One-in-four ophthalmology trials are single-armed, which poses challenges to their interpretation. We demonstrate how real-world cohorts used as external/synthetic control arms can contextualise such trials. We herein emulated a target trial on the intention-to-treat efficacy of off-label bevacizumab (q6w) pro re nata relative to fixed-interval aflibercept (q8w) for improving week-54 visual acuity of eyes affected by neovascular age-related macular degeneration. The bevacizumab arm (n 65) was taken from the ABC randomised controlled trial. A total of 4,471 aflibercept-treated eyes aligning with the ABC trial eligibility were identified from Electronic Health Records and synthetic control arms were created by emulating randomisation conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of ≥ 15, ≥ 10, and ≤ -15 Early Treatment Diabetic Retinopathy (ETDRS) letters at week 54; and a time-to-event analysis on achieving a change in visual acuity of ≥ 15, ≥ 10, and ≤ -15 ETDRS letters by week 54. The findings suggest off-label bevacizumab to be neither non-inferior nor superior to licensed aflibercept. Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed trials when analysed in accord to the target trial framework.
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