Exploring Trial Endpoints in Geographic Atrophy Based on Localized Functional Changes in Microperimetry and AI-Quantified OCT Biomarkers

Purpose: The introduction of novel therapeutics for geographic atrophy (GA) highlights the need to define functional correlates of high-risk optical coherence tomography (OCT) biomarkers, in particular retinal-pigment-epithelium (RPE) loss and ellipsoid zone (EZ) loss. We conducted a pointwise structure/function correlation between OCT-based markers and retinal sensitivity (RS) in microperimetry (MP) in GA. Methods: Patients from the phase III OAKS clinical trial (NCT03525613) examined by OCT (Heidelberg Spectralis) and Macular Integrity Assessment (MAIA, iCare, and Centervue) MP in a 68-point grid were analyzed. Deep-learning-(DL)-based algorithms quantified RPE, EZ loss, and EZ thickness from OCT. Co-registration between MP and OCT was established between each MP stimulus and OCT B-scan location. A multivariable mixed effect model was implemented to identify RS for each OCT biomarker, accounting for eccentricity. Results: Six hundred seventy-eight study and fellow eyes of 406 patients with 41,925 MP points were included. Mean RS was 17 ± 7 decibel (dB), 9 ± 7 dB, and 2 ± 6 dB in intact retina, EZ, and RPE loss, respectively. Increased EZ thickness improved RS by 0.2 dB/µm (95% confidence interval [CI] = 0.2 to 0.2, P < 0.001). In areas of EZ loss, RS was significantly reduced compared to intact retina (-8 dB, 95% CI = -9 to -8]), whereas RPE loss decreased RS by -14 dB (95% CI = -15 to -14), accounting for eccentricity (all P < 0.001). Conclusions: A significant association between RS in MP and EZ and RPE loss on OCT was established using DL. A reliable quantitative structure/function association provides the base for developing functional endpoints in clinical care and approval of novel therapeutics for GA.