An Exploratory Clinical Study on Single Subretinal Injection of ZVS101e (rAAV2/8-hCYP4V2) Into Eyes With Bietti's Crystalline Dystrophy (BCD)
试验速览
- 阶段
- 早期 1 期
- 状态
- 招募中
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Type and severity of ocular and systemic AEs and SAEs after ZVS101e treatment.
研究概览
简要总结
The purpose of the study is to evaluate the safety and tolerability of an adeno-associated virus vector expressing CYP4V2 in patients with Bietti's crystalline dystrophy (BCD).
详细描述
This is a single-arm, open-label, and single-center study of ZVS101e in patients with BCD. A total of 6 participants will be enrolled. A retinal surgeon will administer the vector by subretinal injection. Safety, efficacy and vector shedding characteristics of ZVS101e are then measured over 2 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willingness to adhere to protocol as evidenced by written informed consent;
- •Patients with clinical diagnosis of Bietti's crystalline dystrophy (BCD) (age ≥ 18 years) (the age is based on the time of signing the informed consent form);
- •Genetic test confirmed to carry two pathogenic variants of CYP4V2 and carry no pathogenic mutations of other ophthalmic genetic diseases;
- •Agree to use reliable barrier contraception for 2 year after administration of ZVS101e;
- •The study eye must meet the following requirements: BCVA between 2.3 LogMAR and 0.5 LogMAR (including 2.3 LogMAR and 0.5 LogMAR); No refractive medium turbidity that affects fundus examination; Visible photoreceptor (outer nuclear) layer on a standard optical coherence tomography (OCT) scan.
排除标准
- •Lack of sufficient viable retinal cell. Specifically, if indirect ophthalmoscopy reveals less than I disc area of retina which is not involved by complete retinal degeneration, these eyes will be excluded. In addition, in eyes where OCT scans of sufficient quality can be obtained, areas of retina with thickness measurements less than 100 μm, or absence of neural retina, will not be targeted for delivery of AAV2-hCYP4V2;
- •Existing or pre-existing of choroidal neovascular (CNV) lesions that were secondary to BCD, or other eye conditions interfering with the surgery or the interpretation of the clinical endpoint, in the investigators' opinion;
- •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);
- •The study eye has been treated with the following intraocular procedures: retinal detachment surgery, vitrectomy;
- •Pre-existing eye conditions that the investigator evaluates could interfere with ocular evaluation, preclude surgery, interfere with interpretation of study endpoints or surgical complications (such as glaucoma, high refractive error, diabetes retinopathy or retinal vasculitis );
- •Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen;
- •Patient with allergic constitution (such as those allergic to two or more drugs and food);
- •Those with the following laboratory abnormalities which are clinically significant:
- •Liver function: chronic liver disease, ALT increased >3 times the upper limit of normal; With uncontrolled hypertension, mean systolic blood pressure ≥ 160 mmHg or mean diastolic blood pressure ≥ 100 mmHg; With uncontrolled diabetes, HbA1c>10%; Patients with abnormal 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; Abnormality of tumor markers (alpha fetoprotein, carcinoembryonic antigen, CA125 carbohydrate antigen, CA153 carbohydrate antigen, CA199 carbohydrate antigen)
- •Having any past or present medical history that may affect the safety of the trial or the in vivo process of the drug, especially the medical history of cardiovascular, hepatic, renal, endocrine, gastrointestinal, pulmonary, neurological, hematological, oncologic, immunological or metabolic disorders and others that are thought clinically significant by the investigator, such as diabetes, severe cardiac failure (New York Heart Association Class III and IV);
- •Participation in any medicine or medical device clinical trials within 3 months prior to enrollment;
- •Neutralizing antibodies to rAAV> 1:1000 by immunologic test;
- •For females in pregnancy or lactation period;
- •Any other conditions which leads the investigator to determine the participant is unsuitable for this study.
研究组 & 干预措施
Dose escalation
2 cohorts of 3 patients each. All the patients enrolled in the study will receive a single subretinal injection in one eye.
Cohort 1: Subretinal administration of a single low dose ZVS101e at Day 0. Cohort 2: Subretinal administration of a single high dose ZVS101e at Day 0.
干预措施: ZVS101e (Drug)
结局指标
主要结局
Type and severity of ocular and systemic AEs and SAEs after ZVS101e treatment.
时间窗: Baseline up to Week 52
Safety as the primary endpoint will be assessed by best-corrected visual acuity (BCVA), slit-lamp examination, ophthalmoscopy, fundus photography, intraocular pressure (IOP), optical coherence tomography (OCT), laboratory tests, vital signs, physical examinations, electrocardiogram (ECG), immunopathology and biodistribution of ZVS101e.
Incidence of ocular and systemic adverse events (AEs) after ZVS101e treatment.
时间窗: Baseline up to Week 52
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product; the event will not need to have a causal relationship with the treatment.
Incidence of ocular and systemic serious adverse events (SAEs) after ZVS101e treatment.
时间窗: Baseline up to Week 52
A serious adverse event (SAE) is any untoward medical occurrence at any dose that leading to the following: Results in death; Life-threatening, refers to an event in which the patient is at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe; Significant or permanent disability/incapacity, where disability refers to a serious disruption and damage of a person's ability to perform normal life functions; Requires inpatient hospitalization or prolongation of existing hospitalization; Congenital anomaly or birth defect; Other medically important events.
次要结局
- Change from Baseline in color vision(Baseline up to Week 52)
- Change from Baseline in retinal thickness(Baseline up to Week 52)
- Change from Baseline in fundus autofluorescence (FAF).(Baseline up to Week 52)
- Change from Baseline in multi-luminance mobility test (MLMT)(Baseline up to Week 52)
- Mean change from baseline in BCVA after ZVS101e treatment;(Baseline up to Week 52)
- Change from Baseline in visual field(Baseline up to Week 52)
- Change from Baseline in NEI VFQ-25 total score(Baseline up to Week 52)
- Incidence of ocular and systemic AEs after ZVS101e treatment.(Week 53 to Week 104)
- Change from Baseline in contrast sensitivity(Baseline up to Week 52)
- Change from Baseline in mfERG(Baseline up to Week 52)
- Incidence of ocular and systemic SAEs after ZVS101e treatment.(Week 53 to Week 104)
- Type and severity of ocular and systemic AEs and SAEs after ZVS101e treatment.(Week 53 to Week 104)