A Phase 1/2/3, Multi-center, Two-part Clinical Trial to Evaluate the Safety and Efficacy of Gene Therapy for Leber's Hereditary Optic Neuropathy (LHON) Associated With ND4 Mutation
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 102
- 试验地点
- 1
- 主要终点
- Safety and tolerability of NR082 at different doses
研究概览
简要总结
The objective of this clinical study is to select the optimal dose and evaluate the safety and efficacy of NR082 in treatment of LHON caused by mitochondrial ND4 gene mutation. Part 1 (Phase 1/2) is a safety dose-finding study, which will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single unilateral intravitreal (IVT) injection of NR082 to observe its safety and efficacy. In Part 2 (Phase 3) of the clinical study, the dose recommended after the end of Part 1 is used to further verify the safety and efficacy of the study drug. Part 2 of the study is divided into the safety run-in phase and the randomized, double-blind and control study. Subjects aged ≥ 12 years and ≤ 75 years will be enrolled in the Part 2. The run-in phase will enroll 6 evaluable subjects. After monitoring for at least 6 weeks, if no new safety signals are observed, the clinical trial will enter the randomized, double-blind and control study phase upon approval by the Safety Review Committee(SRC). The clinical manifestation of all subjects is reduced visual acuity caused by LHON associated with ND4 mutation, and central laboratory test showed G11778A mutation (a CLIA-certified laboratory), while the reduced visual acuity lasted for > 6 months and < 10 years.
详细描述
Part 1: Dose-Finding At the dose-finding part, the principle is that the Safety Review Committee (SRC) will determine whether to make dose adjustment based on the safety data of the starting dose in Part 1. The recommended dose (safe and effective dose) of the Part 2 study will be determined jointly by the SRC, IDMC, sponsor and the drug regulatory authority after the interim analysis in Part 1 is completed.
The starting dose in Part 1 is 1.5 × 109 vg, 0.05 mL eye/dose. The safety of the starting dose will be reviewed by the SRC and the dose escalation or de-escalation will be recommended by the SRC.
The safety of the starting dose will first be performed in 6 evaluable subjects.
Part 2 (including the safety run-in phase and the randomized, double-blind and sham-injection control study):
First Stage: safety run-in phase:
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)
盲法说明
Part 1: Dose-Finding: open label；12 subjects Part 2: First Stage: safety run-in phase: open label；6 subjects Part 2: Second Stage: randomized, double-blind, sham-injection; 90 subjects.
入排标准
- 年龄范围
- 12 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
NR082 injection
0.5E9 viral genomes (vg), 0.05 mL eye/dose ,single-dose,only one eye per subject; 1.5E9 viral genomes (vg), 0.05 mL eye/dose single-dose,only one eye per subject; 4.5E9 viral genomes (vg) , 0.05 mL eye/dose single-dose,only one eye per subject Part 1: Dose-Finding；The recommended dose (safe and effective dose) of the Part 2 study will be determined jointly by the SRC, IDMC, sponsor and the drug regulatory authority after the interim analysis in Part 1 is completed.
干预措施: NR082 injection (Drug)
sham-injection
Part2.Second Stage: randomized, double-blind, sham-injection control study One eye of each participant will undergo sham injection. Sham intravitreal injection will be performed by applying pressure to the eye at the location of a typical intravitreal injection procedure using the blunt end of a syringe without a needle.
干预措施: Sham Injection (Device)
结局指标
主要结局
Safety and tolerability of NR082 at different doses
时间窗: Part 1 (Phase1/2): 12 weeks
Incidence rates of AEs, SAEs and DLTs within 12 weeks after injection of NR082 at different doses
Safety after NR082 treatment among subjects 12 ≤ aged ≤ 75 years
时间窗: Part 2 (Stage 1) : 6 weeks
Incidence rates of AEs and SAEs within 6 weeks after NR082 treatment
Efficacy of NR082 in study eye
时间窗: Part 2 (Stage 2): 52 weeks
Proportion of ≥ 0.3 LogMAR from baseline in BCVA in the study eye in the NR082 treatment and the sham-injection at Week 52 after treatment
次要结局
- Safety and efficacy of NR082 caused by mitochondrial gene ND4 mutation(Part 2 (Stage 2): Week 2, 6, 12, 26, 40 and 52)
- Immunogenicity and vector shedding/biodistribution(Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 6, 12, 26, 40 and 52)
- Morphological improvement after NR082 treatment(Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 6, 12, 26, 40 and 52)
- Further assess the efficacy and safety following intravitreal injection of NR082 at different doses(Part 1 (Phase1/2) and Part 2 (Stage 1): At Weeks 26, 40 and 52)
- The change in quality of life from baseline(Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 26 and 52)
- The efficacy and safety following intravitreal injection of NR082 at different doses(Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 6, 12, 26, 40 and 52)