A Phase 2A, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of PTC518 in Subjects With Huntington's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 159
- 试验地点
- 32
- 主要终点
- Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3
研究概览
简要总结
The primary goal of this study is to evaluate the safety and pharmacodynamic effects of PTC518 compared with placebo in participants with HD.
详细描述
Participants will first be randomized to Part A or Part B or Parts D or E in a 1:1 randomization ratio, depending on their Huntington's disease Integrated Staging System (HD-ISS) staging criteria and then to active treatment (PTC518 5 mg in Parts A and D and 10 mg in Parts B and E) or matching placebo within each part in a 2:1 ratio of active treatment to placebo. A Drug Safety Monitoring Board (DSMB) Charter will undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide a recommendation on when Parts C and F (with a 20 mg active treatment arm) can be initiated. At that time, participants will be randomized to any study Part that is currently open for enrollment, and then to either active treatment or placebo (in a 2:1 ratio) within that Part.
Participants who complete this study and agree to participate in a long-term extension (LTE) study, will be enrolled in a separate LTE study PTC518-CNS-004-HD (NCT06254482).
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)
入排标准
- 年龄范围
- 25 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length from 40 to 50, inclusive
- •Eligibility for HD-ISS Stage 2 Group (Parts A, B, and C):
- •A Unified Huntington's Disease Rating Scale (UHDRS)-Independence Scale (IS) score of 100
- •A UHDRS Total Functional Capacity (TFC) score of 13
- •A score between 0.18 and 4.93 inclusive on the normed version of the HD prognostic index (PINHD)
- •Eligibility for HD-ISS Mild Stage 3 Group (Parts D, E, and F):
- •A UHDRS Total Functional Capacity (TFC) score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of <100
排除标准
- •Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or anytime over the duration of this study, ribonucleic acid (RNA)- or deoxyribonucleic acid (DNA)-targeted HD-specific investigational agents such as antisense oligonucleotides, cell transplantation, or any other experimental brain surgery
- •Any history of gene therapy exposure for the treatment of HD
- •Participation in an investigational study or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation, etc) within 90 days prior to Screening or anytime over the duration of this study
- •Any medical history of brain or spinal disease that would interfere with the lumbar puncture process safety assessments
- •Any medical history or condition that would interfere with the ability to complete the protocol-specified assessments (for example, implanted shunt, conditions precluding magnetic resonance imaging [MRI] scans)
- •Pregnancy, planning on becoming pregnant during the course of the study or within 6 months of end of treatment, or currently breastfeeding
- •Note: Other inclusion and exclusion criteria may apply.
研究组 & 干预措施
PTC518 20 mg
Participants will receive PTC518 20 mg tablets once daily orally for 12 months.
干预措施: PTC518 (Drug)
PTC518 5 mg
Participants will receive PTC518 5 milligrams (mg) tablets once daily orally for 12 months.
干预措施: PTC518 (Drug)
Placebo
Participants will receive placebo matching to PTC518 tablets once daily orally for 12 months.
干预措施: Placebo (Drug)
PTC518 10 mg
Participants will receive PTC518 10 mg tablets once daily orally for 12 months.
干预措施: PTC518 (Drug)
结局指标
主要结局
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3
时间窗: Baseline, Month 3
Least square (LS) mean and 95% confidence interval (CI) were calculated using mixed-model repeated measures (MMRM). The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: Baseline up to Month 18
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A TEAE was defined as an AE that had an onset date or date of worsening on or after the first dose of study drug. A summary of other non-serious AEs and all serious adverse events (SAEs), regardless of causality is located in the 'Reported AE section'.
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3
时间窗: Baseline, Month 3
Least square (LS) mean and 95% confidence interval (CI) were calculated using mixed-model repeated measures (MMRM). The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
次要结局
- Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12(Baseline, Month 12)
- Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12(Baseline, Month 12)
- Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12(Baseline, Month 12)
- Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12(Baseline, Month 12)
- Percent Change From Baseline in Blood mHTT Protein at Month 12(Baseline, Month 12)
- Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12(Baseline, Month 12)
- Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12(Baseline, Month 12)
- Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12(Baseline, Month 12)
- Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12(Baseline, Month 12)
- Percent Change From Baseline in Blood mHTT Protein at Month 12(Baseline, Month 12)