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Stanley Lambertus, Moritz Lindner, Nathalie Bax, Matthias Marten Mauschitz, Matthias Schmid, Steffen Schmitz-Valckenberg, Bernhard HF Weber, Frank G Holz, Gert Jan van der Wilt, Monika Fleckenstein, Carel C B Hoyng; Progression of late-onset Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2693.
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© 2017 Association for Research in Vision and Ophthalmology.
Accurate biomarkers are crucial to determine potential effects of emerging therapeutic trials for Stargardt disease. The natural course of late-onset Stargardt includes a typical phenotype of retinal pigment epithelium (RPE) atrophy that often spares the fovea, and is surrounded by yellow-white flecks. To this end, areas of RPE atrophy could serve as a sensitive monitor for this disease. We therefore performed a retrospective cohort study to show the accuracy of this outcome measure and calculated sample sizes for a simulated trial.
We analyzed retinal features, visual acuity, and RPE atrophy progression using fundus autofluorescence and near-infrared reflectance imaging in 47 late-onset Stargardt patients (disease onset ≥45 years). Endpoints of visual acuity were observed using Turnbull’s estimators. Progression of RPE atrophy was analyzed by a two-level random effects linear mixed model. Sample size calculations were performed for a 2-year study duration and a dropout rate of 15%.
Survival analysis yielded a median interval between disease onset and a decline in visual acuity to 20/32, 20/80, and 20/200 of 2.74 (95% confidence interval, 0.54-4.41), 10.15 (95% CI, 6.13-11.38), and 11.38 (95% CI, 6.13-13.34) years, respectively. Over time, progression of RPE atrophy was observed (mean, 0.22±0.02 mm/year; p<0.001). If only patients with bilateral RPE atrophy are included in a 2-year study, 32 patients are needed to reach a power of 80% (95% CI, 79.3-82.4), assuming a fixed therapeutic effect size of 30%.
The development of RPE atrophy reflects the most prominent feature of disease progression in late-onset Stargardt. Expansion rates appeared to be fairly slow. Nonetheless, measurements of RPE atrophy resulted in a robust biomarker for disease progression.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Statistical power of a simulated 2-year interventional study in late-onset Stargardt as a function of sample size. Calculations were performed for an expected effect size of 50 % (red), 40 % (blue) and 30 % (green) reduction of atrophy progression. Shown are means (±95% confidence intervals) of 10000 simulations per data point.
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