An Operationally Seamless Phase 1/2/3 Study Consisting of a Safety and Dose-finding Phase 1/2 and Randomized, Open-label, Active-controlled Phase 3 to Evaluate UX701 AAV Gene Therapy in Adults With Wilson Disease
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 82
- 试验地点
- 32
- 主要终点
- Stage 1: Number of Consecutive Weeks off SOC Medication at Week 52
研究概览
简要总结
The primary objectives of this study are to evaluate the safety of single IV doses of UX701 in patients with Wilson disease, to select the UX701 dose with the best benefit/risk profile based on the totality of safety and efficacy data and to evaluate the effect of UX701 on copper regulation.
详细描述
Stage 1 (Phase 1/2) is an open-label safety and dose-finding stage designed to evaluate the safety and efficacy of 4 dose levels of UX701 to establish initial safety of UX701 and select a safe and efficacious dose for further evaluation. Stage 2 (Phase 3) is a randomized, open-label, active-controlled stage to evaluate the safety and efficacy of UX701 using the dose selected in Stage 1. Stage 3 is a long-term follow-up stage designed to evaluate the safety, efficacy, and clinical benefit of UX701 for at least 5 years from the time of UX701 administration.
Participants who receive UX701 will receive premedication, prophylactic oral corticosteroids and immunomodulation therapy.
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
- Single (Outcomes Assessor)
盲法说明
Those responsible for reviewing MRI assessments, ophthalmology assessments, and analyzing liver biopsy samples will be double-blinded.
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
- •Confirmed diagnosis of Wilson disease based on genetic confirmation of heterozygous or homozygous biallelic ATP7B mutation.
- •Stable Wilson disease as evidenced by ongoing copper chelator (ie, penicillamine, trientine) and/or zinc therapy for at least 2 months at screening, with no medication or dose changes for at least 2 months at screening.
- •Ongoing restriction of high copper containing foods for at least 2 months at Screening and continued through study participation.
- •Willing and able to comply with all study procedures and requirements, including frequent blood collection, total urine collection over a 24-hour period, patient-reported outcome assessments, and long-term follow-up
排除标准
- •Detectable pre-existing antibodies to the AAV9 capsid.
- •Stage 1 only: History of copper chelator or zinc therapy noncompliance, in the Investigator's judgment, within 6 months prior to Screening.
- •History of liver transplant.
- •Active decompensated hepatic cirrhosis or history of hepatic encephalopathy.
- •Significant hepatic inflammation as evidenced by laboratory abnormalities.
- •Model for End-Stage Liver Disease (MELD) score >
- •Hemoglobin < 9 g/dL
- •Presence of Stage 3 or higher chronic kidney disease based on estimated glomerular filtration rate < 60 mL/min/1.73 m
- •Marked neurological deficit or compromise that, in the Investigator's opinion, would interfere with the subject's safety or ability to participate in the study.
- •Moderate to severe depression, recent or active suicidal ideation with intent or suicidal behavior, psychosis, or unstable psychiatric illness.
- •Known hypersensitivity to UX701 or its excipients, copper chelators, zinc, rituximab, tacrolimus, corticosteroids, or eculizumab that, in the Investigator's judgement, places the participant at increased risk for adverse events.
- •Participation in another gene transfer study or use of another gene transfer product before or during study participation.
- •Subjects with known hypersensitivity to amide-containing local anesthetics are excluded from participating in the optional liver biopsy substudy.
- •Note: Other protocol defined Inclusion/ Exclusion criteria may apply
研究组 & 干预措施
Stage 1: UX701 Dose Level 1
Participants receive a single, peripheral intravenous (IV) infusion of UX701 at dose level 1.
干预措施: UX701 (Genetic)
Stage 1: UX701 Dose Level 2
Participants receive a single, peripheral IV infusion of UX701 at dose level 2.
干预措施: UX701 (Genetic)
Stage 1: UX701 Dose Level 3
Participants receive a single, peripheral IV infusion of UX701 at dose level 3.
干预措施: UX701 (Genetic)
Stage 1: UX701 Dose Level 4
Participants receive a single, peripheral IV infusion of UX701 at dose level 4.
干预措施: UX701 (Genetic)
Stage 2: UX701 at Selected Dose
Participants randomized to UX701 receive a single, peripheral IV infusion of UX701 at the selected dose.
干预措施: UX701 (Genetic)
Stage 2: Standard of Care (SOC) to UX701
Participants randomized to SOC will continue their baseline SOC medications for 52 weeks, followed by a single, peripheral IV infusion of UX701 at the selected dose. Following UX701 administration, participants will be evaluated for modification of their SOC medications.
干预措施: UX701 (Genetic)
Stage 2: Standard of Care (SOC) to UX701
Participants randomized to SOC will continue their baseline SOC medications for 52 weeks, followed by a single, peripheral IV infusion of UX701 at the selected dose. Following UX701 administration, participants will be evaluated for modification of their SOC medications.
干预措施: Standard of Care (SOC) (Drug)
结局指标
主要结局
Stage 1: Number of Consecutive Weeks off SOC Medication at Week 52
时间窗: Week 52
Stage 1: Change in Free Copper from Baseline at Week 52
时间窗: Baseline, Week 52
Stage 1: Change in Ceruloplasmin Activity from Baseline at Week 52
时间窗: Baseline, Week 52
Stage 1: Percent Reduction in Standard of Care (SOC) Medication by Week 52
时间窗: Week 52
Stage 1: Number of Participants Who Discontinue SOC Medication by Week 52
时间窗: Week 52
Stage 2: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52, Evaluated for Superiority
时间窗: Baseline, Week 52
Stage 2: Percent Reduction in SOC Medication by Week 52, Evaluated for Superiority
时间窗: Week 52
Stage 1: Incidence of Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Adverse Events of Special Interest (AESIs), Treatment-Related TEAEs, and Treatment-Related TESAEs
时间窗: Up to Week 52
Stage 1: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52
时间窗: Baseline, Week 52
Stage 1: Change in Total Copper from Baseline at Week 52
时间窗: Baseline, Week 52
Stage 1: Change in Ceruloplasmin-bound Copper from Baseline at Week 52
时间窗: Baseline, Week 52
Stage 1: Change in Ceruloplasmin from Baseline at Week 52
时间窗: Baseline, Week 52
Stage 1: Change in Non-Ceruloplasmin-bound Copper (NCC) from Baseline at Week 52
时间窗: Baseline, Week 52
次要结局
- Stage 2: Change in Ceruloplasmin Activity Levels from Baseline at Week 52, Evaluated for Superiority(Baseline, Week 52)
- Stage 2: Change in FACIT-Fatigue Scale Score from Baseline at Week 52(Baseline, Week 52)
- Stage 2: Change in Liver Copper Concentration Assessed by Liver Biopsy from Baseline at Week 52(Baseline, Week 52)
- Stage 2: Number of Participants who Discontinue SOC Medication by Week 52(Week 52)