 48) up to OLE Week 336 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.
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs OLE Baseline (BE period Week 48) up to OLE Week 336 Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. Number of participants with clinically significant change from baseline in vital signs were reported. Clinical Significance was decided by the investigator.
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters OLE Baseline (BE period Week 48) up to OLE Week 336 Laboratory parameters included hematology, biochemistry, and urinalysis. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator.
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs) OLE Baseline (BE period Week 48) up to OLE Week 336 ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in ECG were reported. Clinical Significance was decided by the investigator.
OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288 Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288 Change from baseline in the serum levels of IgG, IgA, IgM were assessed.
Trial Locations
- Locations (3)
Research Site
🇺🇦Zaporizhzhia, Ukraine
Research Site 1
🇧🇬Pleven, Bulgaria
Research Site 2
🇧🇬Pleven, Bulgaria