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Study of Evobrutinib in Participants With Relapsing Multiple Sclerosis (RMS)

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ClinicalTrials.gov Identifier: NCT04032158
Recruitment Status : Terminated (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 MS200527-0073. Consequently, this trial terminated early.)
First Posted : July 25, 2019
Results First Posted : August 5, 2021
Last Update Posted : August 5, 2021
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

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 RMS.

Condition or disease Intervention/treatment Phase
Relapsing-remitting Multiple Sclerosis Drug: Evobrutinib Drug: Avonex® Drug: Avonex® matched Placebo Drug: Evobrutinib matched Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety
Actual Study Start Date : August 26, 2019
Actual Primary Completion Date : April 16, 2020
Actual Study Completion Date : April 16, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Evobrutinib + Avonex® matched Placebo
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.
Drug: Evobrutinib
Participants received evobrutinib twice daily (BID).
Other Name: M2951

Drug: Avonex® matched Placebo
Participants received IM injection of placebo matched to Avonex® once a week.

Active Comparator: Avonex® + Evobrutinib matched Placebo
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.
Drug: Avonex®
Participants received avonex® IM injection once a week.

Drug: Evobrutinib matched Placebo
Participants received placebo matched to evobrutinib twice a day.




Primary Outcome Measures :
  1. Annualized Relapse Rate (ARR) [ Time Frame: At Week 96 ]
    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 :
  1. Time to First Occurrence of 12-Week Confirmed Expanded Disability Status Scale (EDSS) Progression [ Time Frame: Baseline up to 96 weeks ]
    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.

  2. Time to First Occurrence of 24-Week Confirmed Expanded Disability Status Scale (EDSS) Progression [ Time Frame: Baseline up to 96 weeks ]
    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.

  3. Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Short Form Score at Week 96 [ Time Frame: Baseline, 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.

  4. Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Fatigue Score at Week 96 [ Time Frame: Baseline, 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.

  5. Total Number of Gadolinium-Enhancing (Gd+) Time Constant 1 (T1) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96 [ Time Frame: At Week 24, 48 and 96 ]
    Total number of Gd+ T1 lesions was to be assessed using magnetic resonance imaging (MRI).

  6. Total Number of New or Enlarging Time Constant 2 (T2) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96 [ Time Frame: At Week 24, 48 and 96 ]
    Total number of new or enlarging T2 lesions was to be assessed using magnetic resonance imaging (MRI).

  7. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) [ Time Frame: Baseline up to 235 days ]
    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 and was serious, related to study drug, or resulted in death, discontinuation, interruption or reduction of study therapy. TEAEs includes both serious TEAEs 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.

  8. 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) [ Time Frame: Baseline up to 235 days ]
    TEAE is an AE that started after study drug treatment; or if the event was continuous from baseline and was serious, related to investigational medicinal product (IMP), or resulted in death, discontinuation, interruption or reduction of study therapy. 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.

  9. Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) [ Time Frame: At Day 1, 83, 125 and 155 ]
    DBP and SBP were measured in semi-supine position after 5 minutes rest for the participants at indicated time points.

  10. Vital Signs: Pulse Rate [ Time Frame: At Day 1, 83, 125 and 155 ]
    Pulse rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.

  11. Vital Signs: Respiratory Rate [ Time Frame: At Day 1, 83, 125 and 155 ]
    Respiration rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.

  12. Vital Signs: Temperature [ Time Frame: At Day 1, 83, 125 and 155 ]
    Temperature was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.

  13. Vital Signs: Weight [ Time Frame: At Day 1, 83, 125 and 155 ]
  14. Number of Participants With Abnormal Lab Values [ Time Frame: Baseline up to 235 days ]
    The total number of participants with laboratory test abnormalities was assessed. Clinical laboratory tests included hematology, coagulation, biochemistry and urinalysis.

  15. Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: Baseline up to 235 days ]
    ECG parameters included heart rhythm, heart rate, QRS intervals, QT intervals, RR intervals and corrected QT (QTc) intervals.

  16. Absolute Concentrations of Immunoglobulin (Ig) A Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Absolute concentrations of Immunoglobulin (Ig) A was reported.

  17. Absolute Concentrations of Immunoglobulin (Ig) E Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Absolute concentrations of Immunoglobulin (Ig) E was reported.

  18. Absolute Concentrations of Immunoglobulin (Ig) G Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Absolute concentrations of Immunoglobulin (Ig) G was reported.

  19. Absolute Concentrations of Immunoglobulin (Ig) M Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Absolute concentrations of Immunoglobulin (Ig) M was reported.

  20. Change From Baseline in Immunoglobulin (Ig) A Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Change from baseline in immunoglobulin (Ig) A level was reported.

  21. Change From Baseline in Immunoglobulin (Ig) E Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Change from baseline in immunoglobulin (Ig) E level was reported.

  22. Change From Baseline in Immunoglobulin (Ig) G Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Change from baseline in immunoglobulin (Ig) G level was reported.

  23. Change From Baseline in Immunoglobulin (Ig) M Level [ Time Frame: At Day 1, 83, 125 and 155 ]
    Change from baseline in immunoglobulin (Ig) M level was reported.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: - Participants are 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 Expanded Disability Status Scale (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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04032158


Locations
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United States, Massachusetts
Please Contact U.S. Medical Information
Rockland, Massachusetts, United States, 02370
Germany
Please Contact the Communication Center
Darmstadt, Germany, 64293
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
  Study Documents (Full-Text)

Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Study Protocol  [PDF] September 5, 2019
Statistical Analysis Plan  [PDF] May 28, 2020

Additional Information:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT04032158    
Other Study ID Numbers: MS200527_0073
2018-004701-11 ( EudraCT Number )
First Posted: July 25, 2019    Key Record Dates
Results First Posted: August 5, 2021
Last Update Posted: August 5, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Evobrutinib
Avonex®
Interferon-beta 1a
Relapsing Multiple Sclerosis
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Interferon beta-1a
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents