Study of Evobrutinib in Participants With RMS (evolutionRMS 1)

Phase 3TerminatedNCT04338022

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany1,124 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

1,124

Conditions

Relapsing Multiple Sclerosis

Interventions

Teriflunomide

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

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.

Locations (279)

Research Site 629

Mobile, Alabama, United States

Research Site 614

Phoenix, Arizona, United States

Research Site 677

Phoenix, Arizona, United States

Research Site 642

Long Beach, California, United States

Research Site 644

Pasadena, California, United States

Research Site 672

Outcomes

Primary Outcomes

Double Blind Treatment Period (DBTP) and Double Blind Extension (DBE) Period: Annualized Relapse Rate (ARR)

The qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than \[\>\] 24 hours, no fever, infection, injury, adverse events (AEs,) and preceded by a stable or improving neurological state for more than or equal to \[\>=\] 30 days).

Time frame: From baseline to 172 weeks

Open Label Extension (OLE) Period: Number of Participants With Adverse Events (AEs) and Serious AEs

Adverse event (AE): Any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important.

Time frame: From OLE Baseline (DBTP Week 96) to OLE Week 52

Secondary Outcomes

DBTP and DBE Period: Percentage of Participants Without 12-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)

Disability progression was defined as increase in EDSS of greater than or equal to \[\>=\] 1 point from baseline EDSS score, if EDSS score at baseline is 5.0 or less and an increase of \>=0.5 point, if the baseline score is 5.5. Disability progression is considered sustained for 12 weeks when the initial increase in the EDSS is confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of participants without 12-week CDP.

Time frame: Week 96 and Week 156 (combined DBTP and DBE period)

DBTP and DBE Period: Percentage of Participants Without 24-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)

Disability progression was defined as increase in EDSS of greater than or equal to \[\>=\] 1 point from baseline EDSS score, if EDSS score at baseline is 5.0 or less and an increase of \>=0.5 point, if the baseline score is 5.5. Disability progression is considered sustained for 24 weeks when the initial increase in the EDSS is confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of participants without 24-week CDP.

Time frame: Week 96 and Week 156 (combined DBTP and DBE periods)

DBTP and DBE Period: Percentage of Participants With 24-Week Confirmed Disability Improvement (CDI) as Measured by Expanded Disability Status Scale (EDSS)

Disability improvement was defined as a reduction of 1 point from Baseline EDSS score when the Baseline score is \>= 2 and less than or equal to \[\<=\] 6 and a reduction of 0.5 point from Baseline EDSS score when the Baseline score is \>= 6.5 and \<= 9.5. Disability improvement is considered sustained when the initial reduction in the EDSS score is confirmed at a regularly scheduled visit at least 24 weeks after the initial reduction. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of participants with 12-week CDI.

Time frame: Week 96 and Week 156 (combined DBTP and DBE periods)

DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 48, Week 96, Week 120, Week 144 and Week 156

Physical function was assessed with PROMISnq Short Form v2.0 - Physical Function - Multiple Sclerosis 15a (PROMISnq PF(MS) 15a). PROMISnq PF(MS) 15a assesses a participant's abilities and limitations with respect to everyday physical activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 10 to 65. Higher T-scores represent higher physical function. Change from baseline in PROMIS PF score was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the result of the 2 periods (DBTP and DBE).

Time frame: Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (combined DBTP and DBE periods)

DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Score at Week 48, Week 96, Week 120, Week 144 and Week 156

PROMIS Fatigue score was assessed with PROMIS Short Form v1.0 - Fatigue - Multiple Sclerosis 8a (PROMIS Fatigue (MS) 8a). PROMIS Fatigue (MS) 8a assesses level of fatigue and its interference on daily activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 33 to 85. Higher T-scores represent higher fatigue. Change from baseline in PROMIS fatigue score was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the result of the 2 periods (DBTP and DBE).

Time frame: Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (combined DBTP and DBE periods)

DBTP and DBE Period: Total Number of T1 Gadolinium-positive (Gd+) Lesions

Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans.