Application of Kidney Hierarchical Composite Endpoints in Trials of CKD Progression

Application of Kidney Hierarchical Composite Endpoints in Trials of CKD Progression

Report of a Scientific Workshop Sponsored by the National Kidney Foundation

Senior Authors: Leila Zelnick, PhD and Ian de Boer, MD, MS

Despite approved therapies for chronic kidney disease (CKD), many patients experience progressive loss of kidney function, and there remains an unmet need for additional therapies. Hierarchical composite end points (HCEs) have emerged as candidate tools to improve the efficiency of randomized controlled trials (RCTs) by integrating multiple outcomes ranked by clinical importance. The National Kidney Foundation convened a Scientific Workshop involving a broad group of stakeholders to consider the application of HCEs to CKD. A proposed kidney HCE includes all-cause mortality, kidney failure with or without initiation of kidney replacement therapy, time to sustained declines in glomerular filtration rate (GFR), and GFR slope. Workshop participants concluded that a kidney HCE is a promising candidate for establishing efficacy of therapies in settings in which we typically conduct large trials that use kidney composite end points to establish efficacy. It was acknowledged that no end point is universally applicable in all situations. The ideal population for an HCE would be one at risk for progression but unlikely to yield sufficient clinical events during the trial period to permit application of the traditional time-to-event end point. Additional investigations are required to address key challenges in application of HCE to CKD, such as how to best assess differences in individual GFR slope.

For chronic kidney disease (CKD), several new therapies significantly reduce the risks of progression to kidney failure, cardiovascular events, and mortality while maintaining favorable benefit-risk profiles.1, 2, 3, 4 Despite these advancements, significant unmet needs remain, with many patients continuing to face a high risk of progression to kidney failure.

Clinical trial end points that establish benefits of new therapies or treatment strategies in a more efficient manner could help address these needs. Hierarchical composite end points (HCEs) have been applied in various medical domains to establish drug efficacy in randomized controlled trials (RCTs).5, 6, 7, 8, 9, 10, 11, 12 In contrast to composite end points typically examined in a time-to-first event framework, HCEs integrate multiple outcomes by ranking them according to their clinical relevance. While conceptually appealing, there are several methodological and interpretive challenges to the use of HCEs that pose barriers to adoption and widespread application.