To investigate the prognostic value of demographic, functional, genetic, and imaging parameters on retinal pigment epithelium atrophy progression secondary to ABCA4-related retinopathy. Patients with retinal pigment epithelium atrophy secondary to ABCA4-related retinopathy were examined longitudinally with fundus autofluorescence imaging. Lesion area, perimeter, circularity, caliper diameters, and focality of areas with definitely decreased autofluorescence were determined. A model was used to predict the lesion enlargement rate based on baseline variables. Sample size calculations were performed to model the power in a simulated interventional study. Sixty-eight eyes of 37 patients (age range, 14-78 years) with a follow-up time of 10 to 100 months were included. The mean annual progression of retinal pigment epithelium atrophy was 0.89 mm. The number of atrophic areas, the retina-wide functional impairment, and the age-of-onset category constituted significant predictors for future retinal pigment epithelium atrophy growth, explaining 25.7% of the variability. By extension of a simulated study length and/or specific patient preselection based on these baseline characteristics, the required sample size could significantly be reduced. Trial design based on specific shape-descriptive factors and patients' baseline characteristics and the adaption of the trial duration may provide potential benefits in required cohort size and absolute number of visits.