Methodological Appraisal of Phase 3 Clinical Trials in Geographic Atrophy

Abstract

Geographic atrophy (GA) secondary to age-related macular degeneration is a common cause of blindness worldwide. Given the recent approval of the first therapy for GA, pegcetacoplan, we critically appraise methodological aspects of the phase 3 clinical trials published so far in this disease in relation to their design, analysis and interpretation. We reviewed some of the key attributes of all phase 3 clinical trials in GA available in the main public registry of clinical trials as of 20 May 2023. The topics discussed included types of endpoints, eligibility criteria, p-value and effect size, study power and sample size, the intention to treat principle, missing data, consistency of results, efficacy–safety balance and application of results. Five phase 3 clinical trials have reported results, either partially or completely: GATHER1, DERBY/OAKS, CHROMA/SPECTRI, SEATTLE and GATE. Although there are many similarities between these trials in terms of endpoints or broad eligibility criteria, they differ in several aspects (metric of the primary endpoint, sample size, type of adverse events, etc.) that can influence the results, which are discussed. Readers should understand key methodological aspects of clinical trials to improve their interpretation. On the other hand, authors should adhere to clinical trial reporting guidelines to communicate what was done and how it was done.

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“…KITE, KESTREL and KINGFISHER, phase III studies found an intraocular inflammation in 2.2% to 4.7% of cases with brolucizumab (3 - 6 mg) versus 0.5% to 1.7% with aflibercept (2mg). These studies report a posterior involvement in the form of a retinal vasculitis in up to 1.6% [ 136 – 138 ]. According to the approved label, brolucizumab is contraindicated in eyes with active intraocular inflammation [ 139 ].…”

“…Recently, intravitreal injections of pegcetacoplan (15 mg) to slow progression of atrophy in AMD have shown an incidence of 3% intraocular inflammation, including anterior chamber cells, iritis, and anterior chamber flare, in the DERBY and OAKS phase 3 randomized controlled clinical trials [ 138 ].…”

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“…One of them-pegcetacoplan, additionally denoted as APL-2-is a PEGylated peptide inhibitor of C3 formulated by Apellis Pharmaceuticals that is administered intravitreally [6]. Moreover, on 17 February 2023, the Food and Drug Administration approved Syfovre ® (intravitreal pegcetacoplan, 15 mg, Apellis Pharmaceuticals, Waltham, MA, USA) based on a slower progression of atrophy in the DERBY and OAKS phase 3 randomized controlled clinical trials [7].…”

“…In a tutorial, Biarnés et al [7] critically appraise the methodological aspects of phase 3 clinical trials in GA in relation to their design, analysis, and interpretation. The authors reviewed some of the key methodological attributes of phase 3 clinical trials in GA available in the main public registry of clinical trials as of 20 May 2023 (GATHER1, DERBY/OAKS, CHROMA/SPECTRI, SEATTLE, and GATE) to improve their interpretation.…”

“…The authors reviewed some of the key methodological attributes of phase 3 clinical trials in GA available in the main public registry of clinical trials as of 20 May 2023 (GATHER1, DERBY/OAKS, CHROMA/SPECTRI, SEATTLE, and GATE) to improve their interpretation. The topics discussed included types of endpoints, eligibility criteria, p-value and effect size, study power and sample size, the intention to treat principle, missing data, the consistency of results, efficacy-safety balance, and the application of results [7]. While these clinical studies share many outcomes and general eligibility requirements, there are several aspects that might affect outcomes which are discussed in this work.…”