Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

• Published in: PloS one 2017-03, Vol.12 (3), p.e0174020-e0174020
• Main Authors: Lambertus, Stanley, Bax, Nathalie M, Fakin, Ana, Groenewoud, Joannes M M, Klevering, B Jeroen, Moore, Anthony T, Michaelides, Michel, Webster, Andrew R, van der Wilt, Gert Jan, Hoyng, Carel B
• Format: Article
• Language: English
• Subjects: Acuity; Adolescent; Adult; Age; Age of Onset; Alzheimer's disease; Analysis; ATP-Binding Cassette Transporters - genetics; Biology and Life Sciences; Child; Child, Preschool; Clinical trials; Cognition & reasoning; Development and progression; Disease Progression; Dystrophy; Eccentricity; Endpoint Determination; Female; Fluorescein Angiography; Gene Expression; Gene therapy; Genetic aspects; Heterogeneity; Hospitals; Humans; Longitudinal Studies; Macular degeneration; Macular Degeneration - congenital; Macular Degeneration - diagnostic imaging; Macular Degeneration - genetics; Macular Degeneration - pathology; Male; Measurement; Medical imaging; Medicine and Health Sciences; Models, Genetic; Optimization; Patients; Photoreceptors; Physical Sciences; Physiological aspects; Polymorphism, Genetic; Prevalence studies (Epidemiology); Randomized Controlled Trials as Topic; Retina; Retina - diagnostic imaging; Retina - metabolism; Retina - pathology; Retinal degeneration; Simulation; Social Sciences; Structure-function relationships; Tomography; Tomography, Optical Coherence; Visual perception
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0174020

Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.