Visual Acuity, Full-field Stimulus Thresholds, and Electroretinography for 4 Years in The Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) Study

Abstract Purpose To describe progression of best-corrected visual acuity (BCVA), full-field stimulus thresholds (FST), and electroretinography (ERG) over 4 years in the RUSH2A study and to assess their suitability as clinical trial endpoints. Design Prospective natural history study. Participants Participants (n=105) with biallelic disease-causing sequence variants in USH2A and BCVA letter score of ≥54 were included. Methods BCVA, FST, fundus-guided microperimetry, static perimetry and spectral domain optical coherence tomography were performed annually and ERG at baseline and 4 years only. Mixed effects models were used to estimate annual rates of change with 95% confidence intervals (CI). Associations of change from baseline to 4 years between BCVA, FST, ERG and other metrics were assessed with Spearman correlation coefficients (rs). Main Outcome Measures BCVA, FST, ERG. Results The annual rate of decline in BCVA was 0.83 (95% CI: 0.65, 1.02) letters/year. For FST, the change was 0.09 (0.07, 0.11) log cd.s/m²/year for white threshold, 0.10 (0.08, 0.12) log cd.s/m²/year for blue threshold and 0.05 (0.04, 0.06) log cd.s/m²/year for red threshold. Changes were 22.6 (17.4, 28.2) %/year for white threshold, 26.0 (20.3, 32.1) %/year for blue threshold, and 12.3 (8.7, 16.0) %/year for red threshold. The high percentage of eyes with undetectable ERGs at baseline limited assessment of change. Conclusion BCVA was not a sensitive measure of progression over 4 years. FST was a more sensitive measure; however, additional information on the clinical relevance of changes in FST is needed before this test can be adopted as an endpoint for clinical trials.