A Phase 1 Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 Administered Intrathecally to Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Biogen
- 入组人数
- 106
- 试验地点
- 1
- 主要终点
- Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The primary objective of this study is to evaluate the safety and tolerability of BIIB078 in adults with C9ORF72-Amyotrophic Lateral Sclerosis (ALS). The secondary objectives of this study are to evaluate the pharmacokinetic profile of BIIB078 and to evaluate the effects of BIIB078 on clinical function. As the first-in-human study, the study enrolls a small number of participants in each cohort. Every participant in a cohort is treated with the same dose or placebo. The study is designed to evaluate and confirm the safety of each dose before enrolling and exposing new participants to a higher dose in the next cohort.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ability of the participant to understand the purpose and risks of the study, to provide signed and dated informed consent, and to authorize the use of confidential health information in accordance with national and local participant privacy regulations; or, in the event of the participant's physical incapacity to sign, to confirm that understanding and consent orally to a legally authorized representative (LAR) for the express purpose of having said informed consent and authorization signed on his/her behalf.
- •All participants of childbearing potential must agree to practice highly effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment.
- •Must meet the possible, laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria and have documentation of a clinical genetic test demonstrating the presence of a pathogenic mutation in C9ORF
- •Slow vital capacity (SVC) ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position).
- •Participants taking concomitant riluzole at study entry must be on a stable dose for ≥ 30 days prior to the first dose of study treatment (Day 1).
- •Participants taking concomitant edaravone at study entry must be on a stable dose for ≥ 60 days prior to the first dose of study treatment (Day 1).
- •ALS Cognitive Behavioral Screen (ALS-CBS) score ≥ 11 for the cognitive portion; ≥ 33 for the behavioral portion.
- •Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
- •Screening values of coagulation parameters including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) should be within normal ranges.
- •Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at Screening.
排除标准
- •History of drug abuse or alcoholism ≤ 6 months of Screening that would limit participation in the study, as determined by the Investigator.
- •Tracheostomy.
- •Prescreening ALSFRS-R slope less than 0.4 points/month, where prescreening ALSFRS-R slope is defined as follows: (48 - ALSFRS-R score at Screening) / (months from date of symptom onset to date of Screening).
- •History of or positive test result at Screening for human immunodeficiency virus. .
- •History of, or positive test result at Screening for, hepatitis C virus antibody.
- •Treatment with another investigational drug or biological agent within 1 month of Screening or 5 half-lives of study agent, whichever is longer.
- •Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for lumbar puncture (LP) according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber.
- •Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
- •Female participants who are pregnant or currently breastfeeding.
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Cohort 1: BIIB078 First Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.
干预措施: BIIB078 (Drug)
Cohort 2: BIIB078 Second Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.
干预措施: BIIB078 (Drug)
Cohort 3: BIIB078 Third Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.
干预措施: BIIB078 (Drug)
Cohort 4: BIIB078 Fourth Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.
干预措施: BIIB078 (Drug)
Cohort 5: BIIB078 Fifth Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.
干预措施: BIIB078 (Drug)
Cohort 6: BIIB078 Sixth Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.
干预措施: BIIB078 (Drug)
Cohorts 1-6: Placebo
Matching placebo will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days (Cohorts 1 through 3) and five maintenance doses on five later days (Cohorts 4 through 6).
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Baseline through End of Study (Approximately Day 323)
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, places participant at immediate risk of death, requires initial or prolonged inpatient hospitalization, results in persistent or significant disability/incapacity, results in congenital anomaly, is a medically important event.
次要结局
- Area Under the Concentration-Time Curve (AUC) from Time 0 to Infinity (AUCinf)(Baseline and at multiple time points up to Day 260)
- AUC from Time 0 to Time of the Last Measurable Concentration (AUClast)(Baseline and at multiple time points up to Day 260)
- Maximum Observed Concentration (Cmax)(Baseline and at multiple time points up to Day 260)
- Serum BIIB078 Concentration(Baseline and at multiple time points up to Day 260)
- Time to Reach Cmax (Tmax)(Baseline and at multiple time points up to Day 260)
- Terminal Elimination Half-Life (t 1/2)(Baseline and at multiple time points up to Day 260)
- Change from Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Scores(Baseline up to Day 323)
- Change from Baseline in Percent of Predicted Slow Vital Capacity (SVC)(Baseline up to Day 260)
- Change from Baseline in Muscle Strength(Baseline up to Day 260)
- Change from Baseline in Bulbar Strength(Baseline up to Day 260)