Back to resultsStudy of Evobrutinib in Participants With RMS
Primary Purpose
Relapsing-remitting Multiple Sclerosis
Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Evobrutinib
Avonex®
Avonex® matched Placebo
Evobrutinib matched Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Relapsing-remitting Multiple Sclerosis focused on measuring Evobrutinib, Avonex®, Interferon-beta 1a, Relapsing Multiple Sclerosis
Eligibility Criteria
Inclusion Criteria:
- Participants 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 EDSS score of 0 to 5.5 at Baseline. Participants with an EDSS score <= 2 at screening 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 and 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.
- Participants have given written informed consent prior to any study-related procedure.
- Other protocol defined inclusion criteria could apply
Exclusion Criteria:
- 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.
Sites / Locations
- Please Contact U.S. Medical Information
- Please Contact the Communication Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Evobrutinib + Avonex® matched Placebo
Avonex® + Evobrutinib matched Placebo
Arm Description
Participants received active evobrutinib twice daily (BID) along with concomitant intramuscular (IM) injection of placebo matched to Avonex® once a week. Treatment period was planned to be of 96 weeks.
Participants received IM injection of active Avonex® once a week along with concomitant placebo matched to evobrutinib BID. Treatment period was planned to be of 96 weeks.
Outcomes
Primary Outcome Measures
Annualized Relapse Rate (ARR)
The annualized relapse rate at 96 weeks was to be calculated based on qualified relapses. A qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to MS. The relapse should be accompanied by an increase of 0.5 points or more on Expanded Disability Status Scale (EDSS), or 2 points increase on one of the Functional System Scores (FSS), or 1 point increase on at least two of the FSS. The increase in FSS scores must be related to the neurological symptoms which were reported as new or worsening.
Secondary Outcome Measures
Time to First Occurrence of 12-Week Confirmed Expanded Disability Status Scale (EDSS) Progression
EDSS is an ordinal scale in half-point increments that measures disability in participants with MS. EDSS progression is defined as an increase of 1 point or more from Baseline EDSS score when the Baseline score is 5.0 or less, and an increase of 0.5 points or more when the Baseline score is 5.5 or greater. Time to first occurrence of 12-week confirmed EDSS progression is defined as the time from randomization to the first EDSS progression event that was confirmed at a regularly scheduled visit at least 12 weeks later.
Time to First Occurrence of 24-Week Confirmed Expanded Disability Status Scale (EDSS) Progression
EDSS is an ordinal scale in half-point increments that measures disability in participants with MS. EDSS progression is defined as an increase of 1 point or more from Baseline EDSS score when the Baseline score is 5.0 or less, and an increase of 0.5 points or more when the Baseline score is 5.5 or greater. Time to first occurrence of 24-week confirmed EDSS progression is defined as the time from randomization to the first EDSS progression event that was confirmed at a regularly scheduled visit at least 24 weeks later.
Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Short Form Score at Week 96
The PROMIS PF Short Form is specific to measuring the physical function domain of MS patients, with each item on the form scored on a T-score metric. Higher scores indicate higher PF. Change from baseline at Week 96 is the difference between the PROMIS PF scores at 96 weeks and at baseline.
Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form Score at Week 96
The PROMIS Fatigue Short Form is specific to measuring the fatigue domain of MS patients, with each item on the form scored on a T-score metric. Higher scores indicate higher fatigue. Change from baseline at Week 96 is the difference between the PROMIS Fatigue scores at 96 weeks and at baseline.
Total Number of Gadolinium-Enhancing (Gd+) Time Constant 1 (T1) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96
Total number of Gd+ T1 lesions was to be assessed using magnetic resonance imaging (MRI).
Total Number of New or Enlarging Time Constant 2 (T2) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96
Total number of new or enlarging T2 lesions was to be assessed using magnetic resonance imaging (MRI).
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. TEAE is an AE that started after study drug treatment; or if the event was continuous from baseline & was serious, related to investigational medicinal product (IMP), or resulted in death, discontinuation, interruption or reduction of study therapy. TEAEs included both serious and non-serious TEAEs. AESIs included liver AEs (possible drug-induced, non-infectious, non-alcoholic and immune-mediated) infections (serious and opportunistic infections), lipase and amylase elevation, and seizure.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in participant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs included both serious TEAEs and non-serious TEAEs. Severity of TEAEs were graded using NCI CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs based on severity were reported.
Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
DBP and SBP were measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Vital Signs: Pulse Rate
Pulse rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Vital Signs: Respiratory Rate
Respiration rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Vital Signs: Temperature
Temperature was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Vital Signs: Weight
Number of Participants With Abnormal Lab Values
The total number of participants with laboratory test abnormalities was assessed. Clinical laboratory tests included hematology, coagulation, biochemistry and urinalysis.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
ECG parameters included heart rhythm, heart rate, QRS intervals, QT intervals, RR intervals and corrected QT (QTc) intervals.
Absolute Concentrations of Immunoglobulin (Ig) A Level
Absolute concentrations of Immunoglobulin (Ig) A was reported.
Absolute Concentrations of Immunoglobulin (Ig) G Level
Absolute concentrations of Immunoglobulin (Ig) E was reported.
Absolute Concentrations of Immunoglobulin (Ig) M Level
Absolute concentrations of Immunoglobulin (Ig) M was reported.
Absolute Concentrations of Immunoglobulin (Ig) E Level
Absolute concentrations of Immunoglobulin (Ig) E was reported.
Change From Baseline in Immunoglobulin (Ig) A Level
Change from baseline in immunoglobulin (Ig) A level was reported.
Change From Baseline in Immunoglobulin (Ig) E Level
Change from baseline in immunoglobulin (Ig) E level was reported.
Change From Baseline in Immunoglobulin (Ig) G Level
Change from baseline in immunoglobulin (Ig) G level was reported.
Change From Baseline in Immunoglobulin (Ig) M Level
Change from baseline in immunoglobulin (Ig) M level was reported.
Full Information
NCT ID
NCT04032171
First Posted
July 23, 2019
Last Updated
July 13, 2021
Sponsor
EMD Serono Research & Development Institute, Inc.
Collaborators
Merck KGaA, Darmstadt, Germany
1. Study Identification
Unique Protocol Identification Number
NCT04032171
Brief Title
Study of Evobrutinib in Participants With RMS
Official Title
A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active Controlled Study of Evobrutinib Compared With an Interferon Beta 1a (Avonex®), in Participants With RMS to Evaluate Efficacy and Safety
Study Type
Interventional
2. Study Status
Record Verification Date
July 2021
Overall Recruitment Status
Terminated
Why Stopped
Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0074. Consequently, this trial terminated early.
Study Start Date
September 10, 2019 (Actual)
Primary Completion Date
May 20, 2020 (Actual)
Study Completion Date
May 20, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EMD Serono Research & Development Institute, Inc.
Collaborators
Merck KGaA, Darmstadt, Germany
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The study was to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Interferon-beta-1a (Avonex®), once a week intramuscularly in participants with Relapsing Multiple Sclerosis (RMS).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing-remitting Multiple Sclerosis
Keywords
Evobrutinib, Avonex®, Interferon-beta 1a, Relapsing Multiple Sclerosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Evobrutinib + Avonex® matched Placebo
Arm Type
Experimental
Arm Description
Participants received active evobrutinib twice daily (BID) along with concomitant intramuscular (IM) injection of placebo matched to Avonex® once a week. Treatment period was planned to be of 96 weeks.
Arm Title
Avonex® + Evobrutinib matched Placebo
Arm Type
Active Comparator
Arm Description
Participants received IM injection of active Avonex® once a week along with concomitant placebo matched to evobrutinib BID. Treatment period was planned to be of 96 weeks.
Intervention Type
Drug
Intervention Name(s)
Evobrutinib
Other Intervention Name(s)
M2951
Intervention Description
Participants received evobrutinib twice daily (BID).
Intervention Type
Drug
Intervention Name(s)
Avonex®
Intervention Description
Participants received avonex® IM injection once a week.
Intervention Type
Drug
Intervention Name(s)
Avonex® matched Placebo
Intervention Description
Participants received IM injection of placebo matched to avonex® once a week.
Intervention Type
Drug
Intervention Name(s)
Evobrutinib matched Placebo
Intervention Description
Participants received placebo matched to evobrutinib twice a day.
Primary Outcome Measure Information:
Title
Annualized Relapse Rate (ARR)
Description
The annualized relapse rate at 96 weeks was to be calculated based on qualified relapses. A qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to MS. The relapse should be accompanied by an increase of 0.5 points or more on Expanded Disability Status Scale (EDSS), or 2 points increase on one of the Functional System Scores (FSS), or 1 point increase on at least two of the FSS. The increase in FSS scores must be related to the neurological symptoms which were reported as new or worsening.
Time Frame
At Week 96
Secondary Outcome Measure Information:
Title
Time to First Occurrence of 12-Week Confirmed Expanded Disability Status Scale (EDSS) Progression
Description
EDSS is an ordinal scale in half-point increments that measures disability in participants with MS. EDSS progression is defined as an increase of 1 point or more from Baseline EDSS score when the Baseline score is 5.0 or less, and an increase of 0.5 points or more when the Baseline score is 5.5 or greater. Time to first occurrence of 12-week confirmed EDSS progression is defined as the time from randomization to the first EDSS progression event that was confirmed at a regularly scheduled visit at least 12 weeks later.
Time Frame
Baseline up to 96 weeks
Title
Time to First Occurrence of 24-Week Confirmed Expanded Disability Status Scale (EDSS) Progression
Description
EDSS is an ordinal scale in half-point increments that measures disability in participants with MS. EDSS progression is defined as an increase of 1 point or more from Baseline EDSS score when the Baseline score is 5.0 or less, and an increase of 0.5 points or more when the Baseline score is 5.5 or greater. Time to first occurrence of 24-week confirmed EDSS progression is defined as the time from randomization to the first EDSS progression event that was confirmed at a regularly scheduled visit at least 24 weeks later.
Time Frame
Baseline up to 96 weeks
Title
Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Short Form Score at Week 96
Description
The PROMIS PF Short Form is specific to measuring the physical function domain of MS patients, with each item on the form scored on a T-score metric. Higher scores indicate higher PF. Change from baseline at Week 96 is the difference between the PROMIS PF scores at 96 weeks and at baseline.
Time Frame
Baseline, Week 96
Title
Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form Score at Week 96
Description
The PROMIS Fatigue Short Form is specific to measuring the fatigue domain of MS patients, with each item on the form scored on a T-score metric. Higher scores indicate higher fatigue. Change from baseline at Week 96 is the difference between the PROMIS Fatigue scores at 96 weeks and at baseline.
Time Frame
Baseline, Week 96
Title
Total Number of Gadolinium-Enhancing (Gd+) Time Constant 1 (T1) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96
Description
Total number of Gd+ T1 lesions was to be assessed using magnetic resonance imaging (MRI).
Time Frame
At Week 24, 48 and 96
Title
Total Number of New or Enlarging Time Constant 2 (T2) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96
Description
Total number of new or enlarging T2 lesions was to be assessed using magnetic resonance imaging (MRI).
Time Frame
At Week 24, 48 and 96
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs)
Description
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. TEAE is an AE that started after study drug treatment; or if the event was continuous from baseline & was serious, related to investigational medicinal product (IMP), or resulted in death, discontinuation, interruption or reduction of study therapy. TEAEs included both serious and non-serious TEAEs. AESIs included liver AEs (possible drug-induced, non-infectious, non-alcoholic and immune-mediated) infections (serious and opportunistic infections), lipase and amylase elevation, and seizure.
Time Frame
Baseline up to 254 days
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Description
Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in participant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs included both serious TEAEs and non-serious TEAEs. Severity of TEAEs were graded using NCI CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs based on severity were reported.
Time Frame
Baseline up to 254 days
Title
Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Description
DBP and SBP were measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Time Frame
At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation (ED) (up to approximately 36 weeks
Title
Vital Signs: Pulse Rate
Description
Pulse rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Time Frame
At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation ED (up to approximately 36 weeks)
Title
Vital Signs: Respiratory Rate
Description
Respiration rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Time Frame
At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation ED (up to approximately 36 weeks)
Title
Vital Signs: Temperature
Description
Temperature was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.
Time Frame
At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation (ED) (up to approximately 36 weeks)
Title
Vital Signs: Weight
Time Frame
At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation (up to approximately 36 weeks)
Title
Number of Participants With Abnormal Lab Values
Description
The total number of participants with laboratory test abnormalities was assessed. Clinical laboratory tests included hematology, coagulation, biochemistry and urinalysis.
Time Frame
Baseline up to 254 days
Title
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
Description
ECG parameters included heart rhythm, heart rate, QRS intervals, QT intervals, RR intervals and corrected QT (QTc) intervals.
Time Frame
Baseline up to 254 days
Title
Absolute Concentrations of Immunoglobulin (Ig) A Level
Description
Absolute concentrations of Immunoglobulin (Ig) A was reported.
Time Frame
At Day 1 and Day 92
Title
Absolute Concentrations of Immunoglobulin (Ig) G Level
Description
Absolute concentrations of Immunoglobulin (Ig) E was reported.
Time Frame
At Day 1 and Day 92
Title
Absolute Concentrations of Immunoglobulin (Ig) M Level
Description
Absolute concentrations of Immunoglobulin (Ig) M was reported.
Time Frame
At Day 1 and Day 92
Title
Absolute Concentrations of Immunoglobulin (Ig) E Level
Description
Absolute concentrations of Immunoglobulin (Ig) E was reported.
Time Frame
At Day 1 and Day 92
Title
Change From Baseline in Immunoglobulin (Ig) A Level
Description
Change from baseline in immunoglobulin (Ig) A level was reported.
Time Frame
At Day 1 and Day 92
Title
Change From Baseline in Immunoglobulin (Ig) E Level
Description
Change from baseline in immunoglobulin (Ig) E level was reported.
Time Frame
At Day 1 and Day 92
Title
Change From Baseline in Immunoglobulin (Ig) G Level
Description
Change from baseline in immunoglobulin (Ig) G level was reported.
Time Frame
At Day 1 and Day 92
Title
Change From Baseline in Immunoglobulin (Ig) M Level
Description
Change from baseline in immunoglobulin (Ig) M level was reported.
Time Frame
At Day 1 and Day 92
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participants 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 EDSS score of 0 to 5.5 at Baseline. Participants with an EDSS score <= 2 at screening 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 and 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.
Participants have given written informed consent prior to any study-related procedure.
Other protocol defined inclusion criteria could apply
Exclusion Criteria:
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Responsible
Organizational Affiliation
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Official's Role
Study Director
Facility Information:
Facility Name
Please Contact U.S. Medical Information
City
Rockland
State/Province
Massachusetts
ZIP/Postal Code
02370
Country
United States
Facility Name
Please Contact the Communication Center
City
Darmstadt
ZIP/Postal Code
64293
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html.
Links:
URL
https://clinicaltrials.emdgroup.com/en/trial-details/?id=MS200527_0074
Description
Trial Awareness and Transparency website
URL
https://medical.emdserono.com/en_US/home.html
Description
US Medical Information website, Medical Resources
Learn more about this trial
Study of Evobrutinib in Participants With RMS
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