Rate of Progression in USH2A-related Retinal Degeneration

Study Overview
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Brief Summary
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The overall goal of this project funded by the Foundation Fighting Blindness is to characterize the natural history of disease progression in patients with USH2A related retinal degeneration associated with congenital hearing loss (Usher syndrome type 2a) or non-syndromic retinitis pigmentosa (RP39).

Detailed Description
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This natural history study of patients with USH2A mutations will accelerate the development of outcome measures for clinical trials. Sensitive, objective outcome measures of retinal degeneration will greatly facilitate development of treatments for Usher syndrome patients. Together these approaches are expected to have an impact on understanding USH2A-related retinal degeneration, developing experimental treatment protocols, and assessing their effectiveness. The goals and expected impact of this natural history study are to: Report the natural history of retinal degeneration in patients with biallelic mutations in the USH2A gene Identify sensitive structural and functional outcome measures to use for future multicenter clinical trials in USH2A-related retinal degeneration Identify well-defined subpopulations for future clinical trials of investigative treatments for USH2A-related retinal degeneration Study Objectives The primary objectives of the natural history study are to: Characterize the natural history of retinal degeneration associated with biallelic pathogenic mutations in the USH2A gene over 4 years, as measured using functional outcome measures (static perimetry, microperimetry, full-field stimulus threshold (FST), electroretinography (ERG), and visual acuity) Characterize the natural history of retinal degeneration associated with biallelic pathogenic mutations in the USH2A gene over 4 years, as measured using structural outcome measures (spectral-domain optical coherence tomography (SD-OCT) ellipsoid zone (EZ) area) Investigate structure-function relationships for insights into the mechanisms of retinal degeneration by relating changes in SD-OCT EZ area to visual field progression in individuals with biallelic pathogenic mutations in the USH2A gene Assess for possible genotype, phenotype, and environmental risk factors with progression of the outcome measures at 4 years in individuals with biallelic pathogenic mutations in the USH2A gene Some additional secondary objectives of this study include: Characterize baseline cross-sectional retinal degeneration associated with biallelic pathogenic mutations in the USH2A gene (as measured using the main outcome measures) Investigate comorbidities associated with disease (baseline cross-sectional) and disease progression (longitudinal natural history study) in individuals with biallelic pathogenic mutations in the USH2A gene Explore patient reported outcome (PRO) measures associated with disease (baseline cross-sectional) and disease progression (longitudinal natural history study) in individuals with biallelic pathogenic mutations in the USH2A gene Evaluate variability and symmetry of left and right eye kinetic perimetry and SD-OCT outcomes at baseline and at 4 years in individuals with biallelic pathogenic mutations in the USH2A gene

Official Title
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Rate of Progression in USH2A-related Retinal Degeneration

Conditions
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Usher Syndrome, Type 2A, Retinitis Pigmentosa 39

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to complete the informed consent process Ability to return for all study visits over 48 months if in the natural history study Age ≥ 8 years At least 2 pathogenic or likely pathogenic mutations in USH2A gene from a clinically certified lab report Ocular Inclusion Criteria Both eyes must meet all of the following: Clinical diagnosis of a rod-cone degeneration Clear ocular media and adequate pupil dilation to permit good quality photographic imaging Ability to perform kinetic and static perimetry reliably Exclusion Criteria: Mutations in genes that cause autosomal dominant RP, X-linked RP, or presence of biallelic mutations in autosomal recessive RP/retinal dystrophy genes other than USH2A Expected to enter experimental treatment trial at any time during this study History of more than 1 year of cumulative treatment, at any time, with an agent associated with pigmentary retinopathy (including hydroxychloroquine, chloroquine, thioridazine, and deferoxamine) Ocular Exclusion Criteria If either eye has any of the following, the patient is not eligible: Current vitreous hemorrhage Current or any history of rhegmatogenous retinal detachment Current or any history of (e.g., prior to cataract or refractive surgery) spherical equivalent of the refractive error worse than -8 Diopters of myopia History of intraocular surgery (e.g., cataract surgery, vitrectomy, penetrating keratoplasty, or LASIK) within the last 3 months Current or any history of confirmed diagnosis of glaucoma (e.g., based on glaucoma visual field, nerve changes, or glaucoma filtering surgery) Current or any history of retinal vascular occlusion or proliferative diabetic retinopathy Expected to have cataract removal surgery during the study History or current evidence of ocular disease that, in the opinion of the investigator, may confound assessment of visual function History of treatment for retinitis pigmentosa that could affect the progression of retinal degeneration (including participation in a clinical trial within the last year or a retained drug delivery device)

Ages Eligible for Study
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Minimum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Primary Cohort<br>Participants with baseline visual acuity ETDRS letter score of 54 or more [approximate Snellen equivalent 20/80 or better] and stable fixation and clinically determined [on Octopus 900 Pro] kinetic visual field III4e area 10° or more in the study eye (primary cohort) will be enrolled into the longitudinal natural history study | |
| Secondary Cohort<br>Participants with baseline visual acuity ETDRS letter score of 53 or less [approximate Snellen equivalent 20/100 or worse] or unstable fixation or clinically determined [on Octopus 900 Pro] kinetic visual field III4e area less than 10°in the study eye (secondary cohort) will be enrolled in the cross-sectional baseline study | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize Change using Visual Field Sensitivity | Measured by static perimetry with topographic analysis (Hill of Vision) | Baseline and every year until study completion (4 years) | 
| Characterize Change using Visual Acuity | Best corrected E-ETDRS visual acuity | Baseline and every year until study completion (4 years) | 
| Characterize Change using Mean Retinal Sensitivity | Measured by fundus-guided microperimetry | Baseline and every year until study completion (4 years) | 
| Characterize Change in EZ area | Measured by SD-OCT | Baseline and every year until study completion (4 years) | 
| Characterize Change in Rod- and cone-mediated retinal function | Measured by FST | Baseline and every year until study completion (4 years) | 
| Characterize Change in Retinal function | Full-field ERG amplitudes and timing in response to rod- and cone-specific stimuli | Baseline and after four years |