Trial of Subretinal Injection of (rAAV2-VMD2-hMERTK)

• Sponsor: King Khaled Eye Specialist Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01482195
• Collaborator: King Faisal Specialist Hospital & Research Center (Other)
• Enrollment: 6
• Location: 1
• Arms: 2
• Actual Duration (Months): 96
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study was to assess the safety of gene transfer via subretinal administration of rAAV2-VMD2-hMERTK in subjects with MERTK-associated retinitis pigmentosa (RP).

Condition or Disease	Intervention/Treatment	Phase
Retinal Disease; Retinitis Pigmentosa	Biological: Subretinal administration of rAAV2-VMD2-hMERTKRecombinant Adeno-Associated Virus	Phase 1

Detailed Description

In this phase I open-label, dose-escalation trial, one eye of each patient (the worse-seeing eye in five subjects) will receive a submacular injection of the subretinal rAAV2-VMD2-hMERTK. Patients will be followed daily for 10 days and then at 30, 60, 90, 180, 270, 365, 540, and 730 days post-injection. Data will be collected on (1) full ophthalmologic examination including best-corrected VA, intraocular pressure, color fundus photographs, macular spectral-domain optical coherence tomography, and full-field stimulus threshold test (FST) in both the study and fellow eyes; (2) systemic safety data including CBC, liver, and kidney function tests, coagulation profiles, urine analysis, AAV antibody titers, peripheral blood PCR and ASR measurement; and (3) listing of ophthalmological or systemic adverse effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Ocular Subretinal administration of rAAV2-VMD2-hMERTK .Ocular Subretinal administration of rAAV2-VMD2-hMERTK .
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Trial of Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus (rAAV2-VMD2-hMERTK) Gene Vector to Patients With Retinal Disease Due to MERTK Mutations
• Actual Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subretinal Injection of rAAV2-VMD2-hMERTKRecombinant Adeno-Associated Virus Single arm of 6 patients undergoing subretinal injection of Gene Therapy using rAAV2-VMD2-hMERTKRecombinant Adeno-Associated Virus. Each patient received the injection in one eye.	Biological: Subretinal administration of rAAV2-VMD2-hMERTKRecombinant Adeno-Associated Virus; The study is an open-label, dose-escalation, phase I clinical trial of subretinal administration of rAAV2-VMD2-hMERTK in patients with retinitis pigmentosa due to MERTK mutation.
No Intervention: fellow eye without intervention fellow eye without intervention

Outcome Measures

Primary Outcome Measures

1. Systemic and Ocular Safety [2 years]

   Detailed history & physical exam were obtained at baseline visit and each post-injection protocol visit searching for systemic adverse events. Included were electrocardiogram, chest X-ray, complete blood count & differential, prothrombin time & INR, partial thromboplastin time, serum electrolytes, full serum chemistries including liver and renal function, urinalysis; serum antibody titers to AAV2 capsid components and antigen-specific reactivity (ASR) assays; blood analysis by DNA PCR to detect vector spread. Ophthalmic safety monitored changes from baseline included 1) corneal abnormalities, afferent pupillary defect, intraocular inflammation, cataract & intraocular pressure changes; 2) retinal changes based on fundus photos; 3) Macular SD-OCT changes in Central macular (CMT) and central foveal thickness (CFT) measurements when patient fixation allowed it, and 4) full field stimulus threshold (FST) to detect any retinal toxicity .

Secondary Outcome Measures

1. Visual Acuity Measurement [2 years and up to 5 years]

   Although candidates may have very severe loss of function, an attempt was made to measure a best-corrected visual acuity using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, and measurements were recorded as the number of letters read on each line of the chart (Diabetic Retinopathy Study Research Group 1985). If a patient was unable to read at least three letters of the first line correctly, the chart distance was progressively halved from the standard 4 m until either the first line was correctly read or the shortest distance of 0.5 m was reached. Patients who were unable to read any letters on the chart were tested for light perception and if they perceived light they were assigned the acuity score equivalent of <20/6400. Measurements were performed at baseline and each protocol follow up visit. Improvement in patients who could read was defined as a gain in 5 letters, and in those with those LP vision only to start seeing hand motion.

2. Full-field Stimulus Threshold Testing (FST). [2 years]

   Full-field stimulus threshold testing (FST) measures sensitivity of the entire visual field by estimating the lowest luminance of a flash that elicits a visual sensation. The FST measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes, and changes in FST results were analyzed.

3. Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). [2 years]

   Central foveal thickness (CFT) measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes (whenever possible), and changes in CFT values were analyzed.

4. Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT). [2 years]

   Central macular thickness (CMT) measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes (whenever possible), and changes in CMT values were analyzed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• MERTK-associated retinal disease;

• VA: 20/100 or less in worse eye

• Ability to perform tests of visual and retinal function;

• Good general health based on a complete physical examination and hematology and chemistry studies performed at a pre-treatment evaluation;

• Ability to comply with research procedures;

Exclusion Criteria:

• Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints or surgical complications (for example, glaucoma, corneal or lenticular opacities);

• Complicating systemic diseases (such as medical conditions causing immunosuppression) that would preclude the gene transfer, ocular surgery or known sensitivity or allergy to medications planned for use in the peri-operative period;

• Use of anti-platelet agents that may alter coagulation within 7 days prior to study agent administration;

• Use of immunosuppressive medications;

• Pregnancy or breastfeeding;

• Individuals (males and females) of childbearing potential who are unwilling to use effective contraception for 1 year following agent administration and barrier contraception for 3 months following agent administration;

• Any other condition that would prevent a subject from completing follow-up examinations during the course of the study and that, in the opinion of the investigator, makes the subject unsuitable for the study.

• Current, or recent (within the past 30 days, or 10 half lives of the drug) participation, in any other research protocol involving investigational agents or therapies.

• Recent (within past 6 months) receipt of an investigational biologic therapeutic agent.Subjects will not be excluded based on their gender, race or ethnicity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	King Khaled Eye Specialist Hospital	Riyadh		Saudi Arabia	11462

Sponsors and Collaborators

• King Khaled Eye Specialist Hospital
• King Faisal Specialist Hospital & Research Center

Investigators

• Principal Investigator: Fowzan S Alkuraya, MD, King Faisal Specialist Hospital & Research Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: King Khaled Eye Specialist Hospital
• ClinicalTrials.gov Identifier: NCT01482195
• Other Study ID Numbers: 0916-P
• First Posted: Nov 30, 2011
• Last Update Posted: Jan 26, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by King Khaled Eye Specialist Hospital: Retinal Disease; subretinal gene therapy; MERTK; retinitis pigmentosa
• Additional relevant MeSH terms: Retinitis; Retinitis Pigmentosa; Retinal Diseases

Study Results

Participant Flow

Recruitment Details	Six eyes of 6 patients were enrolled in this phase of the study. All patients had the typical clinical signs and symptoms of retinitis pigmentosa and tested positive for MERTK mutation. All patients were recruited from the outpatient clinics at King Khaled Eye specialist Hospital (KKESH) starting September 2011.

Arm/Group Title	Recombinant Adeno-Associated Virus
Arm/Group Description	Recombinant Adeno-Associated Virus: Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus
Period Title: Overall Study
STARTED	6
One Year Results	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Recombinant Adeno-Associated Virus
Arm/Group Description	Recombinant Adeno-Associated Virus: Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus
Overall Participants	6
Age (Count of Participants)
<=18 years	1 16.7%
Between 18 and 65 years	5 83.3%
>=65 years	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	33.3
Sex: Female, Male (Count of Participants)
Female	1 16.7%
Male	5 83.3%
Region of Enrollment (participants) [Number]
Saudi Arabia	5 83.3%
Bahrain	1 16.7%

Outcome Measures

1. Primary Outcome

Title	Systemic and Ocular Safety
Description	Detailed history & physical exam were obtained at baseline visit and each post-injection protocol visit searching for systemic adverse events. Included were electrocardiogram, chest X-ray, complete blood count & differential, prothrombin time & INR, partial thromboplastin time, serum electrolytes, full serum chemistries including liver and renal function, urinalysis; serum antibody titers to AAV2 capsid components and antigen-specific reactivity (ASR) assays; blood analysis by DNA PCR to detect vector spread. Ophthalmic safety monitored changes from baseline included 1) corneal abnormalities, afferent pupillary defect, intraocular inflammation, cataract & intraocular pressure changes; 2) retinal changes based on fundus photos; 3) Macular SD-OCT changes in Central macular (CMT) and central foveal thickness (CFT) measurements when patient fixation allowed it, and 4) full field stimulus threshold (FST) to detect any retinal toxicity .
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Recombinant Adeno-Associated Virus Injected Eyes	Fellow Eyes
Arm/Group Description	Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Measure Participants	6	6
Systemic events	0 0%	0 NaN
Corneal abnormalities	1 16.7%	0 NaN
Afferent pupillary defect	0 0%	0 NaN
Intraocular inflammation	0 0%	0 NaN
Cataract	1 16.7%	0 NaN
Intraocular pressure changes	0 0%	0 NaN
Retinal changes	2 33.3%	2 NaN
Macular thinning on OCT	0 0%	1 NaN
Toxicity seen on FST	0 0%	0 NaN

2. Secondary Outcome

Title	Visual Acuity Measurement
Description	Although candidates may have very severe loss of function, an attempt was made to measure a best-corrected visual acuity using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, and measurements were recorded as the number of letters read on each line of the chart (Diabetic Retinopathy Study Research Group 1985). If a patient was unable to read at least three letters of the first line correctly, the chart distance was progressively halved from the standard 4 m until either the first line was correctly read or the shortest distance of 0.5 m was reached. Patients who were unable to read any letters on the chart were tested for light perception and if they perceived light they were assigned the acuity score equivalent of <20/6400. Measurements were performed at baseline and each protocol follow up visit. Improvement in patients who could read was defined as a gain in 5 letters, and in those with those LP vision only to start seeing hand motion.
Time Frame	2 years and up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Recombinant Adeno-Associated Virus Injected Eyes	Fellow Eyes
Arm/Group Description	Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Measure Participants	6	6
Improved VA at 2 years	3 50%	1 NaN
Decreased VA at 2 years	0 0%	2 NaN
Stable VA at 2 years	3 50%	3 NaN
Improvement of VA after 2years	0 0%	0 NaN

3. Secondary Outcome

Title	Full-field Stimulus Threshold Testing (FST).
Description	Full-field stimulus threshold testing (FST) measures sensitivity of the entire visual field by estimating the lowest luminance of a flash that elicits a visual sensation. The FST measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes, and changes in FST results were analyzed.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Six Patients with the clinical diagnosis of RP with a proven MERTK mutation were included. Patients had to be older than 14 years of age and had the viral vector injected into their worse seeing one eye (except case #4).

Arm/Group Title	Recombinant Adeno-Associated Virus Injected Eyes	Fellow Eyes
Arm/Group Description	Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Measure Participants	6	6
FST at baseline	-23.34	-24.14
FST at 10 days	-19.58	-20.13
FST at 30 days	-19.22	-23.40
FST at 90 days	-13.94	-24.68
FST at 180 days	-20.01	-22.02
FST at 365 days	-20.59	-22.26
FST at 1.5 year	-21.09	-21.66
FST at 2 years	-20.38	-15.92

4. Secondary Outcome

Title	Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT).
Description	Central foveal thickness (CFT) measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes (whenever possible), and changes in CFT values were analyzed.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Recombinant Adeno-Associated Virus Injected Eyes	Fellow Eyes
Arm/Group Description	Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Measure Participants	5	5
CFT at Baseline	65.80	74.80
CFT at 2 years	69.20	75.00

5. Secondary Outcome

Title	Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT).
Description	Central macular thickness (CMT) measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes (whenever possible), and changes in CMT values were analyzed.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Recombinant Adeno-Associated Virus Injected Eyes	Fellow Eyes
Arm/Group Description	Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Measure Participants	3	3
CMT at baseline	128.00	132.67
CMT at 2 years	132.33	123.76

Adverse Events

Time Frame	through study completion, an average of 2 years
Adverse Event Reporting Description	The adverse events were collected : systematically ( blood samples withdrawn to test for rise in antiViral titers). One temporary rise occurred in the post-operative period in one patient = non serious adverse events) Non systematic collection: ( one patient reported filamentary keratitis, another patient eported oscillopsiain the injected eye- = Other non serious adverse events
Arm/Group Title	Recombinant Adeno-Associated Virus
Arm/Group Description	Recombinant Adeno-Associated Virus: Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus
All Cause Mortality
	Recombinant Adeno-Associated Virus
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Serious Adverse Events
	Recombinant Adeno-Associated Virus
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Other (Not Including Serious) Adverse Events
	Recombinant Adeno-Associated Virus
	Affected / at Risk (%)	# Events
Total	3/6 (50%)
Blood and lymphatic system disorders
systemic	1/6 (16.7%)	1
Eye disorders
Filamentary keratitis	1/6 (16.7%)	1
delayed resolution of subretinal fluid postoperatively, cataract, oscillopsia	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.