Rate of Progression in EYS 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 EYS mutations in order to accelerate the development of outcome measures for clinical trials.

Detailed Description
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This natural history study of patients with EYS mutations will accelerate the development of outcome measures for clinical trials. Sensitive, reliable outcome measures of retinal degeneration will greatly facilitate development of treatments for retinitis pigmentosa due to EYS mutations. Together these approaches are expected to have an impact on understanding EYS-related retinal degeneration, developing experimental treatment protocols, and assessing their effectiveness. The goals and expected impact of this natural history study are to: Describe the natural history of retinal degeneration in patients with biallelic mutations in the EYS gene Identify sensitive structural and functional outcome measures to use for future multicenter clinical trials in EYS-related retinal degeneration Identify well-defined subpopulations for future clinical trials of investigative treatments for EYS-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 EYS gene over 4 years, as measured using functional, structural, and patient-reported outcome measures Investigate whether structural outcome measures can be validated as surrogates for functional outcomes in individuals with biallelic pathogenic mutations in the EYS gene Evaluate possible risk factors (genotype, phenotype, environmental, and comorbidities) for progression of the outcome measures at 4 years in individual with biallelic pathogenic mutations in the EYS gene Evaluate variability and symmetry of left and right eye outcomes over 4 years in individuals with biallelic pathogenic mutations in the EYS gene

Official Title
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Rate of Progression in EYS Related Retinal Degeneration (Pro-EYS)

Conditions
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Eye Diseases, Retinitis Pigmentosa

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to participate in the study and able to communicate consent during the consent process Ability to return for all study visits over 48 months Age ≥ 18 years Must meet one of the Genetic Screening Criteria, defined below: Screening Group A: At least 2 disease-causing variants in the EYS gene which are homozygous or heterozygous in trans, based on a report from a clinically-certified lab (or a report from a research lab that has been pre- approved by the Genetics Committee) Screening Group B: Only 1 disease-causing variant in the EYS gene, based on a report from a clinically-certified lab (or a report from a research lab which has been pre-approved by the Genetics Committee) Screening Group C: At least 2 disease-causing variants in the EYS gene which are unknown phase, based on a report from a clinically-certified lab (or a report from a research lab which has been pre-approved by the Genetics Committee) Note pertaining to all Screening Groups: if a participant has a variant(s) of unknown significance, he/she would still qualify as long as there is at least 1 disease-causing variant(s) on the EYS gene. Ocular Inclusion Criteria: Both eyes must meet all of the following: Clinical diagnosis of retinal dystrophy Clear ocular media and adequate pupil dilation to permit good quality photographic imaging Exclusion Criteria: Mutations in genes that cause autosomal dominant retinitis pigmentosa (ADRP), X-linked retinitis pigmentosa (RP), or presence of biallelic mutations in autosomal recessive RP/retinal dystrophy genes other than EYS 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 participant 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 glaucomatous VF changes or nerve changes, or history of glaucoma filtering surgery) Current or any history of retinal vascular occlusion or proliferative diabetic retinopathy History or current evidence of ocular disease that, in the opinion of the investigator, may confound assessment of visual function History or evidence of active treatment for retinitis pigmentosa that could affect the progression of retinal degeneration, including: Any use of ocular stem cell or gene therapy Any treatment with ocriplasmin Treatment with an ophthalmic oligonucleotide within the last 9 months (last treatment date is less than 9 months prior to Screening Visit date) Treatment with any other product within five times the expected half-life of the product (time from last treatment date to Screening Visit date is at least 5 times the half-life of the given product)

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Vision Cohort 1<br>Participants with the better eye Screening Visit visual acuity ETDRS letter score of 54 or more [approximate Snellen equivalent 20/80 or better] and visual field diameter 10 degrees or more in every meridian of the central field | |
| Vision Cohort 2<br>Participants with the better eye Screening Visit visual acuity ETDRS letter score of 19-53 [approximate Snellen equivalent 20/100 - 20/400] or (visual acuity ETDRS letter score of 54 or more [approximate Snellen equivalent 20/80 or better] and visual field diameter less than 10 degrees in any meridian of the central field) | |
| Vision Cohort 3<br>Participants with the better eye Screening Visit visual acuity ETDRS letter score of 18 or less [approximate Snellen equivalent 20/500 or worse] | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Visual Field Sensitivity | Measured by static perimetry with topographic analysis (Hill of Vision) and assessed by a central reading center for cohorts 1 and 2. | Baseline and every year until study completion (4 years) | 
| Change in Best Corrected Visual Acuity | Measured on the Electronic Visual Acuity (EVA) system or ETDRS charts. Berkeley Rudimentary Vision Test (BRVT) will be used for patients unable to see letters. | Screening visit and every year until study completion (4 years) with the exception of baseline for cohorts 1 and 2. Screening visit and 48 month follow-up for cohort 3. | 
| Change in Mean Retinal Sensitivity | Measured by fundus-guided microperimetry (MP) and assessed by a central reading center at selected sites with requisite equipment for cohorts 1 and 2. | Baseline and every year until study completion (4 years). | 
| Change in Full-field Retinal Sensitivity | Measured by full-field stimulus threshold (FST) testing to blue, white, and red stimuli | Baseline and every year until study completion (4 years) for cohort 1 and 2. Baseline and 4 year follow-up for cohort 3. | 
| Change in Best Corrected Low Luminance visual acuity | Measured by letter score | Screening visit and every year until study completion (4 years) with the exception of baseline for cohorts 1 and 2. Screening visit and 48 month follow-up for cohort 3. | 
| Change in Contrast Sensitivity Function | Measured by the CSV-1000E VectorVision chart for cohorts 1 and 2. | Baseline and every year until study completion (4 years). | 
| Change in Retinal Function | Measured by full-field electroretinogram (ERG) amplitudes and timing in response to rod- and cone-specific stimuli for cohorts 1 and 2. | Baseline and 4 year follow-up visit. | 
| Change in Ellipsoid zone (EZ) area | Measured by spectral domain optical coherence tomography (SD-OCT) and assessed by a central reading center | Baseline and every year until study completion (4 years) for cohorts 1 and 2. Baseline and 4 year follow-up for cohort 3. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Explore Qualitative categorization of Fundus Autofluorescence (FAF) pattern | Assessed by a central reading center | Baseline and every year until study completion (4 years) for cohorts 1 and 2. Baseline and 4 year follow-up for cohort 3. | 
| Explore quantitative measures of FAF | assessed by a central reading center | Baseline and every year until study completion (4 years) for cohorts 1 and 2. Baseline and 4 year follow-up for cohort 3. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EYS mutation, Retinitis Pigmentosa