Clinical trial NCT04820244: Characterizing Rate of Progression in USHer Syndrome (CRUSH) Study
Official title: Characterizing Rate of Progression in USHer Syndrome (CRUSH) Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Usher Syndrome, Type 2A
Retinitis Pigmentosa
USH2A
Keywords: USH2A
Non-Syndromal USH2 related Retinitis Pigmentosa
Natural history study
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Stichting Ushersyndroom
First posted: 2021-03-29
Enrollment: 36
Sex: ALL
Minimum age (years): 16
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The Dutch Usher syndrome population consists of an estimated 850 patients. Additionally we would like to include patients with USH2A associated nsRP. Subjects will be recruited from this population. In the past years it has been clear that patients are highly motivated to participate in research for their disease. We aim to include 50 subjects and given our past experiences, we consider this a feasible number of participants. The study population consists of both males and females between 16 and 55 years of age with a confirmed genetic diagnosis of USH2A associated RP either syndromic or nonsyndromic.

Brief summary: Mutations in USH2A give rise to two phenotypes: Usher syndrome type 2a (USH2A) and nonsyndromic RP (USH2A associated nsRP). Usher syndrome is the most common form of congenital deafblindness. Patients with Usher syndrome are hearing impaired or profoundly deaf from birth and this can be rehabilitated with hearing aids or a cochlear implant. Furthermore, these patients develop retinitis pigmentosa (RP), a slowly progressive type of retinal degeneration that usually starts in the first or second decade of life. In both USH2A and nsRP patients the disease leads to severe visual impairment and eventually blindness around the 50th-70th year of life. There are no treatment options for the retinal degeneration. We do not know if they also suffer from balance complaints.

Currently, genetic therapy for Usher syndrome type 2 and USH2A associated nsRP is in development. But to measure the effect of a (genetic) therapy, it is crucial to know the detailed natural course of the visual and hearing deterioration over time. Several genetic therapy studies for other disorders are currently delayed, because the natural history of the disease has not been studied in detail previously.

The main objective is to map the natural course of the visual and hearing deterioration in Usher Syndrome 2 and USH2A associated nsRP for upcoming genetic therapy studies. Secondary objectives are: 1) To determine the necessary type of (combined) examinations, the sample size and length of studies (in years) essential to evaluate future genetic therapy in Usher syndrome. 2) To improve counselling of patients with Usher syndrome type 2 and USH2A associated nsRP with detailed information on the prognosis. 3) To identify additional etiological factors that explain variability in hearing impairment by adding questionnaires and psychophysical audiometric tests; and to assess the vestibular phenotype in Usher syndrome type 2 and USH2A associated nsRP patients.

This is a longitudinal, prospective natural history study. The study population consists of healthy human volunteers, 16 - 55 yr old with a confirmed genetic diagnosis of Usher Syndrome type 2 or and USH2A associated nsRP.

The main study endpoint is the natural course of the visual and hearing deterioration in Usher Syndrome type 2 and USH2A associated nsRP, over a time span of 4 years.

There are no risks associated with participation.


Eligibility criteria: Inclusion Criteria:

* Clinically diagnosed with rod-cone degeneration and at least two; pathogenic or likely pathogenic mutations in one of the Usher type 2 genes;
* Willing and able to complete the informed consent process;
* Ability to return for all study visits over 48 months;
* Age ≥ 16 years.

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;
* Baseline visual acuity ETDRS letter score of 54 or more \[approximate Snellen equivalent 20/80 or better\];
* Stable fixation;
* Clinically determined \[on Octopus 900 Pro\] kinetic visual field III4e area 7,5°, or more in the study eye.

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 Usher genes;
* 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).

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).

If either ear has any of the following, the patient is not eligible:

* The audiometric PTA(1-2-4kHz) for the best hearing ear should not exceed 75dB HL;
* Patients with bilateral cochlear implants cannot participate in the study;
* A planned, second, cochlear implantation during the study.

Primary outcomes:
measure: Change in perceived visual functioning
timeFrame: Baseline, 2 years and study completion at 4 years
measure: Change in perceived handicap due to hearing impairment
timeFrame: Baseline, 2 years and study completion at 4 years
measure: Change in perceived handicap due to dizziness
timeFrame: Baseline, 2 years and study completion at 4 years
measure: Change in lifestyle adjustment due to Usher syndrome.
timeFrame: Baseline, 2 years and study completion at 4 years
measure: Change in perceived health
timeFrame: Baseline, 2 years and study completion at 4 years
measure: Change in the indication of depressive symptoms
timeFrame: Baseline, 2 years and study completion at 4 years
measure: Change in overall condition of the eye
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in visual acuity
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in visual fields area
timeFrame: Baseline and study completion at 4 years
measure: Change in visual fields sensitivity
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in mean retinal sensitivity
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in ellipsoid zone (EZ) area
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in retinal autofluorescence and Robson ring size
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in condition of the retina, macula, optic nerve and ocular vascularization
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in rod- and cone-mediated retinal function
timeFrame: Baseline and every year until study completion at 4 years
measure: Change in retinal function
timeFrame: Baseline and study completion at 4 years
measure: Change in hearing thresholds
timeFrame: Baseline and study completion at 4 years
measure: Change in auditory speech recognition abilities in noise
timeFrame: Baseline and study completion at 4 years
measure: Change in integrity of the outer hair cells
timeFrame: Baseline and study completion at 4 years
measure: Change in integrity of the inner hair cells, the synapse and the first stage on the auditory nerve
timeFrame: Baseline and study completion at 4 years
measure: Vestibular function
timeFrame: 3 years
measure: Function of individual vestibular semicircular canals
timeFrame: 3 years
measure: Function of saccule and utricule of the vestibular organ
timeFrame: 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud universitair medisch centrum
state: Gelderland
Study officials:
affiliation: Radboud Universitair Medisch Centrum
name: Ronald Pennings, Dr
role: STUDY_DIRECTOR
affiliation: Radboud Universitair Medisch Centrum
name: Erwin van Wyk, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud Universitair Medisch Centrum
name: Carel Hoyng, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud Universitair Medisch Centrum
name: Ronald Pennings, Dr
role: PRINCIPAL_INVESTIGATOR
References: