Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
Condition: Inherited Retinal Dystrophy Due to RPE65 Mutations; Leber Congenital Amaurosis
MeSH terms: Blindness; Retinal Dystrophies; Leber Congenital Amaurosis
Intervention: AAV2-hRPE65v2,voretigene neparvovec-rzyl
Intervention description: Subretinal administration of gene therapy vector AAV2-hRPE65v2 (1.5E11 vector genomes per eye) to both eyes via surgical procedures on separate days.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Minimum age: 3 Years
Healthy volunteers: No
Keywords: Adeno-associated virus; AAV; Leber congenital amaurosis; RPE65; Gene therapy; Gene transfer; voretigene neparvovec-rzyl; Retinitis pigmentosa

Summary:

      The study is a Phase 3, open-label, randomized controlled trial of gene therapy intervention
      by subretinal administration of AAV2-hRPE65v2 (voretigene neparvovec-rzyl). At least
      twenty-four subjects, three years of age or older, will be recruited. The intervention group
      will receive AAV2-hRPE65v2 at either The Children's Hospital of Philadelphia or University of
      Iowa to determine if it improves visual and retinal function in individuals with RPE65 gene
      mutations.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Willingness to adhere to protocol and long-term follow-up as evidenced by written
             informed consent or parental permission and subject assent (where applicable).

          -  Diagnosis of LCA due to RPE65 mutations; molecular diagnosis is to be performed, or
             confirmed, by a CLIA-approved laboratory.

          -  Age three years old or older.

          -  Visual acuity worse than 20/60 (both eyes) and/or visual field less than 20 degrees in
             any meridian as measured by a III4e isopter or equivalent (both eyes).

          -  Sufficient viable retinal cells as determined by non-invasive means, such as optical
             coherence tomography (OCT) and/or ophthalmoscopy. Must have either: 1) an area of
             retina within the posterior pole of >100 µm thickness shown on OCT; 2) ≥ 3 disc areas
             of retina without atrophy or pigmentary degeneration within the posterior pole; or 3)
             remaining visual field within 30 degrees of fixation as measured by a III4e isopter or
             equivalent.

          -  Subjects must be evaluable on mobility testing (the primary efficacy endpoint) to be
             eligible for the study. Evaluable is defined as: 1) The ability to perform mobility
             testing within the luminance range evaluated in the study. Individuals must receive an
             accuracy score of ≤ 1 during screening mobility testing at 400 lux or less to be
             eligible; individuals with an accuracy score of > 1 on all screening mobility test
             runs at 400 lux, or those who refuse to perform mobility testing at screening, will be
             excluded. 2) The inability to pass mobility testing at 1 lux. Individuals must fail
             screening mobility testing at 1 lux to be eligible; individuals that pass one or more
             screening mobility test runs at 1 lux will be excluded.

        Exclusion Criteria:

          -  Unable or unwilling to meet requirements of the study, including receiving bilateral
             subretinal vector administrations.

          -  Any prior participation in a study in which a gene therapy vector was administered.

          -  Participation in a clinical study with an investigational drug in the past six months.

          -  Use of retinoid compounds or precursors that could potentially interact with the
             biochemical activity of the RPE65 enzyme; individuals who discontinue use of these
             compounds for 18 months may become eligible.

          -  Prior intraocular surgery within six months.

          -  Known sensitivity to medications planned for use in the peri-operative period.

          -  Pre-existing eye conditions or complicating systemic diseases that would preclude the
             planned surgery or interfere with the interpretation of study. Complicating systemic
             diseases would include those in which the disease itself, or the treatment for the
             disease, can alter ocular function. Examples are malignancies whose treatment could
             affect central nervous system function (for example: radiation treatment of the orbit;
             leukemia with CNS/optic nerve involvement). Subjects with diabetes or sickle cell
             disease would be excluded if they had any manifestation of advanced retinopathy (e.g.,
             macular edema or proliferative changes). Also excluded would be subjects with
             immunodeficiency (acquired or congenital) as there could be susceptibility to
             opportunistic infection (such as CMV retinitis).

          -  Individuals of childbearing potential who are pregnant or unwilling to use effective
             contraception for four months following vector administration.

          -  Individuals incapable of performing mobility testing (the primary efficacy endpoint)
             for reason other than poor vision, including physical or attentional limitations.

          -  Any other condition that would not allow the potential subject to complete follow-up
             examinations during the course of the study or, in the opinion of the investigator,
             makes the potential subject unsuitable for the study.

          -  Subjects will not be excluded based on their gender, race, or ethnicity.