Clinical trial NCT05832684: Safety and Efficacy of ZVS101e in Patients With Bietti 's Crystalline Dystrophy
Official title: A Phase I/II Clinical Study to Evaluate the Safety and Efficacy of ZVS101e Administered as a Single Monocular Subretinal Injection in Subjects With Bietti's Crystalline Dystrophy (BCD)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Bietti's Crystalline Dystrophy
Lead sponsor: Chigenovo Co., Ltd
Sponsor class: NETWORK
First posted: 2023-04-27
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the safety and efficacy of ZVS101e administered by subretinal injection in subjects with Bietti's crystalline dystrophy (BCD) and to select the optimal effective dose.

Detailed description: This is a single-arm, open-label, and multi-center study of ZVS101e in patients with BCD. Up to 24 subjects are expected to be enrolled. Each participant will receive ZVS101e by subretinal injection in one eye on a single occasion. Safety, efficacy and vector shedding characteristics of ZVS101e are then measured over 180 days. Participants will subsequently enter a long-term follow-up study over a 4.5-year period.

Eligibility criteria: Inclusion Criteria:

* 1. Fully understand the purpose and requirements of this trial, voluntarily participate in the clinical trial, sign the informed consent form, and be able to complete the whole trial processes as required by the protocol;
* 2. Patients with clinical diagnosis of Bietti's crystalline dystrophy (BCD) (age ≥ 18 years) (including the critical value, and the age is based on the time of signing the informed consent form);
* 3. Genetic test confirmed to carry two pathogenic variants of CYP4V2 and carry no pathogenic mutations of other ophthalmic genetic diseases;
* 4. The study eye must meet the following requirements: Best-corrected visual acuity between 2.3 LogMAR and 0.5 LogMAR (including 2.3 LogMAR and 0.5 LogMAR).

Exclusion Criteria:

* 1. Subjects with insufficient viable retinal cells, or macular retinal less than 100 μm thick;
* 2. Pre-existing eye conditions in the study eye that the investigator determines could interfere with ocular evaluation, preclude surgery, interfere with interpretation of study endpoints or pose surgical complications;
* 3. The study eye has been treated with the following intraocular procedures: retinal detachment surgery, vitrectomy;
* 4. The study eye has been treated with other drugs within 3 months that could affect the evaluation of the investigational drug (such as ranibizumab, bevacizumab, aflibercept, conbercept);
* 5. Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen;
* 6. Those with the following laboratory abnormalities which are clinically significant:

  * Liver function: chronic liver disease, ALT increased \> 2 times the upper limit of normal;
  * Hypertension, mean SBP ≥ 160 mmHg or mean DBP ≥ 100 mmHg;
  * Coagulation function (prothrombin time ≥ upper limit of normal (3 seconds' longer), activated partial thromboplastin time ≥ upper limit of normal (10 seconds' longer));
  * Serum virology test: Active hepatitis B, hepatitis C virus antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab) or syphilis antibody positive;
* 7. Patients with rAAV8 neutralizing antibody titer ≥ 1:1000;
* 8. Complicating systemic diseases (such as medical conditions causing immunosuppression) that would preclude the gene transfer, ocular surgery and drug in vivo activity;
* 9. Known drug allergy to the drug planned to be used in the study;
* 10. Patients who cannot communicate or cooperate with medical staff due to neurological, mental illness or language disorder, which affects patient compliance;
* 11. Treatment of either eye with gene therapy drugs for BCD and other ocular diseases, including but not limited to other viral vector gene therapies, mRNA therapy, etc.;
* 12. Has or has had a systemic immune-compromising disease;
* 13. Subjects of reproductive age without any effective contraception and female subjects who have tested positive for pregnancy or are lactating at screening or baseline;
* 14. A condition that, in the opinion of the investigator, would preclude participation in the study.

Primary outcomes:
measure: Incidence of ocular and systemic adverse events (AEs) after ZVS101e treatment
timeFrame: Up to day 180
measure: Incidence of ocular and systemic serious adverse events (SAEs) after ZVS101e treatment
timeFrame: Up to day 180
measure: Mean change from baseline in BCVA (LogMAR)
timeFrame: Up to day 180
Secondary outcomes:
measure: Change from Baseline in visual field
timeFrame: Up to day 180
measure: Change from Baseline in contrast sensitivity
timeFrame: Up to day 180
measure: Change from Baseline in microperimetry
timeFrame: Up to day 180
measure: Change from Baseline in mfERG
timeFrame: Up to day 180
measure: Change from Baseline in retinal thickness
timeFrame: Up to day 180
measure: Change from Baseline in NEI VFQ-25 total score
timeFrame: Up to day 180
measure: Change from Baseline in color vision
timeFrame: Up to day 180
Other outcomes:
measure: Change from Baseline in multi-luminance mobility test (MLMT)
timeFrame: Up to day 180
Locations:
city: Beijing
country: China
facility: Peking University Third Hospital
state: Beijing
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Medical University Eye Hospital
state: Tianjin
Study officials:
affiliation: Tianjin Medical University Eye Hospital
name: Xiaorong Li, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jia R, Meng X, Chen S, Zhang F, Du J, Liu X, Yang L. AAV-mediated gene-replacement therapy restores viability of BCD patient iPSC derived RPE cells and vision of Cyp4v3 knockout mice. Hum Mol Genet. 2023 Jan 1;32(1):122-138. doi: 10.1093/hmg/ddac181.
citation: Wang J, Zhang J, Yu S, Li H, Chen S, Luo J, Wang H, Guan Y, Zhang H, Yin S, Wang H, Li H, Liu J, Zhu J, Yang Q, Sha Y, Zhang C, Yang Y, Yang X, Zhang X, Zhao X, Wang L, Yang L, Wei W. Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial. Signal Transduct Target Ther. 2024 Apr 24;9(1):95. doi: 10.1038/s41392-024-01806-3.