A Study of Diroximel Fumarate (DRF) in Adult Participants From the Asia-Pacific Region With Relapsing Forms of Multiple Sclerosis (RMS)

Biogen136 enrolled

Overview

The primary objectives of this study are to determine the safety and tolerability of DRF administered for up to 24 weeks in adult East Asian participants with RMS (Part 1) and to determine the safety and tolerability of DRF administered for up to 48 weeks in adult East Asian participants with RMS (Part 2). The secondary objective of this study is to evaluate the pharmacokinetic(s) (PK) of DRF metabolites (monomethyl fumarate \[MMF\] and 2-hydroxyethyl succinimide \[HES\]) following multiple doses of DRF in a subset of adult East Asian participants with RMS (Part 1).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

136

Conditions

Relapsing Forms of Multiple Sclerosis

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Must have a diagnosis of RMS, as defined by revised 2017 McDonald's criteria. * Expanded Disability Status Scale (EDSS) score between 0.0 and 5.0, inclusive, at screening and baseline visit (Day 1). * Neurologically stable with no evidence of relapse within 30 days prior to baseline visit (Day 1). * For Japanese participants: Born in Japan and biological parents and grandparents were of Japanese origin. If previously lived outside of Japan for more than 5 years, must not have had a significantly modified diet since leaving Japan. * For Chinese participants: Born in China, and biological parents and grandparents were of Chinese origin. If previously lived outside of China for more than 5 years, must not have had a significantly modified diet since leaving China. Key Exclusion Criteria: * Has a multiple sclerosis (MS) relapse that has occurred within the 30 days prior to randomization and/or the participant has not stabilized from a previous relapse prior to randomization. * History of severe allergic or anaphylactic reactions or of any allergic reactions that, in the opinion of the investigator, are likely to be exacerbated by any component of the study treatment. * History of, or ongoing, malignant disease, including solid tumors and hematologic malignancies. * Has a history of gastrointestinal (GI) surgery (except appendectomy or cholecystectomy that occurred more than 6 months prior to screening), irritable bowel syndrome, inflammatory bowel disease (Crohn's disease, ulcerative colitis), or other clinically significant and active GI condition per the investigator's discretion. * History of clinically significant recurring or active GI symptoms (e.g., nausea, diarrhea, dyspepsia, constipation) within 90 days of screening, including symptoms that require the initiation of symptomatic medical treatment (e.g., initiation of a medication to treat gastroesophageal reflux disease) or a change in symptomatic medical treatment (e.g., an increase in dose) within 90 days prior to screening. * History of systemic hypersensitivity reaction to DRF, dimethyl fumarate (DMF), MMF or other fumaric esters, the excipients contained in the formulation, and if appropriate, any diagnostic agents to be administered during the study. * Evidence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 14 days prior to Screening, between screening and baseline visit (Day 1), or at baseline visit (Day 1), including but not limited to a fever (temperature \>37.5 degrees Celsius \[°C\]), new and persistent cough, breathlessness, or loss of taste and/or smell. Evidence of current SARS-CoV-2 infection within 14 days prior to Screening or during Screening, will be eligible for rescreening, provided that the participant is asymptomatic for 14 days prior to rescreening. * Have close contact within 14 days prior to Day 1 with individual(s) with suspected SARS-CoV-2 infection. * For participants who had close contact with individual(s) with suspected SARS-CoV-2 infection within 14 days prior to Day 1, as determined by the Investigator, will be eligible for rescreening, provided that the participant is asymptomatic for 14 days after the contact. * History or positive test result at screening for human immunodeficiency virus (HIV). * Previous participation in this study or previous studies with DRF, DMF, or MMF. * Has a clinically significant history of suicidal ideation or suicidal behavior occurring in the past 12 months as assessed by the C-SSRS at Screening. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Locations (52)

The First Affiliated Hospital of Anhui Medical University

Hefei, Anhui, China

Beijing Hospital

Beijing, Beijing Municipality, China

Beijing Tiantan Hospital, Capital Medical University

Beijing, Beijing Municipality, China

Fujian Medical University Union Hospital

Fuzhou, Fujian, China

Lanzhou University Second Hospital

Lanzhou, Gansu, China

Outcomes

Primary Outcomes

Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An adverse event (AE) was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether/not related to the medicinal (investigational) product. An AE was considered treatment-emergent if it starts or worsens on or after the date of the first dose of study drug in the study until 1 day after the last dose of treatment, or completion of the safety follow-up visit, if applicable.(i.e. for participants who prematurely discontinued study treatment or withdrew from the study) . An SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization or prolongation of existing hospitalization, results in a significant disability/incapacity or congenital anomaly, is a medically important event. TEAEs included both serious and non-serious TEAEs.

Time frame: Baseline (Day 1) up to Week 24 (for prematurely discontinued participants, AEs were reported up to 2 weeks post discontinuation)

Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters

Laboratory assessments included hematology, blood chemistry, and urinalysis parameters. Hematology parameters:basophils, hematocrit, red blood cell, total and differential leukocytes, platelets, lymphocytes, monocytes, neutrophils, eosinophils, hemoglobin. Blood chemistry parameters:sodium, potassium, chloride, glucose, calcium, uric acid, total protein, albumin, creatine phosphokinase, Lipid profile: blood cholesterol,high-density lipoprotein,low-density lipoprotein, and triglycerides,serum follicle-stimulating hormone,Vitamin D,thyroid stimulating hormone,serum pregnancy, HIV/Hepatitis screen,tuberculosis test,alanine aminotransferase,aspartate aminotransferase,Lactate Dehydrogenase,alkaline phosphatase,gamma glutamyl transferase,total bilirubin,blood urea nitrogen,creatinine and bicarbonate. Urinalysis parameters:color,pH,specific gravity,ketones,protein,glucose, bilirubin,nitrite,urobilinogen,occult blood,microscopic examination,urine albumin,beta-2-microglobulin,urine creatinine.

Time frame: Baseline (Day 1) to Week 24

Part 1: Number of Participants With Abnormal Shift in 12-Lead Electrocardiogram (ECG) Values

The number of participants with shifts to categorical values of ECG interpretation (e.g. abnormal) were presented by each cohort. Abnormal shift includes a shift from normal or unknown to abnormal.

Time frame: Baseline (Day 1) to Week 24

Part 1: Number of Participants With Clinically Relevant Abnormalities in Vital Sign Parameters

Vital sign assessment included temperature, pulse rate systolic blood pressure, diastolic blood pressure, and respiratory rate. The criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature \< 36 and \> 38 degrees Celsius (C), pulse rate \< 60 and \> 100 beats per minute (bpm), systolic blood pressure (\< 90, \> 140 and \> 160 millimeters of mercury \[mmHg\]), diastolic blood pressure \< 50, \> 90 and \> 100 mmHg, weight (7% or more increase from baseline, 7% or more decrease from baseline) and respiratory rate \< 12 and \> 20 breaths per minute.

Time frame: Baseline (Day 1) to Week 24

Part 1: Number of Participants With Columbia Suicide Severity Rating Scale (C-SSRS) Events

The C-SSRS was an interview-based rating scale to systematically assess suicidal ideation, suicidal behavior and non-suicidal self-injurious behavior. The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal behavior (preparatory acts or behavior, aborted attempt, interrupted attempt, Suicidal behavior, completed suicide), suicidal ideation (wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods, active suicidal ideation with some intent, active suicidal ideation with specific plan and intent) and non-suicidal self-injurious behavior.

Time frame: Baseline (Day 1) to Week 24

Parts 1 and 2: Number of Participants With TEAEs and TESAEs

An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with use of medicinal (investigational) product, whether/not related to medicinal (investigational) product. AE was considered treatment-emergent if it starts or worsens on or after the date of the first dose of study drug in the study until 1 day after the last dose of treatment. SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization or prolongation of existing hospitalization, results in a significant disability/incapacity or congenital anomaly, is a medically important event. TEAEs included both serious and non-serious TEAEs. TEAEs and TESAEs for participants were collected cumulatively for Parts 1 and 2.

Time frame: From Day 1 up to the end of the study (up to Week 50)

Part 2: Number of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters

Time frame: Baseline (Day 1) to Week 48

Part 2: Number of Participants With Abnormal Shift in 12-Lead ECG Values

The number of participants with shifts to categorical values of ECG interpretation (e.g. abnormal) were presented by each cohort. Abnormal shift includes a shift from normal or unknown to abnormal.

Time frame: Baseline (Day 1) to Week 48

Part 2: Number of Participants With Clinically Relevant Abnormalities in Vital Sign Parameters

Vital sign assessment included temperature, pulse rate systolic blood pressure, diastolic blood pressure, and respiratory rate. The criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature \< 36 and \> 38 degrees C, pulse rate \< 60 and \> 100 bpm, systolic blood pressure (\< 90, \> 140 and \> 160 mmHg), diastolic blood pressure \< 50, \> 90 and \> 100 mmHg, weight (7% or more increase from baseline, 7% or more decrease from baseline) and respiratory rate \< 12 and \> 20 breaths per minute.

Time frame: Baseline (Day 1) to Week 48

Part 2: Number of Participants With C-SSRS Events

Time frame: Baseline (Day 1) to Week 48

Secondary Outcomes

Part 1: Plasma Concentrations of Monomethyl Fumarate (MMF)-Intensive Pharmacokinetic (PK) Analysis Set

Summarized data for plasma concentration of MMF at all timepoints is reported.

Time frame: Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169

Part 1: Plasma Concentration of 2-Hydroxyethyl Succinimide (HES)-Intensive PK Analysis Set

Summarized data for plasma concentration of HES at all timepoints is reported.

Time frame: Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169

Part 1: Plasma Concentrations of MMF-Sparse PK Analysis Set

Time frame: Pre-dose and 2 to 3 hours post-dose on Day 29 and Day 57

Part 1: Plasma Concentrations of HES-Sparse PK Analysis Set

Time frame: Pre-dose and 2 to 3 hours post-dose on Day 29 and Day 57

Part 1: Maximum Observed Concentration (Cmax) of MMF-Intensive PK Analysis Set

Summarized data for Cmax at all timepoints is reported.

Time frame: Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169

Part 1: Cmax of HES-Intensive PK Analysis Set

Summarized data for Cmax at all timepoints is reported.

Time frame: Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169

Part 1: Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) of MMF-Intensive PK Analysis Set

Summarized data for AUClast at all timepoints is reported.

Time frame: Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169

Part 1: AUClast of HES-Intensive PK Analysis Set

Summarized data for AUClast at all timepoints is reported.