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
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.
• Age at signing of informed consent form
‣ In Part 1, the age of the subjects must be ≥ 18 years old and ≤ 75 years old
⁃ In Part 2, the age of the subjects must be ≥ 12 years old and ≤ 75 years old, and the 6 evaluable subjects must be monitored for at least 6 weeks during the safety run-in phase. If SRC believes that there is no safety issue, the randomized double-blind control study will be initiated Subject Type and Disease Characteristics
• The clinical manifestation caused by LHON is vision loss, with a visual acuity of ≥ 0.5 LogMAR in BCVA in either eye
• The genotype test result is that there is G11778A mutation in ND4 gene, and there are no other primary LHON-associated mutations in the mitochondrial DNA (mtDNA) (ND1\[G3460A\] or ND6\[T14484C\]) (confirmed by a CLIA-certified international laboratory)
• The duration of vision loss in the eye with worse visual acuity lasted \> 6 months and \< 10 years at screening
• Pupils can be adequately dilated for a comprehensive eye examination and visual acuity test
• Each eye of the subject must maintain the VA determined by manual visual acuity test (≤ 2.3 LogMAR) as defined in the ocular/vision examination manual (operating manual for optometry and VA examinations) in this study
• Sign the written informed consent form and willing to comply with the clinical study protocol Sex
• Male or female
‣ Male subjects:
‣ • A male subject must agree to take contraceptive measures at least 6 months after the treatment visit, see Appendix 5 for details
⁃ Female subjects:
∙ A female subject is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least one of the following conditions applies:
• i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 or ii) A WOCBP who agrees to follow the contraception guidance in Appendix 5 for at least 6 months after the treatment visit Informed Consent
• Written informed consent form must be obtained from the subject or his/her parent/legal guardian (if the subject is under 18 years of age) (Part 2) before any study-related procedures are performed (see Section 10.2) If the subject is legally identified as blind (\>1.0 LogMARor decimal acuity meter reading \< 0.1), an impartial witness must be present throughout the informed consent process and discussion process.