Study of Evobrutinib in Participants With RMS (evolutionRMS 1)

Study Overview
=================
Brief Summary
-----------------
The study is to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Teriflunomide (Aubagio®), administered orally once daily in participants with Relapsing Multiple Sclerosis (RMS). Participants who complete the double-blind treatment period (DBTP) and double-blind extension period (DBEP) prior to approval of a separate long-term follow-up study in their country will get an option for evobrutinib treatment continuation through a 96-week open-label extension (OLE) period.

Official Title
-----------------
A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active Controlled Study of Evobrutinib Compared With Teriflunomide, in Participants With Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety (evolutionRMS 1)

Conditions
-----------------
Relapsing Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: Evobrutinib
* Drug: Placebo (match to Teriflunomide)
* Drug: Teriflunomide
* Drug: Placebo (match to Evobrutinib)


Participation Criteria
=================
Eligibility 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 Screening and Baseline (Day 1). Participants with an EDSS score <= 2 at Screening and Baseline (Day 1) 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 (Day 1) Female participants must be neither pregnant nor breast-feeding or 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 and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure Male participants must refrain from donating sperm and/or abstain from intercourse with women of child-bearing potential or use an effective method of contraception for the duration of the study and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure 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 and Baseline (Day 1) 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
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evobrutinib + Teriflunomide matched Placebo: DB Period<br> | Drug: Evobrutinib<br>* Evobrutinib twice daily (BID) in DBTP.<br>* Other names: M2951;Drug: Placebo (match to Teriflunomide)<br>* Placebo match to Teriflunomide once daily in DBTP.<br>|
| Active Comparator: Teriflunomide + Evobrutinib matched Placebo: DB Period<br> | Drug: Teriflunomide<br>* Teriflunomide once daily in DBTP.<br>Drug: Placebo (match to Evobrutinib)<br>* Placebo match to Evobrutinib BID in DBTP.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DBTP: Annualized Relapse Rate (ARR) | The annualized relapse rates up to 156 weeks will be calculated based on qualified relapses. Qualifying relapse is defined as occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than 24 hours, no fever, infection, injury, adverse events, and preceded by a stable or improving neurological state for greater than or equal to (=>) 30 days). | Up to 156 weeks | 
| DBE Period: ARR | The annualized relapse rates up to 96 weeks will be calculated based on qualified relapses. Qualifying relapse is defined as occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than 24 hours, no fever, infection, injury, adverse events, and preceded by a stable or improving neurological state for greater than or equal to (=>) 30 days). | Up to 96 weeks | 
| OLE Period: Number of Participants with Adverse Events and Serious Adverse Events (SAE)s |  | Baseline OLE up to 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DBTP: Time to First Occurrence of 12-Week Confirmed Disability Progression (CDP) as measured by Expanded Disability Status Scale (EDSS) Progression |  | Up to 156 weeks | 
| DBTP: Time to First Occurrence of 24-Week CDP as measured by EDSS Progression |  | Up to 156 weeks | 
| DBTP: Time to First Occurrence of 24-Week Confirmed Disability Improvement (CDI) as measured by EDSS Improvement |  | Up to 156 weeks | 
| DBTP: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Physical Function (PF) Short Form Score |  | Baseline up to 96 weeks | 
| DBTP: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Fatigue Short Form Score |  | Baseline up to 96 weeks | 
| DBTP: Total Number of Gadolinium-Enhancing (Gd+) T1 Lesions Assessed by all Available Magnetic Resonance Imaging (MRI) Scans |  | Up to Week 156 | 
| DBTP: Total Number of New or Enlarging T2 Lesions Assessed by the Last Available Magnetic Resonance Imaging (MRI) Scan Relative to Baseline MRI Scan |  | Up to Week 156 | 
| DBTP: Neurofilament light chain (NfL) Serum Concentration |  | At Week 12 | 
| DBTP: Number of Participants With Adverse Events (AEs) 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. | Baseline up to 156 weeks | 
| DBTP: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings | Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported. | Baseline up to 156 weeks | 
| DBTP: Absolute Concentrations of Immunoglobulin (Ig) Levels |  | Baseline up to 156 weeks | 
| DBTP: Change From Baseline in Immunoglobulin (Ig) Levels |  | Baseline up to 156 weeks | 
| DBE Period: Time to First Occurrence of 12-Week CDP as measured by EDSS Progression |  | Up to 96 weeks | 
| DBE Period: Time to First Occurrence of 24-Week CDP as measured by EDSS Progression |  | Up to 96 weeks | 
| DBE Period: Time to First Occurrence of 24-Week CDI as measured by EDSS Improvement |  | Up to 96 weeks | 
| DBE Period: Change From Baseline in PROMIS MS PF Short Form Score |  | Baseline up to 96 weeks | 
| DBE Period: Change From Baseline in PROMIS MS Fatigue Short Form Score |  | Baseline up to 96 weeks | 
| DBE Period: Total Number of Gd+ T1 Lesions Assessed by all Available MRI Scans |  | Up to Week 96 | 
| DBE Period: Total Number of New or Enlarging T2 Lesions Assessed on the Last Available MRI Scans Relative to Baseline MRI Scan |  | Up to Week 96 | 
| DBE Period: Number of Participants With Adverse Events (AEs) 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. | Baseline up to 96 weeks | 
| DBE Period: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings | Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported. | Baseline up to 96 weeks | 
| DBE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels |  | Baseline up to 96 weeks | 
| DBE Period: Change From Baseline in Immunoglobulin (Ig) Levels |  | Baseline up to 96 weeks | 
| OLE Period: ARR based on protocol-defined qualified relapses |  | Baseline OLE up to 96 weeks | 
| OLE Period: Time to first occurrence of 24-week CDP as measured by EDSS |  | Baseline OLE up to 96 weeks | 
| OLE Period: Time to first occurrence of 24-week CDI as measured by EDSS |  | Baseline OLE up to 96 weeks | 
| OLE Period: Symbol Digital Modalities Test Over time |  | Baseline OLE up to 96 weeks | 
| OLE Period: PROMISnq PF (MS) 15a score change over time |  | Baseline OLE up to 96 weeks | 
| OLE Period: PROMIS Fatigue (MS) 8a Score Change Over Time |  | Baseline OLE up to 96 weeks | 
| OLE Period: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Electrocardiogram (ECG) and Laboratory Findings |  | Baseline OLE up to 96 weeks | 
| OLE: Total Number of New or Enlarging T2 Lesions Assessed on the Last Available Magnetic Resonance Imaging (MRI) Scans |  | Baseline OLE up to 96 weeks | 
| OLE: Change from Baseline in T2 lesion Volume Over Time |  | Baseline OLE up to 96 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Evobrutinib, Teriflunomide, Aubagio®, Relapsing Multiple Sclerosis