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The objective of this clinical study is to evaluate the safety and efficacy of NR082 in the treatment of LHON caused by mitochondrial ND4 gene mutation. This study will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single unilateral intravitreal (IVT) injection of NR082 to evaluate its safety and efficacy. The clinical manifestations of all subjects are to be reduced visual acuity caused by LHON associated with ND4 mutation, with laboratory test showing G11778A mutation (a CLIA-certified laboratory) and reduced visual acuity lasted for > 6 months and < 10 years.
Full description
At the dose-finding stage, the principle is that the Safety Review Committee (SRC) will decide whether to make dose adjustment based on the safety data of the starting dose. The starting dose is 1.5×109 vg, 0.05 mL eye/dose.The safety of the starting dose will be reviewed by the SRC, and dose escalation or de-escalation is by recommendation of the SRC.The safety of the starting dose will first be performed in 6 evaluable subjects.
Criteria for Dose Modification:
Dose Escalation:
If drug-related dose-limiting toxicity (DLT) events are observed in ≤ 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the starting dose, the dose can be escalated to 4.5×109 vg, 0.05 mL eye/dose (high dose) after the approval by SRC.
Dose De-escalation:
If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the starting dose, the dose can be de-escalated to 0.5×109 vg, 0.05 mL eye/dose (low dose) after the approval by SRC.
If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the high dose, the dose can be de-escalated to 3.0×109vg, 0.05 mL eye/dose (intermediate dose) after the approval by SRC.
Enrollment Sequence:
The 7-day interval is to avoid acute safety events to the greatest possible extent
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Age at the time of signing the informed consent form: the age of the subjects must be ≥ 18 years old and ≤ 75 years old.
The clinical manifested vision loss due to LHON, and any eye BCVA ≥ 0.5 LogMAR
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
The vision loss in the eye with worse visual acuity lasted > 6 months and < 10 years at screening
Pupils can be adequately dilated for a thorough ocular examination and visual acuity test
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
Willingness to comply with the clinical study protocol and 5 years of long-term follow-up after administration
Male or female
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
Any known allergy and/or hypersensitivity to the study drug or its constituents
Contraindication to IVT injection in any eye
IVT drug delivery to any eye within 30 days prior to the screening visit
History of vitrectomy in either eye
Narrow anterior chamber angle in any eye contra-indicating pupillary dilation
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
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
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
Presence of optic neuropathy from any cause other than LHON
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
History of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation
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.
Any eye has previously received ocular gene therapy
Subjects who refused to stop using idebenone
Have undergone ocular surgery of clinical relevance (per investigator's assessment) within 90 days prior to the screening visit
Female subjects who are breastfeeding or plan to breastfeed within the first 6 months after the administration of NR082 Injection
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])
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
Unable to tolerate (e.g., immunomodulatory regimen) or unable or unwilling to comply with all the protocol requirements
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
Any other exclusions determined by the investigator
Primary purpose
Allocation
Interventional model
Masking
12 participants in 1 patient group
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Central trial contact
Bin Li
Data sourced from clinicaltrials.gov
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