Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A)

• ClinicalTrials.gov Identifier: NCT03146078
• Recruitment Status: Active, not recruiting
• First Posted: May 9, 2017
• Last Update Posted: May 25, 2023
• Sponsor: Jaeb Center for Health Research
• Collaborator: Foundation Fighting Blindness
• Information provided by (Responsible Party): Jaeb Center for Health Research

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
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:

1. Report the natural history of retinal degeneration in patients with biallelic mutations in the USH2A gene
2. Identify sensitive structural and functional outcome measures to use for future multicenter clinical trials in USH2A-related retinal degeneration
3. 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:

1. 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)
2. 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)
3. 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
4. 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:

1. Characterize baseline cross-sectional retinal degeneration associated with biallelic pathogenic mutations in the USH2A gene (as measured using the main outcome measures)
2. 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
3. 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
4. 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: August 11, 2017
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: June 2023

Groups and Cohorts

Group/Cohort
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 :

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

Biospecimen Retention:   Samples With DNA

Saliva samples

Eligibility Criteria

• Ages Eligible for Study: 8 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Potential eligibility will be assessed during a routine examination by an investigator prior to obtaining informed consent, as part of usual care

Criteria

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

United States, California

University of California, San Francisco

San Francisco, California, United States, 94143-0344

United States, Florida

Vitreo-Retinal Associates

Gainesville, Florida, United States, 32607

United States, Maryland

Wilmer Eye Institute at Johns Hopkins

Baltimore, Maryland, United States, 21287-9277

United States, Massachusetts

Massachusetts Eye and Ear

Boston, Massachusetts, United States, 02114

United States, Michigan

Kellogg Eye Center, University of Michigan

Ann Arbor, Michigan, United States, 48105

United States, North Carolina

Duke University Eye Center

Durham, North Carolina, United States, 27710

United States, Oregon

OHSU Casey Eye Institute

Portland, Oregon, United States, 97239

United States, Texas

Retina Foundation of the Southwest

Dallas, Texas, United States, 75231

Baylor Eye Physicians and Surgeons

Houston, Texas, United States, 77030

United States, Utah

Moran Eye Center, University of Utah

Salt Lake City, Utah, United States, 84107

United States, Wisconsin

Medical College of Wiconsin

Milwaukee, Wisconsin, United States, 53226

Canada

Hospital for Sick Children

Toronto, Canada

France

Centre hospitalier National d'Ophtalmologie des Quinze-Vingts

Paris, France, 75012

Germany

University of Tubingen

Tübingen, Germany

Netherlands

Radboud University

Nijmegen, Netherlands

United Kingdom

Moorfields Eye Hospital

London, United Kingdom

Sponsors and Collaborators

Jaeb Center for Health Research

Foundation Fighting Blindness

Investigators

• Study Chair: Jacque Duncan, MD; University of California, San Francisco

  Study Documents (Full-Text)

Documents provided by Jaeb Center for Health Research:

Study Protocol  [PDF] December 17, 2020

More Information

Additional Information:

public website 

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT03146078
• Other Study ID Numbers: RUSH2A
• First Posted: May 9, 2017
• Last Update Posted: May 25, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: A de-identified database is available upon request through the public domain on the FFB/Jaeb public website.
• Supporting Materials: Study Protocol; Informed Consent Form (ICF)
• Time Frame: After manuscript is published
• Access Criteria: Users accessing data must enter an email address

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Usher Syndromes; Retinitis; Retinitis Pigmentosa; Retinal Degeneration; Retinal Diseases; Eye Diseases; Eye Diseases, Hereditary; Retinal Dystrophies; Genetic Diseases, Inborn; Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Hearing Loss, Sensorineural; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Blindness; Vision Disorders; Abnormalities, Multiple; Congenital Abnormalities