A Phase I, 2-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-ascending Doses of Intrathecally Administered RG6496 in a Randomized, Placebo-controlled, Investigator/Participant-blind Study With an Open-label Extension in Huntington's Disease Gene Expansion Carriers
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 3
- 试验地点
- 18
- 主要终点
- Part 1: Number of Participants With Adverse Events (AEs)
研究概览
简要总结
This is a first-in-human (FIH) study of RG6496 that will assess the safety and tolerability of single-ascending doses of RG6496 administered to huntington's disease gene expansion carriers (HDGECs). The study consists of two parts: Part 1 [single-ascending dose] followed by Part 2 [open-label extension (OLE)].
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Part 1: Investigator & participants will be blinded; Part 2: Open-label
入排标准
- 年龄范围
- 25 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmation of HDGEC status with cytosine-adenine-guanine (CAG) expansion >
- •Confirmation of SNP carrier status of the target SNP
- •Independence Scale (IS) score of ≥70, total functional capacity (TFC) ≥10, total motor score (TMS) >
- •Ability to read the words "red," "blue," and "green" and be fluent in the language of the informed consent form (ICF) and the tests used at the study site.
- •Ability to walk unassisted.
- •Total body weight > 40 kilogram (kg) and body mass index (BMI) within the range 18-32 kilogram per square meter (kg/m^2) (inclusive) at baseline.
- •Ability to undergo and tolerate MRI scans.
- •Completed the post-dose safety follow-up period in the Part 1 of the study.
- •In the opinion of the Investigator, the participant has not experienced a worsening in health that precludes their safe continued participation in the study.
排除标准
- •Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy or treatment with investigational therapy within 90 days or 5 drug-elimination half-lives, whichever is longer prior to screening
- •Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required
- •Malignancy within 5 years prior to screening
- •Planned brain surgery during the study
- •Positive HIV test, hepatitis B surface antigen and hepatitis B surface antigen at screening
- •Active psychosis, confusional state, or violent behavior, including aggression that could cause harm to self or others, over the 12 weeks prior to screening.
- •Current or previous history of a primary independent psychotic disorder.
- •Scoliosis or spinal deformity or surgery making IT injection not feasible in an outpatient setting
- •History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening.
- •Prematurely discontinued from Part 1 for any reason (i.e., before the completion of the postdose safety follow-up period of Part 1).
- •Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required.
- •Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy
- •Received any active investigational treatment other than RG6496 during or since completion of Part 1 of the study.
- •Had confirmed Dose-Limiting Adverse Event (DLAE)(s) in Part 1 of the study.
研究组 & 干预措施
Part 1: RG6496
Participants will receive single dose of RG6496. Participants will be enrolled in planned sequential cohorts associated with ascending dose levels.
干预措施: RG6496 (Drug)
Part 1: Placebo
Participants will receive a single dose of RG6496 matching placebo.
干预措施: Placebo (Drug)
Part 2: OLE
All participants who have completed Part 1 and are eligible for Part 2 will receive one open-label dose of RG6496.
干预措施: RG6496 (Drug)
结局指标
主要结局
Part 1: Number of Participants With Adverse Events (AEs)
时间窗: Up to approximately 24 months
Part 1: Change From Baseline in Neurological Assessment
时间窗: Up to approximately 24 months
A neurologic examination including fundoscopy, will be performed by a neurologist or an ophthalmologist depending on local practice. A neurologic examination will include an assessment of mental status, level of consciousness, cranial nerve function, motor function, sensory function, reflexes, gait, and coordination.
Part 1: Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score
时间窗: Up to approximately 24 months
C-SSRS measures 4 constructs as follows: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories. Numeric ratings are provided for intensity of ideation (if present), from 1 to 5, with 1 being the least severe and 5 being the most severe.
Part 1: Change from Baseline in Montreal Cognitive Assessment (MoCA)
时间窗: Up to approximately 24 months
MoCA is a rater-administered, participant completed assessment (PerfO instrument) used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0 to 30, where lower scores indicate greater impairment.
Part 2: Number of Participants With AEs
时间窗: Up to approximately 38 months
Part 2: Change From Baseline in Neurological Assessment
时间窗: Up to approximately 38 months
A neurologic examination including fundoscopy, will be performed by a neurologist or an ophthalmologist depending on local practice. A neurologic examination will include an assessment of mental status, level of consciousness, cranial nerve function, motor function, sensory function, reflexes, gait, and coordination.
Part 2: Number of Participants With Suicidal Ideation or Behavior, as Assessed by C-SSRS Score
时间窗: Up to approximately 38 months
C-SSRS measures 4 constructs as follows: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories. Numeric ratings are provided for intensity of ideation (if present), from 1 to 5, with 1 being the least severe and 5 being the most severe.
Part 2: Change from Baseline in MoCA
时间窗: Up to approximately 38 months
MoCA is a rater-administered, participant completed assessment (PerfO instrument) used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0 to 30, where lower scores indicate greater impairment.
次要结局
- Part 1: Plasma Concentration of RG6496(Up to approximately 24 months)
- Part 1 and Part 2: Number of Participants With Anti-drug Antibody (ADA) in Plasma to RG6496(Part 1: Up to approximately 24 months; Part 2: Up to approximately 38 months)
- Part 1 and Part 2: Change From Baseline of Mutant Huntingtin Protein (mHTT) Concentrations in Cerebrospinal Fluid (CSF) Over Time(Part 1: Up to approximately 24 months; Part 2: Up to approximately 38 months)