Gildeuretinol Acetate vs Placebo for Geographic Atrophy Secondary to Age-Related Macular Degeneration: The SAGA Randomized Clinical Trial

Objective To assess the effects of gildeuretinol acetate (C20D3-vitamin A) in geographic atrophy (GA). Design 24-month, double-masked, multicenter, randomized, placebo-controlled trial. Participants Participants ≥60 years with GA. Interventions Randomized 2:1 to oral gildeuretinol acetate 14 mg daily or placebo. Main Outcome Measures The primary endpoint was GA growth rate from baseline to 24 months. A prespecified sensitivity analysis accounted for a 6-month delay in onset of therapeutic effect. Secondary endpoints included change from baseline in low luminance visual acuity (LLVA), best-corrected visual acuity (BCVA), Visual Function Questionnaire (VFQ)-25, and Functional Reading Independence (FRI) Index. Results Among 198 randomized participants (mean [SD] age 78.4 [7.0] years; 68.7% female), 69.2% completed the 24-month study. In the gildeuretinol and placebo groups, baseline mean (SD) total GA lesion area in mm 2 was 7.72 (6.10) and 7.09 (4.16); BCVA letter scores were 56.2 (21.3) (Snellen equivalent: ∼20/80) and 58.8 (18.0) (∼20/70); and LLVA letter scores were 31.1 (19.0) (∼20/200) and 31.6 (17.8) (∼20/250), respectively. Mean GA growth rates were 1.62 mm 2 /year with gildeuretinol and 1.87 mm 2 /year with placebo (least squares [LS] mean difference: -0.25 mm 2 /year; 95% CI: -0.53, 0.03; P = 0.075), a 13.4% relative reduction for gildeuretinol vs placebo. The LS mean (SE) GA growth rates from 6 to 24 months were 1.90 (0.12) mm 2 /year (placebo) and 1.61 (0.08) mm 2 /year (gildeuretinol), a 15.3% relative reduction (-0.29 mm 2 /year; 95% CI: -0.576, -0.004; nominal P = 0.047). At 24 months, LLVA declined 3.9 and 8.3 ETDRS letters in the gildeuretinol and placebo groups, respectively (difference: 4.4 letters; 95% CI: 0.40, 8.41; nominal P = 0.031). BCVA declined 6.9 letters with gildeuretinol and 10.2 letters with placebo (difference: 3.3 letters; 95% CI: -0.63, 7.23; P = 0.099). VFQ-25 scores declined 4.81 fewer points with gildeuretinol than placebo (95% CI: 0.87, 8.76; nominal P = 0.017) and FRI scores declined 0.35 fewer points (95% CI: 0.11, 0.58; nominal P = 0.004). Conclusions The prespecified primary endpoint was not met. Prespecified piecewise and secondary functional/patient-reported analyses favored gildeuretinol with nominal P values; these exploratory findings support further evaluation in adequately powered trials.