Safety and Efficacy Study of Novel Gene Therapy ZM-01 for X-linked Retinoschisis Patients

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Primary Purpose

Status

Recruiting

Phase

Early Phase 1

Locations

China

Study Type

Interventional

Intervention

ZM-01-L

ZM-01-H

About this trial

This is an interventional treatment trial for X-linked Retinoschisis focused on measuring gene therapy, AAV, RS1

Eligibility Criteria

3 Years - 18 Years (Child, Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria: Subjects who meet all of the following criteria will be enrolled into the study Diagnosis of X-linked retinoschisis consistent with the presence of RS1 gene mutation Male, aged between 3 and 18 years old, in overall good health except for XLRS condition Capable of undergoing visual and retinal function assessment. The visual acuity of the study eye not better than: 0.4 (68 ETDRS letters equivalent) No carbonic anhydrase inhibitors have been used at present and for 3 months before treatment Laboratory tests meet the following criteria: Hemoglobin ≥ 11.0 g/dL White blood cell counts ranged from 3,300 to 12,000 cells /mm³; Platelet count 125,000-550,000 /mm³; Alanine aminotransferase (ALT) is not higher than 1.5 times the upper limit of the normal range of laboratory tests; Serum creatinine was no higher than 1.1 times the upper limit of the normal range for laboratory tests; Prothrombin time (PT) ≤14.5 seconds and partial thromboplastin time (PTT) ≤ 36.0 seconds. Willing to discontinue aspirin, aspirin-containing products, and any other medications that may alter clotting function at least 7 days before dosing. Be able to understand and sign informed consent. Exclusion Criteria: Subjects who meet any of the following exclusion criteria before enrollment were excluded from the study Previously received any AAV gene therapy The following mutations in RS1 gene: R141H, C59S or C223S Pre-existing eye conditions that cause severe vision loss or increase the risk of intravitreal injections (e.g., advanced glaucoma, uveitis, or severe retinal detachment) Ocular diseases in which there is opacity of the lens, cornea, or other media, hindering adequate observation and examination of the retina Use anticoagulant or antiplatelet drugs within 7 days before dosing Use any experimental drug within 3 months prior to registration Presented any situation that causes the investigator to believe the subject might not adhere to the study protocol or that participation might pose an unacceptable risk to the subject

Sites / Locations

Wuhan University Renmin Hospital affiliated with Hanchuan HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

group 1

group 2

Arm Description

IVT administration of a single low dose ZM-01 injection

IVT administration of a single high dose ZM-01 injection

Outcomes

Primary Outcome Measures

Incidence of adverse events and serious adverse events

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. 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.

Change in best corrected visual acuity (BCVA)

BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart or tumbling "E" chart. This approach was chosen to facilitate visual acuity testing in children who cannot recognize letters, which was more appropriate for this study.

Secondary Outcome Measures

Incidence of adverse events and serious adverse events

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. 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.

Change in Quality of Life

Quality of Life will be measured using Pediatric Eye Questionnaire (PedEyeQ) or other similar questionnaires before and after treatment

Change in best corrected visual acuity (BCVA)

BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart or tumbling "E" chart. This approach was chosen to facilitate visual acuity testing in children who cannot recognize letters, which was more appropriate for this study.

Change in visual field

Visual field will be assessed by Humphrey perimetry, changes in VFI, MD, PSD will be analyzed.

Change in electrophysiology result

The ERG measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV).

Anti-AAV neutralizing antibody titer, Anti-RS1 neutralizing antibody titer

Peripheral blood samples were collected from each subjects to measure the AAV8 antibody levels and virus titers in the peripheral blood.

Change in the retina cavity assessed by macular OCT

Optical coherence tomography (OCT) of the macula was performed in both eyes of each participant at each visit.

Full Information

NCT ID

NCT06066008

First Posted

September 25, 2023

Last Updated

October 18, 2023

Sponsor

Zhongmou Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT06066008

Brief Title

Safety and Efficacy Study of Novel Gene Therapy ZM-01 for X-linked Retinoschisis Patients

Official Title

Prospective, Dose-Escalating, Investigator Initiated Trial to Evaluate the Safety and Efficacy of ZM-01 in 3-18 Year-old Male Subjects With X-linked Retinoschisis

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 25, 2022 (Actual)

Primary Completion Date

October 2023 (Anticipated)

Study Completion Date

October 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Zhongmou Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

No

Studies a U.S. FDA-regulated Device Product

No

5. Study Description

Brief Summary

This trail is meant to evaluate the safety and efficacy of ZM-01 of X-linked retinoschisis. Unilateral intravitreal injections (IVT) will be given into the subject's Study Eye.

Detailed Description

X-linked retinoschisis (XLRS) is a rare, inherited retinal disease caused by mutations in the RS1 gene. Individuals affected by XLRS often experience progressive visual impairment from a young age, potentially leading to legal blindness. There is currently no established clinical treatment available. We developed a innovative adeno-associated virus (AAV)-based gene therapy for individuals with XLRS. Six to nine subjects with XLRS were received a single unilateral intravitreal injection of ZM-01 at ascending doses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

X-linked Retinoschisis

Keywords

gene therapy, AAV, RS1

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

9 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

group 1

Arm Type

Experimental

Arm Description

IVT administration of a single low dose ZM-01 injection

Arm Title

group 2

Arm Type

Experimental

Arm Description

IVT administration of a single high dose ZM-01 injection

Intervention Type

Drug

Intervention Name(s)

ZM-01-L

Other Intervention Name(s)

rAAV-hRS1

Intervention Description

rAAV-hRS1 intravitreal injection of low dose

Intervention Type

Drug

Intervention Name(s)

ZM-01-H

Other Intervention Name(s)

rAAV-hRS1

Intervention Description

rAAV-hRS1 intravitreal injection of high dose

Primary Outcome Measure Information:

Title

Incidence of adverse events and serious adverse events

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. 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 to day 7, month 1, 2

Title

Change in best corrected visual acuity (BCVA)

Description

BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart or tumbling "E" chart. This approach was chosen to facilitate visual acuity testing in children who cannot recognize letters, which was more appropriate for this study.

Time Frame

baseline to day 7, month 1, 2

Secondary Outcome Measure Information:

Title

Incidence of adverse events and serious adverse events

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. 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 to month 3, 4, 6, 9, 12

Title

Change in Quality of Life

Description

Quality of Life will be measured using Pediatric Eye Questionnaire (PedEyeQ) or other similar questionnaires before and after treatment

Time Frame

baseline to month 9, 12

Title

Change in best corrected visual acuity (BCVA)

Description

BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart or tumbling "E" chart. This approach was chosen to facilitate visual acuity testing in children who cannot recognize letters, which was more appropriate for this study.

Time Frame

baseline to month 3, 4, 6, 9, 12

Title

Change in visual field

Description

Visual field will be assessed by Humphrey perimetry, changes in VFI, MD, PSD will be analyzed.

Time Frame

baseline to month 1, 2, 3, 4, 6, 9, 12

Title

Change in electrophysiology result

Description

The ERG measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV).

Time Frame

baseline to month 1, 2, 3, 4, 6, 9, 12

Title

Anti-AAV neutralizing antibody titer, Anti-RS1 neutralizing antibody titer

Description

Peripheral blood samples were collected from each subjects to measure the AAV8 antibody levels and virus titers in the peripheral blood.

Time Frame

baseline to day 1, 7 and month 1, 2

Title

Change in the retina cavity assessed by macular OCT

Description

Optical coherence tomography (OCT) of the macula was performed in both eyes of each participant at each visit.

Time Frame

baseline to day 7, month 1, 2, 3, 4, 6, 9, 12

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

3 Years

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion Criteria: Subjects who meet all of the following criteria will be enrolled into the study Diagnosis of X-linked retinoschisis consistent with the presence of RS1 gene mutation Male, aged between 3 and 18 years old, in overall good health except for XLRS condition Capable of undergoing visual and retinal function assessment. The visual acuity of the study eye not better than: 0.4 (68 ETDRS letters equivalent) No carbonic anhydrase inhibitors have been used at present and for 3 months before treatment Laboratory tests meet the following criteria: Hemoglobin ≥ 11.0 g/dL White blood cell counts ranged from 3,300 to 12,000 cells /mm³; Platelet count 125,000-550,000 /mm³; Alanine aminotransferase (ALT) is not higher than 1.5 times the upper limit of the normal range of laboratory tests; Serum creatinine was no higher than 1.1 times the upper limit of the normal range for laboratory tests; Prothrombin time (PT) ≤14.5 seconds and partial thromboplastin time (PTT) ≤ 36.0 seconds. Willing to discontinue aspirin, aspirin-containing products, and any other medications that may alter clotting function at least 7 days before dosing. Be able to understand and sign informed consent. Exclusion Criteria: Subjects who meet any of the following exclusion criteria before enrollment were excluded from the study Previously received any AAV gene therapy The following mutations in RS1 gene: R141H, C59S or C223S Pre-existing eye conditions that cause severe vision loss or increase the risk of intravitreal injections (e.g., advanced glaucoma, uveitis, or severe retinal detachment) Ocular diseases in which there is opacity of the lens, cornea, or other media, hindering adequate observation and examination of the retina Use anticoagulant or antiplatelet drugs within 7 days before dosing Use any experimental drug within 3 months prior to registration Presented any situation that causes the investigator to believe the subject might not adhere to the study protocol or that participation might pose an unacceptable risk to the subject

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Pei Cao

Phone

+86 18707134160

Email

zmt@simbaeye.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yin Shen, PhD

Organizational Affiliation

Zhongmou Theraputics

Official's Role

Study Chair

Facility Information:

Facility Name

Wuhan University Renmin Hospital affiliated with Hanchuan Hospital

City

Xiaogan

State/Province

Hubei

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Pei Cao

Phone

+86 18707134160

Email

caopei813@163.com

First Name & Middle Initial & Last Name & Degree

Guangtao Sun, MD

12. IPD Sharing Statement

Plan to Share IPD

No

IPD Sharing Plan Description

publish research paper

X-linked Retinoschisis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial