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Safety and Tolerability Study of Gene Editing Drug ZVS203e in Participants With Retinitis Pigmentosa

Primary Purpose

Retinitis Pigmentosa

Status
Recruiting
Phase
Early Phase 1
Locations
China
Study Type
Interventional
Intervention
ZVS203e
Sponsored by
Peking University Third Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Retinitis Pigmentosa focused on measuring gene editing, retinitis pigmentosa, RHO, rAAV

Eligibility Criteria

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

Inclusion Criteria: 1. Patients with clinical diagnosis of Retinitis Pigmentosa (RP) (age ≥ 18 years) ; 2. Genetic test confirmed to carry a fix mutation of RHO and carry no pathogenic mutations of other ophthalmic genetic diseases; 3. Meet the following target eye selection criteria: Best corrected visual acuity between 2.3 LogMAR and 0.5 LogMAR (including 2.3 LogMAR and 0.5 LogMAR, equivalent to Snellen visual acuity of hand move to 20/63) ; 4. Agree to take effective contraceptive measures from the beginning of the study to 1 year after the administration; 5.Willingness to adhere to protocol as evidenced by written informed consent; Exclusion Criteria: 1. Existing or pre-existing of macular lesions such as retinoschisis or macular membrane, or other eye conditions interfering with the surgery or the interpretation of the clinical endpoint, in the investigators' opinion; 2. The study eye has been treated with other drugs within 3 months that could affect the evaluation of the investigational drug; 3. The study eye has been treated with the following intraocular procedures: retinal detachment surgery, vitrectomy; 4. The presence of an ocular/visual disease, disorder or lesion known to cause, or to be associated with, vision loss, or whose associated treatment or therapy is known to cause, or to be associated with, vision loss; 5. Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen; 6. Known allergy to the drug planned for use in the study; 7.Those with the following laboratory abnormalities which are clinically significant: Liver function: chronic liver disease, ALT increased >2 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; 8. 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; 9. Participation in any medicine or medical device clinical trials within 3 months prior to enrollment; 10. Neutralizing antibodies to rAAV> 1:1000 by immunologic test; 11. For females in pregnancy or lactation period; 12. Any other conditions which leads the investigator to determine the participant is unsuitable for this study.

Sites / Locations

  • Peking University Third HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dose escalation

Arm Description

Three 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 ZVS203e at Day 0. Cohort 2: Subretinal administration of a single medium dose ZVS203e at Day 0. Cohort 3: Subretinal administration of a single high dose ZVS203e at Day 0.

Outcomes

Primary Outcome Measures

Incidence of adverse events (AEs)
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 serious adverse events (SAEs)
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.

Secondary Outcome Measures

Mean change from baseline in BCVA after ZVS203e treatment
BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart.
Change from Baseline in visual field
Visual field will be assessed by Humphrey perimetry, changes in VFI, MD, PSD will be analyzed.
Change from Baseline in contrast sensitivity
Change from baseline in contrast sensitivity will be measured using the CSV-1000E instrument.
Change from Baseline in multi-luminance mobility test (MLMT)
MLMT was assessed at 1 or more of 7 levels of illumination, ranging from 400 lux (a brightly lit office) to 1 lux (a moonless summer night). The score range is between -1 (the worst) and 6 (the best).
Change from Baseline in retinal thickness
Retinal thickness will be assessed for both eyes using OCT.
Change from Baseline in fundus autofluorescence (FAF)
FAF is a noninvasive test to explore the health and metabolic status of retinal pigment epithelial cell/photoreceptor complex.
Change from Baseline in color vision
Subjects' color vision was classified and graded by Farnsworth Munsell 100 hue.
Change from Baseline in mfERG
The measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV).
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.

Full Information

First Posted
March 14, 2023
Last Updated
October 20, 2023
Sponsor
Peking University Third Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05805007
Brief Title
Safety and Tolerability Study of Gene Editing Drug ZVS203e in Participants With Retinitis Pigmentosa
Official Title
A Single-arm, Open-label Exploratory Clinical Study to Assess the Preliminary Safety of the Gene Editing Drug ZVS203e for the Management of Retinitis Pigmentosa Caused by Mutations in the RHO Gene
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 12, 2023 (Actual)
Primary Completion Date
April 2026 (Anticipated)
Study Completion Date
April 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Peking University Third Hospital

4. Oversight

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

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety, tolerability and efficacy of a single escalating doses of ZVS203e administered via subretinal injection in participants with RP caused by RHO site-specific gene mutation (RHO-RP).
Detailed Description
This is a single-arm, open-label, single ascending dose study of ZVS203e in participants with RHO-RP. Up to 9 participants will be enrolled in this study. Safety, efficacy and vector shedding characteristics of ZVS203e are then measured.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Retinitis Pigmentosa
Keywords
gene editing, retinitis pigmentosa, RHO, rAAV

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Dose escalation
Arm Type
Experimental
Arm Description
Three 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 ZVS203e at Day 0. Cohort 2: Subretinal administration of a single medium dose ZVS203e at Day 0. Cohort 3: Subretinal administration of a single high dose ZVS203e at Day 0.
Intervention Type
Drug
Intervention Name(s)
ZVS203e
Intervention Description
ZVS203e is a rAAV-mediated gene editing drug that silences RHO mutant protein expression by CRISPR/Cas9 editing system.
Primary Outcome Measure Information:
Title
Incidence of adverse events (AEs)
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
Baseline up to Week 52
Title
Incidence of serious adverse events (SAEs)
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
Baseline up to Week 52
Secondary Outcome Measure Information:
Title
Mean change from baseline in BCVA after ZVS203e treatment
Description
BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart.
Time Frame
Baseline up to Week 52
Title
Change from Baseline in visual field
Description
Visual field will be assessed by Humphrey perimetry, changes in VFI, MD, PSD will be analyzed.
Time Frame
Baseline up to Week 52
Title
Change from Baseline in contrast sensitivity
Description
Change from baseline in contrast sensitivity will be measured using the CSV-1000E instrument.
Time Frame
Baseline up to Week 52
Title
Change from Baseline in multi-luminance mobility test (MLMT)
Description
MLMT was assessed at 1 or more of 7 levels of illumination, ranging from 400 lux (a brightly lit office) to 1 lux (a moonless summer night). The score range is between -1 (the worst) and 6 (the best).
Time Frame
Baseline up to Week 52
Title
Change from Baseline in retinal thickness
Description
Retinal thickness will be assessed for both eyes using OCT.
Time Frame
Baseline up to Week 52
Title
Change from Baseline in fundus autofluorescence (FAF)
Description
FAF is a noninvasive test to explore the health and metabolic status of retinal pigment epithelial cell/photoreceptor complex.
Time Frame
Baseline up to Week 52
Title
Change from Baseline in color vision
Description
Subjects' color vision was classified and graded by Farnsworth Munsell 100 hue.
Time Frame
Baseline up to Week 52
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).
Time Frame
Baseline up to Week 52
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
Baseline up to Week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 1. Patients with clinical diagnosis of Retinitis Pigmentosa (RP) (age ≥ 18 years) ; 2. Genetic test confirmed to carry a fix mutation of RHO and carry no pathogenic mutations of other ophthalmic genetic diseases; 3. Meet the following target eye selection criteria: Best corrected visual acuity between 2.3 LogMAR and 0.5 LogMAR (including 2.3 LogMAR and 0.5 LogMAR, equivalent to Snellen visual acuity of hand move to 20/63) ; 4. Agree to take effective contraceptive measures from the beginning of the study to 1 year after the administration; 5.Willingness to adhere to protocol as evidenced by written informed consent; Exclusion Criteria: 1. Existing or pre-existing of macular lesions such as retinoschisis or macular membrane, or other eye conditions interfering with the surgery or the interpretation of the clinical endpoint, in the investigators' opinion; 2. The study eye has been treated with other drugs within 3 months that could affect the evaluation of the investigational drug; 3. The study eye has been treated with the following intraocular procedures: retinal detachment surgery, vitrectomy; 4. The presence of an ocular/visual disease, disorder or lesion known to cause, or to be associated with, vision loss, or whose associated treatment or therapy is known to cause, or to be associated with, vision loss; 5. Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen; 6. Known allergy to the drug planned for use in the study; 7.Those with the following laboratory abnormalities which are clinically significant: Liver function: chronic liver disease, ALT increased >2 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; 8. 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; 9. Participation in any medicine or medical device clinical trials within 3 months prior to enrollment; 10. Neutralizing antibodies to rAAV> 1:1000 by immunologic test; 11. For females in pregnancy or lactation period; 12. Any other conditions which leads the investigator to determine the participant is unsuitable for this study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Liping Yang, MD
Phone
010-82266595
Email
alexlipingyang@bjmu.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Jinlu Zhang, MD
Phone
15810570898
Email
zhangjinlu@bjmu.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Liping Yang, MD
Organizational Affiliation
Peking University Third 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
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jinlu Zhang, MD
Phone
15810570898
Email
zhangjinlu@bjmu.edu.cn
First Name & Middle Initial & Last Name & Degree
Bingqian Cong, Bachelor
Phone
18500191916
Email
congbingqian@chinagene.cc
First Name & Middle Initial & Last Name & Degree
Hongliang Dou, MD
First Name & Middle Initial & Last Name & Degree
Xuefeng Feng, MD
First Name & Middle Initial & Last Name & Degree
Liping Yang, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Safety and Tolerability Study of Gene Editing Drug ZVS203e in Participants With Retinitis Pigmentosa

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