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The objective of this Phase 1/2 study is to evaluate the safety and efficacy of NR082 for Leber's hereditary optic neuropathy (LHON) caused by the mitochondrial ND4 gene mutation. Participants receive a single unilateral intravitreal injection of NR082. Eligible subjects are aged 18 to 75 with vision loss due to LHON, laboratory-confirmed G11778A mutation and reduced visual acuity lasting more than 6 months but less than 10 years.
The summary above is a plain-language rendering of the official record. The original English title is shown for reference.
Criteria are reproduced from the ClinicalTrials.gov record in the original English. Only the trial team can determine eligibility.
Inclusion Criteria:
1. Age at the time of signing the informed consent form: the age of the subjects must be ≥ 18 years old and ≤ 75 years old.
2. The clinical manifested vision loss due to LHON, and any eye BCVA ≥ 0.5 LogMAR
3. The genotype testing result shows the presence of G11778A mutation in the ND4 gene, and the absence of the other primary LHON associated mutations in the mitochondrial DNA (mtDNA) (ND1 \[G3460A\] or ND6 \[T14484C\]) (confirmed by a CLIA-certified international laboratory
4. The vision loss in the eye with worse visual acuity lasted \> 6 months and \< 10 years at screening
5. Pupils can be adequately dilated for a thorough ocular examination and visual acuity test
6. Each eye of the subject must maintain at least Hand Motion VA (≤ 2.3 LogMAR) as defined in the ocular/vision examination manual (operating manual for refraction and VA examinations) in this study
7. Willingness to comply with the clinical study protocol and 5 years of long-term follow-up after administration
8. Male or female
1. A male subject must agree to take contraceptive measures at least 6 months after the treatment visit;
2. A female subject is eligible to participate if she is not pregnant , not breastfeeding, and at least one of the following conditions applies:i)Not a woman of childbearing potential (WOCBP) ;ii) A WOCBP who agrees to follow the contraception guidance for at least 6 months after the treatment visit
9. Written informed consent form must be obtained from the subject or his/her parent/legal guardian before any study-related procedures are performed.If the subject is legally blind (\> 1.0 LogMAR or the readings of decimal visual acuity chart \<0.1), an impartial witness must be present throughout the informed consent process and discussion process.
Exclusion Criteria:
1. Any known allergy and/or hypersensitivity to the study drug or its constituents
2. Contraindication to IVT injection in any eye
3. IVT drug delivery to any eye within 30 days prior to the screening visit
4. History of vitrectomy in either eye
5. Narrow anterior chamber angle in any eye contra-indicating pupillary dilation
6. Presence of disorders or diseases of the eye or adnexa, excluding LHON, which may interfere with visual or ocular assessments, including spectral-domain optical coherence tomography (SD-OCT), during the study
7. Presence of known/documented mutations, other than the LHON-related mutation, which are known to cause pathology of the optic nerve, retina or afferent visual system
8. Presence of systemic or ocular/vision diseases, disorders, or pathologies, other than LHON, known to cause or be associated with vision loss, or whose associated treatment(s) or therapy(ies) is/are known to cause or be associated with vision loss
9. Presence of optic neuropathy from any cause other than LHON
10. Presence of illness or disease that, in the opinion of the investigator, include symptoms and/or the associated treatments that can alter visual function, for instance cancers or pathology of the central nervous system (CNS), including multiple sclerosis (diagnosis of multiple sclerosis must be based on the 2010 Revisions to the McDonald Criteria) , and/or diseases or conditions that affect the safety of subjects participating in the study
11. History of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation
12. Participated in another clinical study and receive an IMP within 90 days prior to the screening visit
a) Exceptions: Subjects who have completed the clinical study of idebenone as IMP \> 90 days prior to the screening visit and has completely discontinued idebenone at least 7 days prior to dosing are still eligible to participate in the study.
13. Any eye has previously received ocular gene therapy
14. Subjects who refused to stop using idebenone
15. Have undergone ocular surgery of clinical relevance (per investigator's assessment) within 90 days prior to the screening visit
16. Female subjects who are breastfeeding or plan to breastfeed within the first 6 months after the administration of NR082 Injection
17. History of drug or alcohol abuse (including heavy smoking, i.e., \> 20 cigarettes per day or \>20 pack-years \[equivalent to one pack a day for 20 years or 2 packs a day for 10 years\])
18. Human immunodeficiency virus (HIV) antibody, syphilis antibody and HCV antibody positive are excluded; hepatitis B test that shows a clinically significant active infection requiring treatment (defined as the presence of hepatitis B core antibody \[HBcAb\] positive or hepatitis B surface antigen \[HBsAg\] positive, and hepatitis B virus deoxyribonucleic acid \[HBV-DNA\]) \> 1000 copies/mL or according to local laboratory method above lower limit of quantitative detection) are excluded
19. Unable to tolerate (e.g., immunomodulatory regimen) or unable or unwilling to comply with all the protocol requirements
20. Subjects from the study site fail to comply with or do not agree to comply with local and institutional guidelines for suspected 2019 novel coronavirus (COVID-19) infection/testing
21. Any other exclusions determined by the investigator