Study of Evobrutinib in Participants With RMS

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Relapsing-remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: Evobrutinib
* Drug: Avonex®
* Drug: Avonex® matched Placebo
* Drug: Evobrutinib matched Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evobrutinib + Avonex® matched Placebo<br>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<br>* Participants received evobrutinib twice daily (BID).<br>* Other names: M2951;Drug: Avonex® matched Placebo<br>* Participants received IM injection of placebo matched to avonex® once a week.<br>|
| Active Comparator: Avonex® + Evobrutinib matched Placebo<br>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®<br>* Participants received avonex® IM injection once a week.<br>Drug: Evobrutinib matched Placebo<br>* Participants received placebo matched to evobrutinib twice a day.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Evobrutinib, Avonex®, Interferon-beta 1a, Relapsing Multiple Sclerosis