Study of Evobrutinib in Participants With RMS

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

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).

Study Overview

• Status: Terminated
• Conditions: Relapsing-remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Evobrutinib; Drug: Avonex® matched Placebo; Drug: Avonex®; Drug: Evobrutinib matched Placebo

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Darmstadt, Germany, 64293
    • Please Contact the Communication Center
• United States
  • Massachusetts
    • Rockland, Massachusetts, United States, 02370
      • Please Contact U.S. Medical Information

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline up to 96 weeks
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.	Baseline up to 96 weeks
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.	Baseline, Week 96
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.	Baseline, Week 96
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).	At Week 24, 48 and 96
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).	At Week 24, 48 and 96
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.	Baseline up to 254 days
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.	Baseline up to 254 days
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.	At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation (ED) (up to approximately 36 weeks
Vital Signs: Pulse Rate	Pulse rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.	At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation ED (up to approximately 36 weeks)
Vital Signs: Respiratory Rate	Respiration rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.	At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation ED (up to approximately 36 weeks)
Vital Signs: Temperature	Temperature was measured in semi-supine position after 5 minutes rest for the participants at indicated time points.	At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation (ED) (up to approximately 36 weeks)
Vital Signs: Weight		At Day 1, Week 2 unscheduled 1, Week 12 and Early Discontinuation (up to approximately 36 weeks)
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.	Baseline up to 254 days
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.	Baseline up to 254 days
Absolute Concentrations of Immunoglobulin (Ig) A Level	Absolute concentrations of Immunoglobulin (Ig) A was reported.	At Day 1 and Day 92
Absolute Concentrations of Immunoglobulin (Ig) G Level	Absolute concentrations of Immunoglobulin (Ig) E was reported.	At Day 1 and Day 92
Absolute Concentrations of Immunoglobulin (Ig) M Level	Absolute concentrations of Immunoglobulin (Ig) M was reported.	At Day 1 and Day 92
Absolute Concentrations of Immunoglobulin (Ig) E Level	Absolute concentrations of Immunoglobulin (Ig) E was reported.	At Day 1 and Day 92
Change From Baseline in Immunoglobulin (Ig) A Level	Change from baseline in immunoglobulin (Ig) A level was reported.	At Day 1 and Day 92
Change From Baseline in Immunoglobulin (Ig) E Level	Change from baseline in immunoglobulin (Ig) E level was reported.	At Day 1 and Day 92
Change From Baseline in Immunoglobulin (Ig) G Level	Change from baseline in immunoglobulin (Ig) G level was reported.	At Day 1 and Day 92
Change From Baseline in Immunoglobulin (Ig) M Level	Change from baseline in immunoglobulin (Ig) M level was reported.	At Day 1 and Day 92

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2019
• Primary Completion (Actual): May 20, 2020
• Study Completion (Actual): May 20, 2020

Study Registration Dates

• First Submitted: July 23, 2019
• First Submitted That Met QC Criteria: July 23, 2019
• First Posted (Actual): July 25, 2019

Study Record Updates

• Last Update Posted (Actual): August 5, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Evobrutinib; Avonex®; Interferon-beta 1a; Relapsing Multiple Sclerosis
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interferon beta-1a
• Other Study ID Numbers: MS200527_0074; 2018-004700-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No