Kidney Compass: Hierarchical Composite Endpoints in Nephrology, with Dustin Little, MD, and Niels Jongs, PhD
In this episode of Kidney Compass, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by Dustin Little, MD, and Niels Jongs, PhD, to explore the use of hierarchical composite endpoints (HCEs) in nephrology clinical trials. The discussion highlights the limitations of traditional composite endpoints and the potential advantages of HCEs in improving statistical power, trial efficiency, and the ability to capture meaningful treatment effects. The episode begins with an overview of traditional composite endpoints, which combine multiple clinical outcomes—such as death, dialysis, and significant eGFR decline—but weigh all first events equally, regardless of clinical severity. Little explains how this approach disproportionately relies on rapid disease progressors, leaving much of the trial population underrepresented in efficacy assessments. HCEs address this issue by ranking outcomes hierarchically based on clinical importance, ensuring that all patient data contribute to the analysis. Jongs describes the statistical framework behind HCEs, explaining how win odds—a generalized pairwise comparison method—allows for a more comprehensive evaluation of treatment effects compared to hazard ratios. He emphasizes that win odds maintain strong alignment with hazard ratios while offering enhanced interpretability and increased statistical power. Post hoc analyses of major nephrology trials, including DAPA-CKD, have demonstrated consistency between win odds and traditional hazard ratio-based findings, reinforcing the validity of this approach. The panel explores the practical implications of HCEs, particularly for rare kidney diseases, where large-scale outcomes trials are often unfeasible. By incorporating measures like eGFR slope and expanding the range of contributing patient data, HCEs can reduce required sample sizes and shorten trial durations while maintaining statistical robustness. Wadhwani raises the potential for integrating patient-reported outcomes into HCEs, particularly in diseases like lupus nephritis and polycystic kidney disease, where symptom burden and quality of life are critical considerations. The episode concludes with a discussion on regulatory acceptance, the need for further refinement of HCE methodologies, and the potential of this approach to accelerate therapeutic advancements in nephrology. The panel underscores that while challenges remain, HCEs represent a promising innovation that could reshape kidney disease clinical trial design and improve patient outcomes. Chapters 00:00:00 - Start 00:01:03 - Little & Jongs Introduction 00:02:30 - Traditional Endpoints vs HCEs 00:09:22 - Benefits of HCEs 00:17:58 - Examples of Applying HCEs in Nephrology 00:21:26- Increased Power with HCEs 00:23:59 - Addressing Skepticism, Potential Limitations 00:33:04 - Incorporating PROs in HCEs 00:40:01 - Subgroup Analyses with HCEs 00:48:28 - Conclusions and Outro Check out the video version of the podcast, exclusively on HCPLive: https://www.hcplive.com/view/kidney-compass-hierarchical-composite-endpoints-nephrology-dustin-little-md-niels-jongs-phd