An Open-Label, Single-Arm, Multicenter, Phase 3 Study to Evaluate the Safety and Tolerability, and Pharmacokinetics of Diroximel Fumarate (BIIB098) in Adult Participants From the Asia-Pacific Region With Relapsing Forms of Multiple Sclerosis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Biogen
- 入组人数
- 136
- 试验地点
- 52
- 主要终点
- Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Diroximel Fumarate (DRF)
Japanese and Chinese participants will initiate treatment with DRF 231 milligrams (mg), oral capsule, twice daily on Day 1 through Day 7, followed by DRF 462 mg, oral capsules, twice daily from Day 8 up to Week 48.
干预措施: Diroximel fumarate (Drug)
结局指标
主要结局
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
时间窗: Baseline (Day 1) up to Week 24 (for prematurely discontinued participants, AEs were reported up to 2 weeks post discontinuation)
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.
Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters
时间窗: Baseline (Day 1) to Week 24
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.
Part 1: Number of Participants With Abnormal Shift in 12-Lead Electrocardiogram (ECG) Values
时间窗: Baseline (Day 1) to Week 24
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.
Part 1: Number of Participants With Clinically Relevant Abnormalities in Vital Sign Parameters
时间窗: Baseline (Day 1) to Week 24
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.
Part 1: Number of Participants With Columbia Suicide Severity Rating Scale (C-SSRS) Events
时间窗: Baseline (Day 1) to Week 24
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.
Parts 1 and 2: Number of Participants With TEAEs and TESAEs
时间窗: From Day 1 up to the end of the study (up to Week 50)
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.
Part 2: Number of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters
时间窗: Baseline (Day 1) to Week 48
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.
Part 2: Number of Participants With Abnormal Shift in 12-Lead ECG Values
时间窗: Baseline (Day 1) to Week 48
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.
Part 2: Number of Participants With Clinically Relevant Abnormalities in Vital Sign Parameters
时间窗: Baseline (Day 1) to Week 48
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.
Part 2: Number of Participants With C-SSRS Events
时间窗: Baseline (Day 1) to Week 48
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.
次要结局
- Part 1: Plasma Concentrations of Monomethyl Fumarate (MMF)-Intensive Pharmacokinetic (PK) Analysis Set(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(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(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(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(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(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(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(Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169)
- Part 1: Time to Reach Cmax (Tmax) of MMF-Intensive PK Analysis Set(Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169)
- Part 1: Tmax of HES-Intensive PK Analysis Set(Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169)
- Part 1: Elimination Half-Life (t½) of MMF-Intensive PK Analysis Set(Pre-dose and at 0.5,1,2,3,4,6, and 8 hours post-dose from Day 29 to Day 169)