Brendon Neuen, MBBS, PhD

Welcome to Kidney Compass: Navigating Clinical Trials!

Kidney Compass: Applying Hierarchical Composite Endpoints in Kidney Disease Trials

In the final installment of our 4-part episode of 

, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by special guests Dustin Little, MD, and Niels Jongs, PhD, as they discuss the application of hierarchical composite endpoints (HCEs) in specific kidney disease subpopulations and rare disease trials.

Wadhwani highlights the need to tailor HCEs to disease-specific priorities, such as relapse reduction and immunosuppression minimization in lupus nephritis. The discussion then shifts to subgroup analyses in trials using HCEs. While traditional trials are powered for the overall population, subgroup analyses often lack statistical power. Jongs explains that increasing the efficiency of HCE-powered trials may allow for better-powered subgroup analyses, but achieving statistical certainty in smaller populations remains challenging.

The panel explores a real-world example of focal segmental glomerulosclerosis (FSGS) within the DAPA-CKD trial, where traditional analyses showed numerical benefits of dapagliflozin but lacked statistical significance due to wide confidence intervals. Jongs and Little discuss how applying HCEs and win odds in these cases could refine statistical assessments and potentially strengthen findings, offering greater confidence in treatment effects.

The episode concludes with reflections on the future of HCEs in nephrology research, emphasizing their potential to optimize trial efficiency, improve data interpretation, and advance therapies for rare and complex kidney diseases.

For ease of viewing, we've divided this episode into 4 sections and highlighted them below.

Kidney Compass: Hierarchical Composite Endpoints in Nephrology

Part 1: Introductions, HCEs in Nephrology

Part 2: HCEs in Nephrology Clinical Trials

Part 3: Addressing HCE Skepticism, Potential Limitations

Part 4: Applying HCEs in Kidney Disease Trials

 include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for 

 include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas, and Travere Therapeutics. Relevant disclosures for 

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In the final segments of this 4-part episode, the discussion focuses on the use of HCEs in different kidney disease trials.

Kidney Compass: Addressing Skepticism Around HCEs in Nephrology

In the third installment of our 4-part episode of 

, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by special guests Dustin Little, MD, and Niels Jongs, PhD, as they discuss the implications of hierarchical composite endpoints (HCEs) for kidney disease trials, regulatory considerations, and patient-centered outcomes.

Wadhwani raises concerns about fixed follow-up requirements in clinical trials, particularly when studies are terminated early due to efficacy, as seen in the FLOW and DAPA-CKD trials. Jongs explains how follow-up variability can be statistically managed by adjusting pairwise comparisons to a minimum follow-up period, ensuring fair assessment across different trial durations. While acknowledging theoretical concerns, he emphasizes that empirical analyses suggest this approach does not significantly alter trial conclusions.

The conversation then shifts to skepticism surrounding HCEs, including how event prioritization is determined and how win odds should be interpreted. Little highlights the flexibility of HCEs, noting that they incorporate only validated clinical and surrogate endpoints, making them suitable for regulatory approval.

A key advantage of HCEs, the panel agrees, is their ability to enhance statistical power, potentially reducing required sample sizes—an especially critical benefit for rare kidney diseases. Wadhwani and Little further explore the potential to integrate patient-reported outcomes, such as symptom burden and quality of life, into HCE frameworks. While acknowledging the complexity of arranging hierarchies that blend clinical and PRO measures, they highlight polycystic kidney disease as a prime example where factors like cyst pain and kidney volume could be incorporated alongside traditional renal endpoints.

The episode concludes with a discussion on future applications of HCEs in nephrology. The panel emphasizes that while methodological refinements are ongoing, HCEs offer a promising strategy to improve trial efficiency, capture a broader range of clinically meaningful outcomes, and ultimately accelerate therapeutic advancements for patients with kidney disease.

In part 3 of 4 from this episode, the discussion focuses on potential limitations to HCEs and addressing skepticism around their use in nephrology.

Kidney Compass: HCEs in Nephrology Clinical Trials

In the second installment of our 4-part episode of 

, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, dive into hierarchical composite endpoints (HCEs) and their potential to refine nephrology clinical trials with special guests Dustin Little, MD, and Niels Jongs, PhD.

The discussion begins with a breakdown of how HCEs integrate hard clinical endpoints—such as death, dialysis, and significant declines in eGFR—with eGFR slope, creating a more comprehensive measure of disease progression. Little explains how HCEs combine multiple validated endpoints into a single, prioritized hierarchy, after which Jongs describes the statistical framework behind HCEs, detailing how the win odds approach compares all patients in the treatment and control arms to determine overall treatment effect.

The conversation also contrasts win odds with traditional hazard ratios, with the panel noting that while the two metrics align in direction, win odds offer advantages in interpretability and power. Little highlights post hoc analyses of major nephrology trials, demonstrating strong consistency between win odds and hazard ratio-based findings. The panel also discusses the ability of HCEs to increase statistical power and reduce required sample sizes, potentially making trials more efficient without compromising rigor.

As the discussion continues, Jongs notes that HCEs could significantly improve trial design efficiency by reducing the number of patients needed to detect meaningful treatment effects. The panel underscores the need for continued refinement and validation of this approach to optimize nephrology clinical research.

In part 2 of 4 from this episode, the discussion focuses on hierarchical composite endpoints and their use in nephrology trials and research.

Kidney Compass: Understanding HCEs in Nephrology Clinical Trials

Kidney Compass: Hierarchical Composite Endpoints in Nephrology, with Dustin Little, MD, and Niels Jongs, PhD

Welcome to the first installment of a 4-part series on 

 exploring the use of hierarchical composite endpoints (HCEs) in kidney disease clinical trials.

In this installment, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, begin by introducing their guests Dustin Little, MD, Global Clinical Lead at AstraZeneca, and Niels Jongs, PhD, a statistician at the University of Groningen.

The discussion starts with an overview of traditional composite endpoints commonly used in nephrology trials, such as cardiovascular death, kidney failure, and sustained eGFR decline. Little explains key limitations of these traditional endpoints, including their reliance on first-event analysis and the disproportionate influence of rapid progressors on overall trial results. He emphasizes the need for more efficient trial designs that account for the entire study population rather than just those who reach predefined endpoints.

Jongs and Little both go on to explain how HCEs aim to address these shortcomings by structuring outcomes in a prioritized hierarchy, ensuring every patient contributes meaningfully to efficacy assessments. They discuss the addition of eGFR slope as a component of HCEs, allowing for a more comprehensive evaluation of treatment effects, especially in trials where only a small subset of participants progress to major clinical events.

Jongs expands on these concerns by highlighting statistical limitations, including how composite endpoints weigh events equally despite differences in clinical significance. The conversation then shifts toward the structure of HCEs, which build upon traditional endpoints by incorporating eGFR slope to ensure that all patients contribute to efficacy assessments. By structuring events hierarchically, HCEs aim to better reflect disease progression and provide a more comprehensive assessment of treatment effects.

In part 1 of 4 from this episode, the discussion focuses on traditional composite endpoints in nephrology trials and the use of HCEs.

Brendon Neuen, MBBS, PhD

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