Safety and Effects of Gildeuretinol Acetate on Retinal Atrophic Lesions in Stargardt Disease: The TEASE-1 Randomized Clinical Trial.

IMPORTANCE: Stargardt disease (STGD) is the most common macular dystrophy, resulting in profound loss of vision. There is no approved treatment. OBJECTIVE: To evaluate the safety and effects of oral gildeuretinol acetate on the growth of retinal atrophic lesions in individuals with STGD. DESIGN, SETTING, AND PARTICIPANTS: TEASE-1 was a 2-year, multicenter, double-masked, placebo-controlled randomized clinical trial incorporating a crossover group and additional natural history (NH) cases selected prior to drafting the statistical analysis plan. The trial was conducted at 7 outpatient clinics in the US. Participants were aged 12 years or older, clinically diagnosed with STGD, with well-demarcated area(s) of significantly reduced autofluorescence, and supported with at least 1 ABCA4 disease-causing or likely disease-causing variant. The study was conducted between August 2015 and October 2019; data were analyzed between July and December 2020. INTERVENTIONS: Participants were randomized 1.5:1.5:1:1 to daily oral gildeuretinol acetate, 14 mg; gildeuretinol acetate, 24 mg; or placebo for 24 months; or placebo for 12 months followed by gildeuretinol for 12 months. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the growth rate of well-delineated and homogeneous areas of retinal atrophic lesions over 24 months of treatment on fundus autofluorescence imaging. Safety end points included treatment-emergent adverse events (AEs), serious AEs, and clinical laboratory assessments. RESULTS: A total of 50 participants were randomized, and 54 NH cases included. The mean (range) age of randomized participants was 44.3 (18-60) years. Overall, 58 of 104 participants or cases (55.8%) were female. The growth rate of retinal atrophic lesions was 0.182 mm/y with gildeuretinol and 0.232 mm/y in the untreated group (placebo and NH), representing a mean difference of -0.050 mm/y (95% CI, -0.072 to -0.027; P < .001) and a 21.6% relative reduction. In a prespecified sensitivity analysis restricted to randomized participants, the growth rate was 0.206 mm/y with gildeuretinol and 0.242 mm/y with placebo, representing a mean difference of -0.036 mm/y (95% CI, -0.062 to -0.009; P = .008) and a 14.9% relative reduction. The majority of AEs were mild or moderate and equally distributed between groups. No treatment-related serious AEs, clinically significant liver function abnormalities, or participant-reported night blindness or dark adaption difficulties occurred. CONCLUSIONS AND RELEVANCE: In the TEASE-1 randomized clinical trial, the primary efficacy end point of retinal atrophic lesion growth from 6 to 24 months was 0.05 mm/y greater on average in the untreated group (placebo and NH) than the gildeuretinol acetate group. Further research is needed to determine the clinical relevance of this end point. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02402660.