Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis

• Sponsor: Applied Genetic Technologies Corp (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00749957
• Collaborator: Oregon Health and Science University (Other), University of Massachusetts, Worcester (Other)
• Enrollment: 12
• Locations: 2
• Arms: 2
• Actual Duration (Months): 99.2
• Patients Per Site: 6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the safety and efficacy of an adeno-associated virus vector expressing RPE65 in patients with Leber congenital amaurosis caused by mutations in the RPE65 gene.

Funding Source - FDA OOPD

Condition or Disease	Intervention/Treatment	Phase
Leber Congenital Amaurosis	Biological: rAAV2-CB-hRPE65	Phase 1/Phase 2

Detailed Description

This will be a non-randomized, open label study. A total of 12 participants will be enrolled into two groups of 6 each. Each participant will receive rAAV2 CB hRPE65 by subretinal injection in one eye on a single occasion. Participants in Group 1 will receive 450 µL at a dosage level of 4 x 10^{11 vg/mL containing a total of 1.8 x 10}11 vg of rAAV2-CB-hRPE65. Participants in Group 2 will receive 450 µL at a dosage level of 1.33 x 10^{12 vg/mL containing a total of 6 x 10}11 vg of rAAV2-CB-hRPE65. A retinal surgeon will administer the vector by subretinal injection.

Enrollment will begin with Group 1 and will proceed to Group 2 after review of safety data by a Data and Safety Monitoring Committee.

Safety will be monitored by evaluation of ocular and non ocular adverse events and hematology and clinical chemistry parameters. Efficacy will be measured by evaluation of visual fields, visual acuity and electroretinography.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multiple-Site, Phase 1/2, Safety and Efficacy Trial of a Recombinant Adeno-associated Virus Vector Expressing RPE65 (rAAV2-CB-hRPE65) in Patients With Leber Congenital Amaurosis Type 2
• Actual Study Start Date: Jun 17, 2009
• Actual Primary Completion Date: Sep 23, 2014
• Actual Study Completion Date: Sep 22, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Subjects at least 6 y/o treated with a lower dose of the vector by subretinal injection	Biological: rAAV2-CB-hRPE65; Recombinant adeno-associated virus vector expressing RPE65
Experimental: 2 Subjects at least 6 y/o treated with a higher dose of the vector by subretinal injection	Biological: rAAV2-CB-hRPE65; Recombinant adeno-associated virus vector expressing RPE65

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing Ocular or Non-ocular Adverse Events [2 years]

Secondary Outcome Measures

1. Participants With Changes in Visual Fields [2 years]

   Improvement in the central 30 degree visual field, measured by static perimetry, at one or more time points after treatment, that was greater than the limit of agreement for baseline values .

2. Participants With Changes in Best Corrected Visual Acuity [2 years]

   Increase in BCVA of 7 or more letters at Year 2 visit compared to average baseline value

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Retinal disease consistent with a diagnosis of Leber congenital amaurosis and documented mutations in the RPE65 gene (including null mutations and mutations that code for abnormal RPE65 protein);

• At least 6 years of age;

• Good general health without significant physical examination findings or clinically significant abnormal laboratory results;

• Able to perform tests of visual and retinal function;

• Visual acuity not better than 20/60 and not worse than hand motion in both the treated eye and the fellow eye;

• Visible photoreceptor (outer nuclear) layer on a standard optical coherence tomography (OCT) scan;

• Acceptable hematology, clinical chemistry and urine laboratory parameters;

• For females of childbearing potential, a negative pregnancy test at screening and at baseline, and agreement to use effective contraception for 12 months after administration of rAAV2-CB-hRPE65, for sexual activity that could lead to pregnancy;

• For males of reproductive potential, agreement to use effective contraception for 12 months after administration of rAAV2-CB-hRPE65, for sexual activity that could lead to pregnancy

Exclusion Criteria:

• Pre-existing eye conditions that would preclude the planned surgery or interfere with interpretation of study endpoints or complications of surgery (e.g. glaucoma, corneal or lenticular opacities, or history or retinal detachment);

• Presence of epiretinal membrane on OCT;

• History of immunodeficiency or other medical conditions that might increase the risk of rAAV2-CB-hRPE65 administration;

• Use of anticoagulants or anti-platelet agents within 7 days prior to study agent administration;

• History of allergy or sensitivity to medications planned for use in the peri-operative period;

• For females of childbearing potential, a positive pregnancy test at screening or baseline (within 2 days before rAAV2-CB-hRPE65 administration);

• Females who are breast feeding;

• Use of any investigational agent, or systemic corticosteroids or other immunosuppressive drug(s), within 3 months prior to enrollment;

• Prior receipt of any AAV gene therapy product;

• Any condition which leads the investigator to believe that the participant cannot comply with the protocol requirements or that may place the participant at an unacceptable risk for participation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01605
2	Casey Eye Institue, Oregon Health & Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Applied Genetic Technologies Corp
• Oregon Health and Science University
• University of Massachusetts, Worcester

Investigators

• Principal Investigator: J Timothy Stout, MD, PhD, MBA, Casey Eye Institute, Oregon Health & Science University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Applied Genetic Technologies Corporation home page

Publications

• Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, Jacobson SG. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther. 2005 Dec;12(6):1072-82. Epub 2005 Oct 14.
• Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ, Cideciyan AV, Schwartz SB, Komaromy AM, Doobrajh M, Cheung AY, Sumaroka A, Pearce-Kelling SE, Aguirre GD, Kaushal S, Maguire AM, Flotte TR, Hauswirth WW. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther. 2006 Aug;17(8):845-58.
• Weleber RG, Pennesi ME, Wilson DJ, Kaushal S, Erker LR, Jensen L, McBride MT, Flotte TR, Humphries M, Calcedo R, Hauswirth WW, Chulay JD, Stout JT. Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. Ophthalmology. 2016 Jul;123(7):1606-20. doi: 10.1016/j.ophtha.2016.03.003. Epub 2016 Apr 19.

• Responsible Party: Applied Genetic Technologies Corp
• ClinicalTrials.gov Identifier: NCT00749957
• Other Study ID Numbers: AGTC-RPE65-002; R01FD003694
• First Posted: Sep 10, 2008
• Last Update Posted: Dec 28, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by Applied Genetic Technologies Corp: AAV; adeno-associated virus; RPE65; Leber congenital amaurosis; LCA; gene therapy; human gene transfer
• Additional relevant MeSH terms: Blindness; Leber Congenital Amaurosis

Study Results

Participant Flow

Recruitment Details	Twelve subjects with DNA sequence-confirmed mutations in RPE65 were enrolled, 10 at the Casey Eye Institute and 2 at the University of Massachusetts, between June 2009 and September 2012.

Arm/Group Title	Lower Dose of rAAV2-CB-hRPE65	Higher Dose of rAAV2-CB-hRPE65
Arm/Group Description	Subjects at least 6 y/o administered a lower dose of the rAAV2-CB-hRPE65 vector by subretinal injection	Subjects at least 6 y/o administered a higher dose of the rAAV2-CB-hRPE65 vector by subretinal injection
Period Title: Overall Study
STARTED	6	6
COMPLETED	6	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Lower Dose of rAAV2-CB-hRPE65	Higher Dose of rAAV2-CB-hRPE65	Total
Arm/Group Description	Subjects at least 6 y/o treated with a lower dose of the rAAV2-CB-hRPE65 vector by subretinal injection	Subjects at least 6 y/o treated with a higher dose of the rAAV2-CB-hRPE65 vector by subretinal injection	Total of all reporting groups
Overall Participants	6	6	12
Age (Count of Participants)
<=18 years	3 50%	1 16.7%	4 33.3%
Between 18 and 65 years	3 50%	5 83.3%	8 66.7%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	22	31	31
Sex: Female, Male (Count of Participants)
Female	2 33.3%	4 66.7%	6 50%
Male	4 66.7%	2 33.3%	6 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 33.3%	3 50%	5 41.7%
Not Hispanic or Latino	4 66.7%	3 50%	7 58.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	2 33.3%	2 16.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 33.3%	0 0%	2 16.7%
White	4 66.7%	4 66.7%	8 66.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	6 100%	12 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing Ocular or Non-ocular Adverse Events
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lower Dose of rAAV2-CB-hRPE65	Higher Dose of rAAV2-CB-hRPE65
Arm/Group Description	Subjects at least 6 y/o treated with a lower dose of the rAAV2-CB-hRPE65 vector by subretinal injection	Subjects at least 6 y/o treated with a higher dose of the rAAV2-CB-hRPE65 vector by subretinal injection
Measure Participants	6	6
Number [participants]	6 100%	6 100%

2. Secondary Outcome

Title	Participants With Changes in Visual Fields
Description	Improvement in the central 30 degree visual field, measured by static perimetry, at one or more time points after treatment, that was greater than the limit of agreement for baseline values .
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lower Dose of rAAV2-CB-hRPE65	Higher Dose of rAAV2-CB-hRPE65
Arm/Group Description	Subjects at least 6 y/o administered a lower dose of the rAAV2-CB-hRPE65 vector by subretinal injection	Subjects at least 6 y/o administered a higher dose of the rAAV2-CB-hRPE65 vector by subretinal injection
Measure Participants	6	6
Number [participants]	3 50%	3 50%

3. Secondary Outcome

Title	Participants With Changes in Best Corrected Visual Acuity
Description	Increase in BCVA of 7 or more letters at Year 2 visit compared to average baseline value
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lower Dose of rAAV2-CB-hRPE65	Higher Dose of rAAV2-CB-hRPE65
Arm/Group Description	Subjects at least 6 y/o administered a lower dose of the rAAV2-CB-hRPE65 vector by subretinal injection	Subjects at least 6 y/o administered a higher dose of the rAAV2-CB-hRPE65 vector by subretinal injection
Measure Participants	6	6
Number [participants]	2 33.3%	1 16.7%

Adverse Events

Time Frame	2 years
Arm/Group Title	Lower Dose of rAAV2-CB-hRPE65		Higher Dose of rAAV2-CB-hRPE65
Arm/Group Description	Subjects at least 6 y/o administered a lower dose of the rAAV2-CB-hRPE65 vector by subretinal injection		Subjects at least 6 y/o administered a higher dose of the rAAV2-CB-hRPE65 vector by subretinal injection
All Cause Mortality
	Lower Dose of rAAV2-CB-hRPE65		Higher Dose of rAAV2-CB-hRPE65
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lower Dose of rAAV2-CB-hRPE65		Higher Dose of rAAV2-CB-hRPE65
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Lower Dose of rAAV2-CB-hRPE65		Higher Dose of rAAV2-CB-hRPE65
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)
Eye disorders
subconjunctival hemorrhage	3/6 (50%)	3	5/6 (83.3%)	5
ocular hyperemia	3/6 (50%)	3	1/6 (16.7%)	1
eye inflammation	0/6 (0%)		3/6 (50%)
eye irritation	1/6 (16.7%)	1	1/6 (16.7%)	1
eye pain	1/6 (16.7%)	2	0/6 (0%)	2
eye pruritus	0/6 (0%)		2/6 (33.3%)	2

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.