Characterizing Rate of Progression in USHer Syndrome (CRUSH) Study
试验速览
- 阶段
- 不适用
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Vestibular function
研究概览
简要总结
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 16 Years 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Vestibular function
时间窗: 3 years
Measured by rotational chair test and calorisation.
Change in lifestyle adjustment due to Usher syndrome.
时间窗: Baseline, 2 years and study completion at 4 years
Measured by the Usher lifestyle survey: qualitative questionnaire, no quantitative measures
Change in visual fields area
时间窗: Baseline and study completion at 4 years
Measured by dynamic perimetry with topographical analysis.
Change in visual fields sensitivity
时间窗: Baseline and every year until study completion at 4 years
Measured by static perimetry with topographical analysis.
Function of saccule and utricule of the vestibular organ
时间窗: 3 years
Measured by vestibular evoked myogenic potential (VEMP) test.
Change in perceived visual functioning
时间窗: Baseline, 2 years and study completion at 4 years
Measured by the Visual Functioning Questionnaire-48 (VFQ-48): score of difficulty of performing 48 activities (items). The score is determined using two formulas: 'average item score = total item scores / (48 - U)' in which activities for which a person has non-visual reasons not to do it or in which they are not interested are scored with 'U', and '0.9\*LN((2.34-average item score) / (average item score+2.22))+0.05'. The higher the score, the lower the perceived visual functioning.
Change in perceived handicap due to hearing impairment
时间窗: Baseline, 2 years and study completion at 4 years
Measured by the Speech, Spatial and Qualities of Hearing Scale (SSQ): range 0-500, the higher the score, the fewer the perceived handicap due to hearing impairment.
Change in perceived health
时间窗: Baseline, 2 years and study completion at 4 years
Measured by the 12-item Short-Form Health Survey (SF-12): 12 items with ranges 3-6, transformation of scores: ((patient score - lowest possible score)/range of scores)) \* 100, the higher the score, the greater the perceived health.
Change in visual acuity
时间窗: Baseline and every year until study completion at 4 years
Measured by best-corrected visual acuity.
Change in perceived handicap due to dizziness
时间窗: Baseline, 2 years and study completion at 4 years
Measured by the Dizziness Handicap Inventory (DHI): range 0-100, the higher the score, the greater the perceived handicap due to dizziness.1. Pure tone audiometry and speech audiometry
Change in overall condition of the eye
时间窗: Baseline and every year until study completion at 4 years
Measured by full ophthalmic exam.
Change in ellipsoid zone (EZ) area
时间窗: Baseline and every year until study completion at 4 years
Measured by optical coherence tomography (SD-OCT).
Change in condition of the retina, macula, optic nerve and ocular vascularization
时间窗: Baseline and every year until study completion at 4 years
Measured by assessing stereo color fundus photography.
Change in hearing thresholds
时间窗: Baseline and study completion at 4 years
Measured by pure tone audiometry (PTA) and speech audiometry.
Change in the indication of depressive symptoms
时间窗: Baseline, 2 years and study completion at 4 years
Measured by the Patient Health Questionnaire Mood Scale (PHQ-9): range 0-27, the higher the score, the greater the indication of depressive symptoms.
Change in mean retinal sensitivity
时间窗: Baseline and every year until study completion at 4 years
Measured by fundus-guided microperimetry.
Change in retinal autofluorescence and Robson ring size
时间窗: Baseline and every year until study completion at 4 years
Measured by fundus autofluorescence imaging.
Change in rod- and cone-mediated retinal function
时间窗: Baseline and every year until study completion at 4 years
Measured by full-field stimulus testing (FST).
Change in auditory speech recognition abilities in noise
时间窗: Baseline and study completion at 4 years
Measured by the digits in noise test (DIN).
Change in retinal function
时间窗: Baseline and study completion at 4 years
Measured by full field electroretinogram amplitudes and timing in response to rod- and cone-specific stimuli.
Change in integrity of the outer hair cells
时间窗: Baseline and study completion at 4 years
Measured by otoacoustic emissions (OAEs).
Change in integrity of the inner hair cells, the synapse and the first stage on the auditory nerve
时间窗: Baseline and study completion at 4 years
Measured by electrocochleography (ECochG).
Function of individual vestibular semicircular canals
时间窗: 3 years
Measured by video head impulse test (HIT) test.
次要结局
未报告次要终点