Leber Congenital Amaurosis
Conditions
Keywords
AAV, adeno-associated virus, RPE65, Leber congenital amaurosis, LCA, gene therapy, human gene transfer
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
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.
Interventions
BIOLOGICALrAAV2-CB-hRPE65
Recombinant adeno-associated virus vector expressing RPE65
Sponsors
Oregon Health and Science University
University of Massachusetts, Worcester
Beacon Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants Experiencing Ocular or Non-ocular Adverse Events | 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 . |
| 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 |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Lower Dose of rAAV2-CB-hRPE65 Subjects at least 6 y/o treated with a lower dose of the rAAV2-CB-hRPE65 vector by subretinal injection | 6 |
| Higher Dose of rAAV2-CB-hRPE65 Subjects at least 6 y/o treated with a higher dose of the rAAV2-CB-hRPE65 vector by subretinal injection | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Lower Dose of rAAV2-CB-hRPE65 | Higher Dose of rAAV2-CB-hRPE65 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 8 Participants |
| Age, Continuous | 22 years | 31 years | 31 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Number of Participants Experiencing Ocular or Non-ocular Adverse Events
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lower Dose of rAAV2-CB-hRPE65 | Number of Participants Experiencing Ocular or Non-ocular Adverse Events | 6 participants |
| Higher Dose of rAAV2-CB-hRPE65 | Number of Participants Experiencing Ocular or Non-ocular Adverse Events | 6 participants |
Secondary
Participants With Changes in Best Corrected Visual Acuity
Increase in BCVA of 7 or more letters at Year 2 visit compared to average baseline value
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lower Dose of rAAV2-CB-hRPE65 | Participants With Changes in Best Corrected Visual Acuity | 2 participants |
| Higher Dose of rAAV2-CB-hRPE65 | Participants With Changes in Best Corrected Visual Acuity | 1 participants |
Secondary
Participants With Changes in Visual Fields
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lower Dose of rAAV2-CB-hRPE65 | Participants With Changes in Visual Fields | 3 participants |
| Higher Dose of rAAV2-CB-hRPE65 | Participants With Changes in Visual Fields | 3 participants |