Kidney Compass: Navigating Clinical Trials

• 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

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• The PARASOL Initiative and FSGS Management, with Laura Mariani, MD, MS, and Daniel Gale, PhD, MB BChir

  In this episode of Kidney Compass: Navigating Clinical Trials, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, the director of Clinical trials in the Division of Nephrology and the vice chair of Clinical Research in the Department of Medicine at the University of Texas Medical Branch, are joined by Laura Mariani, MD, MS, co-chair of the PARASOL Initiative associate professor in the Division of Nephrology at the University of Michigan, and Daniel Gale, PhD, MB BChir, director of the UK-based RaDaR Registry and the St Peter's Chair of Nephrology at University College London. During the episode, guests take Neuen and Wadhwani on a deep dive into the Proteinuria and GFR as Clinical Trial Endpoints in FSGS (PARASOL) Initiative. An international collaboration launched in 2023, the initiative is aimed at investigating the link between short-term changes in biomarkers, like proteinuria and GFR, and long-term outcomes to support alternative endpoints for drug approval in focal segmental glomerulosclerosis. The video version of this episode is only available on HCPLive.com. Chapters 00:00:00 - Start 00:02:37 - Mariani & Gale Introduction 00:05:03 - Discussing RaDaR Registry Insights 00:09:52 - Challenges and Opportunities in Rare Kidney Disease Research 00:18:44 - PARASOL Initiative Origins 00:25:45- PARASOL Partnership with US FDA  00:35:10 - Key findings from PARASOL 00:46:35 - Proteinuria as a Surrogate Outcome in FSGS 00:53:45 - Applying PARASOL Findings  01:00:30 - Future of PARASOL Initiative Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics. Relevant disclosures for Mariani include Travere Therapeutics, Boehringer Ingelheim, Reliant Glycosciences, Takeda Pharmaceuticals, HI-Bio, and Calliditas Therapeutics. Relevant disclosures for Gale include Novartis, Alexion, Calliditas, Britannia, Vifor, Judo Bio, Adnovate, Sanofi, Anlylam, Boehringer Ingelheim, and Bayer.

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• Semaglutide for Nondiabetic Kidney Disease, with Hiddo Heerspink, PhD, PharmD, at Kidney Week 2024

  In the latest episode of Kidney Compass: Navigating Clinical Trials, Hiddo Heerspink, PhD, PharmD, of the University of Groningen, joins the podcast after he presented the landmark SMART trial, which suggested the benefit of semaglutide (Ozempic/Wegovy) on chronic kidney disease (CKD) extend to patients without diabetes. Video Version During the episode, Heerspink shares the impetus behind the SMART study, explaining how early pandemic lockdowns offered time to explore semaglutide's application for CKD without diabetes. The group delves into the study's design, patient profile, and a 52% reduction in albuminuria observed with semaglutide. They address dose-dependency, how higher doses may amplify albuminuria reduction, and the relationship between creatinine and cystatin C as filtration markers. The conversation shifts to broader implications, including the drug’s anti-inflammatory benefits, its potential for longer-term GFR protection, and specific impacts on blood pressure and BNP levels. As Heerspink elaborates, these results underscore semaglutide’s versatility, suggesting new therapeutic avenues across kidney and cardiovascular care. The episode concludes with a look at future research needs, including additional trials to clarify semaglutide’s role in non-diabetic CKD and broader nephrology applications. Chapters 00:00 - Start 01:45 - SMART Trial Background 04:30 - Study Population Characteristics 06:10 - SMART Trial Results 07:35 - Dose-Dependent Effects of Semaglutide 09:15 - Filtration Markers 14:15 - Hypertension and BNP --- Relevant disclosures for Heerspink include AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Chinook Therapeutics Inc., Gilead Sciences, Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Travere Therapeutics, and others. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.

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  17:27
• FLOW Insights from Kidney Week 2024, with Katherine Tuttle, MD

  In the third and final on-site edition of Kidney Compass: Navigating Clinical Trials from the American Society of Nephrology’s Kidney Week 2024, Katherine Tuttle, MD, clinical professor of Medicine at University of Washington Medicine and executive director for Research at Providence Health Care, joins the program for a deep dive into new FLOW trial data at the meeting, the role of semaglutide (Ozempic) and GLP-1 receptor agonists in managing kidney disease, and prescribing responsibilities for new therapies with cardio-kidney-metabolic benefits. To begin the episode, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, ask Tuttle to review findings from the FLOW trial, particularly the effects of semaglutide on kidney and cardiovascular outcomes. Tuttle details the groundbreaking findings, which concluded semaglutide not only lowers the risk of kidney failure and GFR decline in patients with type 2 diabetes but also significantly reduces cardiovascular events and overall mortality. They go on to discuss FLOW’s hierarchy of tested outcomes, confirming its broad efficacy across various levels of kidney function and albuminuria, which they highlight should be a notable reassurance for patients with more advanced CKD stages. Tuttle emphasizes the consistency of benefits regardless of SGLT2 inhibitor usage, pointing to potential additive effects when combining these therapies. The group also addresses semaglutide’s surprising reduction in infection rates, including COVID-19, which may point to its immune-modulating effects. Tuttle encourages nephrologists to take an active role in prescribing GLP-1 receptor agonists to enhance holistic, cross-specialty care for patients with CKD. The episode concludes with a call to action for nephrologists to adopt a comprehensive approach to cardiovascular risk management, integrating these new therapies as a primary tool in improving outcomes for patients with complex, interconnected health needs. ---- Chapters 00:00 - Start 00:50 - FLOW Overview 05:50 - Safety Outcomes 11:30 - Deep Dive into Mortality Data 13:30 - Mechanism Behind Lower Infection Risk 15:30 - Future of Kidney Disease Research 17:30 - Nephrologists Responsibility to Prescribe GLP-1s Relevant disclosures for Tuttle include Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca, Gilead, Goldfinch Bio, Novo Nordisk, Travere Therapeutics, and Bayer. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.

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• Atacicept for IgAN & 96-Week ORIGIN Data, with Jonathan Barratt, PhD, at Kidney Week 2024

  Live from Kidney Week 2024! Hosts Neuen and Wadhwani are joined by Prof. Jonathan Barratt to discuss atacicept's 96-week data from ORIGIN OLE, which he presented as a late-breaker at the meeting. Video Version Here Results of the study indicate atacicept use was associated with sustained reductions across multiple endpoints of interest, including a 66% (SE, 2%) mean reduction in Gd-IgA1 levels, a reduction in percentage of patients with hematuria from baseline (percentage change, 75%; 95% CI, -87% to -59%), and a mean reduction in UPCR of 52% (SE, 5%). The mean eGFR annualized slope was just -0.6 (SE, 0.5) mL/min/1.73m2 per year. As the discussion unfolds, Barratt explains atacicept’s unique approach of targeting disease-causing cytokines and highlights the drug’s practical benefit as a weekly self-administered injection, making it accessible for long-term patient use. The conversation wraps up with insights into the global impact of ongoing phase 3 trials, the sponsor’s commitment to extended access, and how these steps could redefine outcomes for patients with IgA nephropathy. Chapters 00:00 – Start 01:30 – Understanding Atacicept and Its Mechanism 05:00 – Phase 2 Trial Results and Clinical Impact 10:00 – Advantages of At-Home Therapy and Patient Adherence 13:00 – Future of IgA Nephropathy Treatment and Phase 3 Trials Relevant disclosures of interest for Barratt included Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos NV, GSK, Novartis, and Travere Therapeutics. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.

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