Defining inclusion criteria and endpoints for clinical trials: a prospective cross‐sectional study in CRB1‐associated retinal dystrophies

PURPOSE: To investigate the retinal structure and function in patients with CRB1‐associated retinal dystrophies (RD) and to explore potential clinical endpoints. METHODS: In this prospective cross‐sectional study, 22 patients with genetically confirmed CRB1‐RD (aged 6–74 years), and who had a decimal best‐corrected visual acuity (BCVA) ≥ 0.05 at the last visit, were studied clinically with ETDRS BCVA, corneal topography, spectral‐domain optical coherence tomography (SD‐OCT), fundus autofluorescence, Goldmann visual field (VF), microperimetry, full‐field electroretinography (ERG) and full‐field stimulus testing (FST). Ten patients were from a genetic isolate (GI). RESULTS: Patients had retinitis pigmentosa (n = 19; GI and non‐GI), cone‐rod dystrophy (n = 2; GI) or macular dystrophy (n = 1; non‐GI). Median age at first symptom onset was 3 years (range 0.8–49). Median decimal BCVA in the better and worse‐seeing eye was 0.18 (range 0.05–0.83) and 0.08 (range light perception‐0.72), respectively. Spectral‐domain optical coherence tomography (SD‐OCT) showed cystoid maculopathy in 8 subjects; inner retinal thickening (n = 20), a well‐preserved (para)foveal outer retina (n = 7) or severe (para)foveal outer retinal atrophy (n = 14). All retinal layers were discernible in 13/21 patients (62%), with mild to moderate laminar disorganization in the others. Nanophthalmos was observed in 8 patients (36%). Full‐field stimulus testing (FST) provided a subjective outcome measure for retinal sensitivity in eyes with (nearly) extinguished ERG amplitudes. CONCLUSIONS: Despite the generally severe course of CRB1‐RDs, symptom onset and central visual function are variable, even at advanced ages. Phenotypes may vary within the same family. Imaging and functional studies in a prospective longitudinal setting should clarify which endpoints may be most appropriate in a clinical trial.