Trial Outcomes & Findings for Trial of Subretinal Injection of (rAAV2-VMD2-hMERTK) (NCT NCT01482195)

NCT ID: NCT01482195

Last Updated: 2022-01-26

Results Overview

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 .

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 6 participants
• Primary outcome timeframe: 2 years
• Results posted on: 2022-01-26

Participant Flow

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.

Participant milestones

Measure	Recombinant Adeno-Associated Virus Recombinant Adeno-Associated Virus: Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus
Overall Study STARTED	6
Overall Study One Year Results	6
Overall Study COMPLETED	6
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Recombinant Adeno-Associated Virus n=6 Participants Recombinant Adeno-Associated Virus: Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus
Age, Categorical <=18 years	1 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	5 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	33.3 years n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants
Region of Enrollment Saudi Arabia	5 participants n=5 Participants
Region of Enrollment Bahrain	1 participants n=5 Participants

PRIMARY outcome

Timeframe: 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 .

Outcome measures

Measure	Recombinant Adeno-Associated Virus Injected Eyes n=6 Participants Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Fellow Eyes n=6 Participants Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Systemic and Ocular Safety Cataract	1 Participants	0 Participants
Systemic and Ocular Safety Systemic events	0 Participants	0 Participants
Systemic and Ocular Safety Corneal abnormalities	1 Participants	0 Participants
Systemic and Ocular Safety Afferent pupillary defect	0 Participants	0 Participants
Systemic and Ocular Safety Intraocular inflammation	0 Participants	0 Participants
Systemic and Ocular Safety Intraocular pressure changes	0 Participants	0 Participants
Systemic and Ocular Safety Retinal changes	2 Participants	2 Participants
Systemic and Ocular Safety Macular thinning on OCT	0 Participants	1 Participants
Systemic and Ocular Safety Toxicity seen on FST	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Recombinant Adeno-Associated Virus Injected Eyes n=6 Participants Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Fellow Eyes n=6 Participants Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Visual Acuity Measurement Improved VA at 2 years	3 Participants	1 Participants
Visual Acuity Measurement Decreased VA at 2 years	0 Participants	2 Participants
Visual Acuity Measurement Stable VA at 2 years	3 Participants	3 Participants
Visual Acuity Measurement Improvement of VA after 2years	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 2 years

Population: 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).

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.

Outcome measures

Measure	Recombinant Adeno-Associated Virus Injected Eyes n=6 Participants Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Fellow Eyes n=6 Participants Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Full-field Stimulus Threshold Testing (FST). FST at baseline	-23.34 dB Interval -29.65 to -17.03	-24.14 dB Interval -30.4 to -17.88
Full-field Stimulus Threshold Testing (FST). FST at 10 days	-19.58 dB Interval -25.93 to -13.23	-20.13 dB Interval -26.59 to -13.67
Full-field Stimulus Threshold Testing (FST). FST at 30 days	-19.22 dB Interval -23.98 to -14.46	-23.40 dB Interval -30.6 to -16.29
Full-field Stimulus Threshold Testing (FST). FST at 90 days	-13.94 dB Interval -42.96 to 15.08	-24.68 dB Interval -33.54 to -15.82
Full-field Stimulus Threshold Testing (FST). FST at 180 days	-20.01 dB Interval -28.12 to -11.9	-22.02 dB Interval -31.83 to -12.21
Full-field Stimulus Threshold Testing (FST). FST at 365 days	-20.59 dB Interval -30.09 to -11.08	-22.26 dB Interval -28.87 to -15.65
Full-field Stimulus Threshold Testing (FST). FST at 1.5 year	-21.09 dB Interval -29.04 to -13.14	-21.66 dB Interval -29.81 to -13.51
Full-field Stimulus Threshold Testing (FST). FST at 2 years	-20.38 dB Interval -28.54 to -12.23	-15.92 dB Interval -29.78 to -2.05

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Recombinant Adeno-Associated Virus Injected Eyes n=5 Participants Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Fellow Eyes n=5 Participants Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). CFT at Baseline	65.80 microns. Interval 36.69 to 94.91	74.80 microns. Interval 41.22 to 108.38
Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). CFT at 2 years	69.20 microns. Interval 39.89 to 98.51	75.00 microns. Interval 50.51 to 99.49

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Recombinant Adeno-Associated Virus Injected Eyes n=3 Participants Eyes with RP which received a single dose of subretinal recombinant Adeno-Associated Virus injection.	Fellow Eyes n=3 Participants Eyes with RP which did not receive subretinal recombinant Adeno-Associated Virus injection.
Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT). CMT at baseline	128.00 microns. Interval 65.75 to 190.25	132.67 microns. Interval 40.56 to 224.76
Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT). CMT at 2 years	132.33 microns. Interval 70.76 to 193.9	123.76 microns. Interval 48.92 to 198.41

Adverse Events

Recombinant Adeno-Associated Virus

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Recombinant Adeno-Associated Virus n=6 participants at risk Recombinant Adeno-Associated Virus: Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus
Eye disorders Filamentary keratitis	16.7% 1/6 • Number of events 1 • through study completion, an average of 2 years The adverse events were collected : 1. 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) 2. Non systematic collection: ( one patient reported filamentary keratitis, another patient eported oscillopsiain the injected eye- = Other non serious adverse events
Eye disorders delayed resolution of subretinal fluid postoperatively, cataract, oscillopsia	16.7% 1/6 • Number of events 1 • through study completion, an average of 2 years The adverse events were collected : 1. 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) 2. Non systematic collection: ( one patient reported filamentary keratitis, another patient eported oscillopsiain the injected eye- = Other non serious adverse events
Blood and lymphatic system disorders systemic	16.7% 1/6 • Number of events 1 • through study completion, an average of 2 years The adverse events were collected : 1. 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) 2. Non systematic collection: ( one patient reported filamentary keratitis, another patient eported oscillopsiain the injected eye- = Other non serious adverse events

Additional Information

Dr. Fowzan Al Kuraya

King Faisal Specialist Hospital and Research Center

Phone: +966 11 442 7875

Email: falkuraya@kfshrc.edu.sa

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place