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
Overview
- Phase
- Phase 2
- Intervention
- NR082 injection
- Conditions
- Leber's Hereditary Optic Neuropathy (LHON)
- Sponsor
- Wuhan Neurophth Biotechnology Limited Company
- Enrollment
- 102
- Locations
- 1
- Primary Endpoint
- Safety and tolerability of NR082 at different doses
- Status
- Recruiting
- Last Updated
- 3 years ago
Overview
Brief Summary
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.
Detailed Description
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: The safety run-in phase of Part 2 will enroll 6 evaluable subjects (including at least 1 minor subject aged ≥ 12 years and \< 18 years) aged ≥ 12 years and ≤ 75 years at the dose determined in Part 1, namely 4.5 x 109 vg, 0.05 mL eye/dose (high dose) and monitor the safety for at least 6 weeks. If there is no new safety concern evaluated by the SRC, the randomized, double-blind, sham-injection control study can be initiated. Second Stage: randomized, double-blind, sham-injection control study: The randomized, double-blind, sham-injection control study of Part 2 is to verify the efficacy and safety of NR082 in LHON caused by mitochondrial gene ND4 mutation at the dose determined in Part 1 of the study, namely 4.5 x 109 vg, 0.05 mL eye/dose (high dose). This part is divided into the NR082 treatment group and the control group (sham-injection group).
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
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.
Intervention: NR082 injection
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.
Intervention: Sham Injection
Outcomes
Primary Outcomes
Safety and tolerability of NR082 at different doses
Time Frame: 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
Time Frame: Part 2 (Stage 1) : 6 weeks
Incidence rates of AEs and SAEs within 6 weeks after NR082 treatment
Efficacy of NR082 in study eye
Time Frame: 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
Secondary Outcomes
- 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)