Study of Evobrutinib in Participants With RMS (evolutionRMS 2)

Phase 3TerminatedNCT04338061

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany1,166 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

1,166

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 less than or equal to \[\<=\] 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 (278)

Research Site 752

Cullman, Alabama, United States

Research Site 741

Scottsdale, Arizona, United States

Research Site 704

Tucson, Arizona, United States

Research Site 751

Hanford, California, United States

Research Site 737

West Hollywood, California, United States

Research Site 759

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: Baseline up to 170 weeks

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 periods)

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.

Time frame: Baseline up to 170 weeks

DBTP and DBE Period: New or Enlarging T2 Lesions Rate

Analysis of new or enlarging T2 lesions rate was done using magnetic resonance imaging (MRI) scans. Negative binomial model for lesion count (summed over scans) includes treatment and covariates based on randomization strata and baseline volume of T2 lesion (continuous), with offset equal to the log of the time in years between the last available MRI scan and the baseline scan.

Time frame: Baseline up to 170 weeks

DBTP Period: Neurofilament Light Chain (NfL) Concentration at Week 12

NfL is a biomarker of neuro-axonal damage whose concentration was assessed in blood at Week 12.

Time frame: Week 12

DBTP and DBE Periods: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs)

Adverse event (AE): Any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the 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. TEAEs: those AEs with an onset date on or after the date of first study intervention administration, or AEs present prior to any study intervention administration but exacerbating after. TEAEs included 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.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity

Severity of adverse events (AE) were assessed by the investigator per the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with Grades 1, 2, 3, 4 and 5 were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure

Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: diastolic blood pressure and systolic blood pressure from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Vital Signs: Pulse Rate

Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: pulse rate from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Vital Signs: Respiratory Rate

Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: respiratory rate from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Vital Signs: Weight

Changes in vital signs: weight from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Vital Signs: Temperature

Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: Temperature from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): Heart Rate

Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: heart rate from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration

QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin. Changes in hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes. Changes in hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Hematology Parameters: Hematocrit

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Hematocrit. Changes in hematology parameter: Hematocrit from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin. Changes in hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume. Changes in hematology parameter: Erythrocytes Mean Corpuscular Volume from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Bilirubin and Creatinine

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Bilirubin and Creatinine. Changes in biochemistry parameters: Bilirubin and Creatinine from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase. Changes in biochemistry parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium. Changes in biochemistry parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Total Protein and Albumin

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Total Protein and Albumin. Changes in biochemistry parameters: Total Protein and Albumin from baseline up to 170 weeks were reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Glomerular Filtration Rate

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameter: Glomerular Filtration Rate. Changes in biochemistry parameter: Glomerular Filtration Rate from baseline up to 170 weeks were reported. The Glomerular Filtration Rate was measured as milliliter per minute per 1.73 square meter (mL/min/1.73m\^2).

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Potential of Hydrogen (pH) of Urine

Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: pH. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Changes in urinalyses parameter: pH from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Specific Gravity of Urine

Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: Specific Gravity of Urine. Changes in urinalyses parameter: Specific Gravity of Urine from baseline up to 170 weeks was reported.

Time frame: Baseline up to 170 weeks

DBTP and DBE Periods: Absolute Concentrations of Immunoglobulin (Ig) Levels

Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.

Time frame: At Week 170

DBTP and DBE Periods: Change From Baseline in Immunoglobulin (Ig) Levels

Change from baseline serum levels of IgG, IgA, IgM were assessed.

Time frame: Baseline up to 170 weeks