Ophthalmology. Retina · 2026
Gildeuretinol Acetate versus Placebo for Geographic Atrophy Secondary to Age-Related Macular Degeneration: The Study of ALK-001 in Geographic Atrophy Randomized Clinical Trial.
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Boyer David S, Saad Leonide, Washington Ilyas, Melamud Alexander, Graham Kenneth B, O'Malley Adrian E, DeBartolomeo Gabrielle M, Jiang Honghua, Harris Lindsey D, Kay Christine N, Ferrone Philip J, Khan Seemi, SAGA Study Team
Аннотация
OBJECTIVE: To assess the effects of gildeuretinol acetate (C20D3-vitamin A) in geographic atrophy (GA).
DESIGN: A 24-month, double-masked, multicenter, randomized, placebo-controlled trial.
PARTICIPANTS: Participants aged ≥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-25, and Functional Reading Independence (FRI) Index.
RESULTS: Among 198 randomized participants (mean [standard deviation {SD}] age, 78.4 [7.0] years; 68.7% women), 69.2% completed the 24-month study. In the gildeuretinol and placebo groups, baseline mean (SD) total GA lesion area in mm2 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 mm2/yr with gildeuretinol and 1.87 mm2/yr with placebo (least squares [LSs] mean difference: -0.25 mm2/yr; 95% confidence interval [CI]: -0.53 to 0.03; P = 0.075), a 13.4% relative reduction for gildeuretinol versus placebo. The LS mean (standard error) GA growth rates from 6 to 24 months were 1.90 (0.12) mm2/yr (placebo) and 1.61 (0.08) mm2/yr (gildeuretinol), a 15.3% relative reduction (-0.29 mm2/yr; 95% CI: -0.576 to -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). Best-corrected visual acuity declined 6.9 letters with gildeuretinol and 10.2 letters with placebo (difference: 3.3 letters; 95% CI: -0.63 to 7.23; P = 0.099). Visual Function Questionnaire-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 and patient-reported analyses favored gildeuretinol with nominal P values; these exploratory findings support further evaluation in adequately powered trials.
TRIAL REGISTRATION: NCT03845582.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
DESIGN: A 24-month, double-masked, multicenter, randomized, placebo-controlled trial.
PARTICIPANTS: Participants aged ≥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-25, and Functional Reading Independence (FRI) Index.
RESULTS: Among 198 randomized participants (mean [standard deviation {SD}] age, 78.4 [7.0] years; 68.7% women), 69.2% completed the 24-month study. In the gildeuretinol and placebo groups, baseline mean (SD) total GA lesion area in mm2 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 mm2/yr with gildeuretinol and 1.87 mm2/yr with placebo (least squares [LSs] mean difference: -0.25 mm2/yr; 95% confidence interval [CI]: -0.53 to 0.03; P = 0.075), a 13.4% relative reduction for gildeuretinol versus placebo. The LS mean (standard error) GA growth rates from 6 to 24 months were 1.90 (0.12) mm2/yr (placebo) and 1.61 (0.08) mm2/yr (gildeuretinol), a 15.3% relative reduction (-0.29 mm2/yr; 95% CI: -0.576 to -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). Best-corrected visual acuity declined 6.9 letters with gildeuretinol and 10.2 letters with placebo (difference: 3.3 letters; 95% CI: -0.63 to 7.23; P = 0.099). Visual Function Questionnaire-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 and patient-reported analyses favored gildeuretinol with nominal P values; these exploratory findings support further evaluation in adequately powered trials.
TRIAL REGISTRATION: NCT03845582.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.