Validity and Utility of a Hierarchical Composite Endpoint for Clinical Trials of Kidney Disease Progression: A Review.

Clinical trials in nephrology often utilize composite endpoints comprising clinical events such as onset of end-stage kidney disease (ESKD) and initiation of kidney function replacement therapy (KFRT), along with a sustained large (e.g., ≥50%) decrease in glomerular filtration rate (GFR). Such events typically occur late in the disease course, resulting in large trials in which most participants do not contribute clinical events. Additionally, components of the endpoint are considered of equal importance; however, their clinical significance varies. For example, KFRT initiation is likely to be clinically more meaningful than GFR decline of ≥50%. In contrast, hierarchical composite endpoints (HCE) combine multiple outcomes and prioritize each patient's most clinically relevant outcome for inclusion in analysis. In this review, we consider the use of HCEs in clinical trials of CKD progression, emphasizing the potential to combine dichotomous clinical events such as those typically utilized in CKD progression trials, with the continuous variable of GFR over time, while ranking all components according to clinical significance. We consider maraca plots to visualize overall treatment effects and the contributions of individual components, discuss the application of win odds in kidney HCE trials, and review general design considerations for clinical trials for CKD progression with kidney HCE as an efficacy endpoint.