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Safety and Efficacy of ZVS101e in Patients With Bietti 's Crystalline Dystrophy

Primary Purpose

Bietti's Crystalline Dystrophy

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
ZVS101e
Sponsored by
Chigenovo Co., Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bietti's Crystalline Dystrophy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Peking University Third Hospital
  • Zhongshan Ophthalmic Center,Sun Yat-sen University
  • West China Hospital, Sichuan University
  • Tianjin Medical University Eye HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental

Arm Description

Dose escalation and expansion of ZVS101e. All patients enrolled in the study will receive a single subretinal injection of ZVS101e in one eye.

Outcomes

Primary Outcome Measures

Incidence of ocular and systemic adverse events (AEs) after ZVS101e treatment
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
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.
Mean change from baseline in BCVA (LogMAR)
BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart.

Secondary Outcome Measures

Change from Baseline in visual field
Visual field will be assessed by Humphrey perimetry, changes in retinal light sensitivity will be analyzed.
Change from Baseline in contrast sensitivity
Change from baseline in contrast sensitivity at all spatial frequency will be measured using the CSV-1000E instrument.
Change from Baseline in microperimetry
Microperimetry will be measured using MP-3,changes in retinal sensitivity (dB) will be analyzed.
Change from Baseline in mfERG
The measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV). Response Amplitude Density will be analyzed.
Change from Baseline in retinal thickness
Retinal thickness will be assessed for both eyes using OCT.
Change from Baseline in NEI VFQ-25 total score
National eye institute 25-item visual function questionnaire (NEI VFQ-25) consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
Change from Baseline in color vision
Subjects' color vision was classified and graded by having them identify the pictures within Color Vision Examination Plates.

Full Information

First Posted
April 2, 2023
Last Updated
April 16, 2023
Sponsor
Chigenovo Co., Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT05832684
Brief Title
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

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 20, 2023 (Actual)
Primary Completion Date
December 2028 (Anticipated)
Study Completion Date
December 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Chigenovo Co., Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bietti's Crystalline Dystrophy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Experimental
Arm Type
Experimental
Arm Description
Dose escalation and expansion of ZVS101e. All patients enrolled in the study will receive a single subretinal injection of ZVS101e in one eye.
Intervention Type
Drug
Intervention Name(s)
ZVS101e
Other Intervention Name(s)
rAAV2/8-hCYP4V2, rAAV8-hCYP4V2, AAV8-hCYP4V2
Intervention Description
ZVS101e contains recombinant adeno-associated virus serotype 8 (rAAV8) vectors which carry human wild type CYP4V2 gene.
Primary Outcome Measure Information:
Title
Incidence of ocular and systemic adverse events (AEs) after ZVS101e treatment
Description
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.
Time Frame
Up to day 180
Title
Incidence of ocular and systemic serious adverse events (SAEs) after ZVS101e treatment
Description
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.
Time Frame
Up to day 180
Title
Mean change from baseline in BCVA (LogMAR)
Description
BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart.
Time Frame
Up to day 180
Secondary Outcome Measure Information:
Title
Change from Baseline in visual field
Description
Visual field will be assessed by Humphrey perimetry, changes in retinal light sensitivity will be analyzed.
Time Frame
Up to day 180
Title
Change from Baseline in contrast sensitivity
Description
Change from baseline in contrast sensitivity at all spatial frequency will be measured using the CSV-1000E instrument.
Time Frame
Up to day 180
Title
Change from Baseline in microperimetry
Description
Microperimetry will be measured using MP-3,changes in retinal sensitivity (dB) will be analyzed.
Time Frame
Up to day 180
Title
Change from Baseline in mfERG
Description
The measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV). Response Amplitude Density will be analyzed.
Time Frame
Up to day 180
Title
Change from Baseline in retinal thickness
Description
Retinal thickness will be assessed for both eyes using OCT.
Time Frame
Up to day 180
Title
Change from Baseline in NEI VFQ-25 total score
Description
National eye institute 25-item visual function questionnaire (NEI VFQ-25) consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
Time Frame
Up to day 180
Title
Change from Baseline in color vision
Description
Subjects' color vision was classified and graded by having them identify the pictures within Color Vision Examination Plates.
Time Frame
Up to day 180
Other Pre-specified Outcome Measures:
Title
Change from Baseline in multi-luminance mobility test (MLMT)
Description
MLMT was assessed using both eyes at 1 or more of 7 levels of illumination, ranging from 400 lux (a brightly lit office) to 1 lux (a moonless summer night).
Time Frame
Up to day 180

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jinlu Zhang, MD
Phone
15810570898
Email
zhangjinlu@chinagene.cc
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xiaorong Li, MD
Organizational Affiliation
Tianjin Medical University Eye Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Peking University Third Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100191
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tingting Wu
Phone
18500191916
Email
wutingting@chinagene.cc
First Name & Middle Initial & Last Name & Degree
Hongliang Dou, MD
Facility Name
Zhongshan Ophthalmic Center,Sun Yat-sen University
City
Guangzhou
State/Province
Guangdong
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tingting Wu
Email
wutingting@chinagene.cc
First Name & Middle Initial & Last Name & Degree
Bingqian Liu, MD
Facility Name
West China Hospital, Sichuan University
City
Chengdu
State/Province
Sichuan
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bingqian Cong
Email
congbingqian@chinagene.cc
First Name & Middle Initial & Last Name & Degree
Fang Lu, MD
Facility Name
Tianjin Medical University Eye Hospital
City
Tianjin
State/Province
Tianjin
ZIP/Postal Code
300392
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Siyuan Ma
Phone
13102055471
Email
siyuan.ma@taiji-medicine.com
First Name & Middle Initial & Last Name & Degree
Tingting Wu
Phone
18500191916
Email
wutingting@chinagene.cc
First Name & Middle Initial & Last Name & Degree
Xiaorong Li, MD
First Name & Middle Initial & Last Name & Degree
Dongjun Xing, MD
First Name & Middle Initial & Last Name & Degree
Boshi Liu, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35925866
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.
Results Reference
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Safety and Efficacy of ZVS101e in Patients With Bietti 's Crystalline Dystrophy

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