A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen in Individuals With Prodromal and Early Manifest Huntington's Disease
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 301
- 试验地点
- 116
- 主要终点
- DB Period: Incidence and Severity of Adverse Events (AEs), With Severity Determined According to the AE Severity Grading Scale
研究概览
简要总结
This study will evaluate the safety, biomarkers, and efficacy of tominersen compared with placebo in participants with prodromal and early manifest Huntington's Disease (HD).
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 25 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HD gene expansion mutation carrier status with a cytosine-adenine-guanine-age product (CAP) score of 400-500 inclusive
- •Prodromal HD (defined as Diagnostic Confidence Level (DCL) 2 to 3, Independence Scale (IS) ≥70, and TFC ≥8); Or
- •Early manifest HD (defined as DCL 4, IS ≥70, and TFC ≥8)
- •Total body weight > 40 kilograms (kg) and a body mass index (BMI) within the range of 18-32 kilograms per meter square (kg/m^2)
- •Study companion
- •OLE Period:
- •Participants must have completed the DB treatment period
- •Participants must remain in the DB Safety follow-up period until OLE period starts
排除标准
- •Current or previous use of an antisense oligonucleotide (ASO) (including small interfering ribonucleic acid [RNA]) or any HTT lowering therapy (including tominersen)
- •Anti-platelet or anticoagulant therapy within 14 days prior to screening or anticipated use during the study, including, but not limited to, aspirin (unless ≤ 81 milligrams per day [mg/day]), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and heparin
- •History of gene therapy, cell transplantation, or brain surgery
- •Hydrocephalus
- •Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug
- •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
- •OLE Period:
- •Early discontinuation from the DB treatment and the safety follow-up (SFU) periods
- •Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required
- •Current or previous use of an ASO other than tominersen (including small interfering RNA) or any other HTT-lowering therapy
- •Hydrocephalus
- •Received any active investigational treatment other than tominersen during or since completion of the DB treatment period
- •Key inclusions/exclusion criteria are listed here. Other protocol-defined I/E criteria may apply.
研究组 & 干预措施
Tominersen 60 milligrams (mg)
60 mg tominersen administered intrathecally (IT) every 16 weeks (Q16W). Tominersen will be administered in the DB period and the OLE period.
干预措施: Tominersen (Drug)
Placebo
Placebo will be administered IT, Q16W in the DB period.
干预措施: Placebo (Drug)
Tominersen 100 mg
100 mg tominersen administered IT, Q16W. Tominersen will be administered in the DB period and the OLE period.
干预措施: Tominersen (Drug)
结局指标
主要结局
DB Period: Incidence and Severity of Adverse Events (AEs), With Severity Determined According to the AE Severity Grading Scale
时间窗: Up to approximately 36 months
DB Period: Change From Baseline in Clinical Laboratory Results - Cerebrospinal Fluid (CSF) White Blood Cell (WBC)
时间窗: Baseline visit (Day 1), and Months 4, 8, 9, 12, 16
DB Period: Change From Baseline in Clinical Laboratory Results - CSF Protein
时间窗: Baseline visit (Day 1), and Months 4, 8, 9, 12, 16
DB Period: Change From Baseline in Structural Magnetic Resonance Imaging (MRI) Assessing Any New Abnormalities Including Radiographic Features Consistent With Hydrocephalus and Other Relevant MRI Safety Findings
时间窗: Baseline, Months 4, 8, 12, 16 and up to approximately 36 months
DB Period: Percentage Change From Baseline in Geometric Means of CSF Mutant Huntingtin (mHTT) Protein Levels at Month 9
时间窗: Baseline, Month 9
DB Period: Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores (non-U.S. Sites) at 16 Months
时间窗: Baseline to 16 months
Change in scores on the scale.
DB Period: Change From Baseline in Total Functional Capacity (TFC) Scores (U.S. Sites) at 16 Months
时间窗: Baseline to 16 months
Change in scores on the scale.
OLE Period: Incidence and Severity of AEs, With Severity Determined According to the AE Severity Grading Scale
时间窗: Up to approximately 29 months
OLE Period: Change Over Time in Clinical Laboratory Results - CSF WBC
时间窗: Up to approximately 24 months
OLE Period: Change Over Time in Clinical Laboratory Results - CSF Protein
时间窗: Up to approximately 24 months
OLE Period: Change From Baseline in Structural MRI Assessing Any New Abnormalities, Including Radiographic Features Consistent With Hydrocephalus and Other Relevant MRI Safety Findings
时间窗: Up to approximately 29 months
次要结局
- DB Period: Titers Determined if ADAs are Identified(Baseline up to approximately 36 months)
- OLE Period: Change Over Time in TFC Score(Up to approximately 29 months)
- OLE Period: Change Over Time in cUHDRS Score(Up to approximately 29 months)
- OLE Period: Change Over Time in SDMT Score(Up to approximately 29 months)
- OLE Period: Change Over Time in TMS(Up to approximately 29 months)
- OLE Period: Change Over Time in SWR Score(Up to approximately 29 months)
- OLE Period: Change Over Time in MoCA Score(Up to approximately 29 months)
- OLE Period: Percentage of Participants With Suicidal I/B, as Assessed by C-SSRS Score at Each Visit, Including Detailed Focus on Any Individual Cases Identified as Having Severe I/B During the Study Conduct(Up to approximately 29 months)
- OLE Period: Incidence of ADAs at Specified Timepoints(Up to approximately 29 months)
- DB Period: Change From Baseline at 16 Months in TFC (non-U.S. Sites) Scores(Baseline to 16 months)
- DB Period: Change From Baseline at 16 Months in cUHDRS (U.S. Sites) Scores(Baseline to 16 months)
- DB Period: Incidence of Anti-drug Antibodies (ADAs) at Specified Timepoints Relative to the Prevalence of ADAs at Baseline(Baseline up to approximately 36 months)
- DB Period: Change From Baseline in Montreal Cognitive Assessment (MoCA) Scores(Baseline, Months 4, 8, 12, 16 and up to approximately 36 months)
- DB Period: Percentage of Participants With Suicidal Ideation or Behavior (I/B), as Assessed by C-SSRS Score at Each Visit, Including Detailed Focus on Any Individual Cases Identified as Having Severe I/B During the Study Conduct(Up to approximately 36 months)
- DB Period: Change From Baseline at 16 Months in Symbol Digit Modalities Test (SDMT) Scores(Baseline to 16 months)
- DB Period: Change From Baseline at 16 Months in Stroop Word Reading (SWR) Score(Baseline to 16 months)
- DB Period: Change From Baseline at 16 Months in Total Motor Score (TMS)(Baseline to 16 months)
- DB Period: Change From Baseline in CSF Neurofilament Light Chain (NfL) Levels at 16 Months(Baseline to 16 months)