Development and Validation of a New Hierarchical Composite Endpoint for Clinical Trials of Kidney Disease Progression

Abstract Background The established composite kidney endpoint in clinical trials combines clinical events with sustained large changes in glomerular filtration rate (GFR). However, the statistical method does not weigh the relative clinical importance of the endpoint components. A hierarchical composite endpoint (HCE) accounts for the clinical importance of the endpoint components and enables combining dichotomous outcomes with continuous measures. Methods We developed and validated a new HCE for kidney disease progression, performing post hoc analyses of seven major phase 3 placebo-controlled trials that assessed the effects of canagliflozin, dapagliflozin, finerenone, atrasentan, losartan, irbesartan and aliskiren in patients with chronic kidney disease. We calculated the win odds (WO) for treatment effects on a kidney HCE, defined as a hierarchical composite of all-cause mortality, kidney failure, sustained 57%, 50%, 40% GFR declines from baseline, and GFR slope. The WO describes the odds of a more favorable outcome for receiving the active compared with the control. We compared the WO with the hazard ratio (HR) of the primary kidney outcome of the original trials. Results In all trials, treatment effects calculated with the WO reflected a similar direction and magnitude of the treatment effect compared with the HR. Clinical trials incorporating the HCE would achieve increased statistical power compared with the established composite endpoint at equivalent sample sizes. Conclusions In seven major kidney clinical trials, the WO and HR provided similar direction of treatment effect estimates with smaller HRs associated with larger WOs. The prioritization of clinical outcomes and inclusion of broader composite endpoints makes the HCE an attractive alternative to the established kidney endpoint.