RUSH2A: Rate of Progression in USH2A-related Retinal Degeneration

Sponsor

Jaeb Center for Health Research (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03146078

Collaborator

Foundation Fighting Blindness (Other)

127

Enrollment

Locations

64.7

Anticipated Duration (Months)

7.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Usher Syndrome, Type 2A Retinitis Pigmentosa 39

Detailed Description

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

Study Design

Study Type:

Observational

Actual Enrollment :

127 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Rate of Progression in USH2A-related Retinal Degeneration

Actual Study Start Date :

Aug 11, 2017

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Primary Cohort 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 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

Outcome Measures

Primary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143-0344
2	Vitreo-Retinal Associates	Gainesville	Florida	United States	32607
3	Wilmer Eye Institute at Johns Hopkins	Baltimore	Maryland	United States	21287-9277
4	Massachusetts Eye and Ear	Boston	Massachusetts	United States	02114
5	Kellogg Eye Center, University of Michigan	Ann Arbor	Michigan	United States	48105
6	Duke University Eye Center	Durham	North Carolina	United States	27710
7	OHSU Casey Eye Institute	Portland	Oregon	United States	97239
8	Retina Foundation of the Southwest	Dallas	Texas	United States	75231
9	Baylor Eye Physicians and Surgeons	Houston	Texas	United States	77030
10	Moran Eye Center, University of Utah	Salt Lake City	Utah	United States	84107
11	Medical College of Wiconsin	Milwaukee	Wisconsin	United States	53226
12	Hospital for Sick Children	Toronto		Canada
13	Centre hospitalier National d'Ophtalmologie des Quinze-Vingts	Paris		France	75012
14	University of Tubingen	Tübingen		Germany
15	Radboud University	Nijmegen		Netherlands
16	Moorfields Eye Hostpital	London		United Kingdom