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Robyn H Guymer, Myra McGuinness, Lauren A Hodgson, Chi D Luu, Zhichao Wu; Nascent Geographic Atrophy as a Surrogate Endpoint in Age-Related Macular Degeneration.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2214. doi: https://doi.org/.
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There is an urgent need to identify robust surrogate endpoints to improve the feasibility of early intervention trials in age-related macular degeneration (AMD). We evaluated the potential for optical coherence tomography (OCT) imaging defined nascent geographic atrophy (nGA) to serve as a surrogate endpoint for the clinical endpoint of color fundus photograph defined geographic atrophy (GA).
The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study was a 36-month, randomized-controlled trial of a sub-threshold laser treatment (SNL) in participants with bilateral large drusen without any multimodal imaging (MMI) signs of atrophy. OCT images were graded for nGA and GA and we evaluated the predictive ability and validity of nGA to serve as a surrogate clinical endpoint for GA. We evaluated 4 criteria required for a surrogate endpoint; (1) a significant effect of treatment on the surrogate (nGA), (2) a significant effect of treatment on the clinical endpoint (GA), (3) a significant correlation between the surrogate and clinical endpoint and (4) the effect of treatment on the clinical endpoint becomes non-significant after accounting for the surrogate endpoint.
292 participants were randomized to receive SNL (n = 147) or sham treatment (n = 145) in the LEAD study. 37 study eyes and 40 non-study eyes developed nGA and 12 study eyes and 11 non-study eyes developed GA over the 36m review. In the study eye, treatment with the SNL significantly reduced the rate of progression to nGA (adjusted HR = 0.43; 95% CI = 0.20 to 0.91; P= 0.028) and to GA (adjusted HR = 0.16; 95% CI = 0.04 to 0.72; P= 0.017), and the presence of nGA was significantly associated with an increased rate of progression to GA (adjusted HR = 55.16; 95% CI = 8.37 to 363.60; P< 0.001). After accounting for nGA in a multivariable model, SNL treatment no longer showed a statistically significant effect on the rate of progression to GA (HR = 0.15; 95% CI = 0.02 to 1.11; P= 0.063), indicating that the effect of treatment on progression to GA can be captured by the development of nGA.
These findings support the utility of nGA as a surrogate endpoint for GA in clinical trials for the early stages of AMD, and its use can substantially improve the feasibility of future intervention trials.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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