Brendon Neuen, MBBS, PhD

Kidney Compass: Navigating Clinical Trials

Kidney Compass: The Future of Cardiovascular-Kidney-Metabolic Trial Design

, host Brendon Neuen, MBBS, PhD, is joined by Richard Pratley, MD, medical director at the Advent Health Diabetes Institute, and Muthiah Vaduganathan, MD, MPH, codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, to discuss the evolving landscape of clinical trials in cardiovascular-kidney-metabolic (CKM) syndrome, exploring how various study designs, patient engagement, and infrastructure development are reshaping research and evidence generation in this growing field.

A central focus of the discussion is the value and nuances of different trial designs, focusing specifically on SURPASS CVOT. The cardiovascular outcome study is the first to directly compare 2 incretin-based therapies, tirzepatide, a dual GIP/GLP-1 receptor agonist, and dulaglutide, a GLP-1 receptor agonist, among patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD).

Topline results showed tirzepatide achieved the primary objective by demonstrating a non-inferior rate of major adverse cardiovascular events (MACE-3), including cardiovascular death, heart attack or stroke, versus dulaglutide. Additionally, while not controlled for multiplicity-adjusted type-1 error, tirzepatide showed improvements on key measures of A1C, weight, renal function and all-cause mortality.

The speakers noted the active control design of the trial with a prespecified hierarchy of testing, highlighting the proven noninferiority of tirzepatide and its lack of association with excess cardiovascular risk, but no proven superiority. Additionally, the group discussed the use of imputed placebo analysis based on data from the REWIND trial of dulaglutide, allowing comparison of tirzepatide against a virtual placebo group and suggesting tirzepatide reduced major adverse cardiovascular events while remaining safe.

With the ability to conduct placebo controlled trials getting “narrower and narrower,” especially in areas like the incretin space, the speakers emphasize the importance of trial designs like SURPASS CVOT, additionally drawing parallels to the FLOW trial of semaglutide for diabetic kidney disease and assessing the possibility of applying a similar imputed placebo design to evaluate new incretin based therapies in CKD.

With standards of care shifting so rapidly in nephrology, the group explores how trials may need to be adjusted moving forward, discussing the need to account for more patients being on background therapy, mandate local standards of care, and incorporate aspects like active comparison against a traditional, accepted standard of care.

The trio goes on to describe potential trial designs for incretin-based therapies, citing the continued need for large outcomes-based trials and potential strategies to minimize placebo exposure as well as the pros and cons of different trial designs. Despite these challenges, the group notes that the difficulties in trial design are far outweighed by the benefits of bringing highly effective drugs to patients to decrease the risk of CKD progression and the cardiovascular consequences of CKD.

Editors’ note: Relevant disclosures for 

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

 include Novo Nordisk, Merck, Bayer, Eli Lilly and Company, Rivus Pharmaceuticals, and others. Relevant disclosures for 

 include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others.

Brooks A. SURPASS-CVOT: Tirzepatide Bests Dulaglutide for Cardiovascular Protection. HCPLive. July 31, 2025. Accessed September 29, 2025. 

https://www.hcplive.com/view/surpass-cvot-tirzepatide-bests-dulaglutide-cardiovascular-protection

Isaacs D, Bellini N. Diabetes Dialogue: FLOW Trial and Semaglutide's Benefit in Chronic Kidney Disease. HCPLive. May 25, 2024. Accessed September 29, 2025. 

https://www.hcplive.com/view/diabetes-dialogue-flow-trial-and-semaglutide-s-benefit-in-chronic-kidney-disease

Neuen B, Wadhwani S. Kidney Compass: FLOW Insights from Kidney Week 2024, with Katherine Tuttle, MD. HCPLive. October 28, 2024. Accessed September 29, 2025. 

https://www.hcplive.com/view/kidney-compass-flow-insights-from-kidney-week-2024-with-katherine-tuttle-md

Podcasts

Neuen is joined by Richard Pratley, MD, and Muthiah Vaduganathan, MD, MPH, to discuss the evolving landscape of CKM trial design.

Shaping the Next Era of IgA Nephropathy Treatment, With Brendon Neuen, MBBS, PhD

 is evolving at an unprecedented pace. Multiple new therapies are now available and others are progressing through clinical development, raising critical questions about how to best use these treatments in practice.

In the past few years, the US Food and Drug Administration (FDA) has granted accelerated approval to Novartis’ iptacopan (Fabhalta) and atrasentan (Vanrafia) as well as full approval to Travere Therapeutics’ sparsentan (Filspari) and Calliditas Therapeutics’ budesonide (Tarpeyo) delayed release capsules.

In a recent systematic review and meta-analysis of pooled phase 2 and phase 3 trial data for nonimmunosuppressive antiproteinuric therapies, corticosteroids, B-cell modulating agents, and complement inhibitors, Brendon Neuen, MBBS, PhD, a senior research fellow with the George Institute for Global Health and director of the Kidney Trials Unit with Royal North Shore Hospital, and a team of investigators found all 4 therapeutic classes reduce proteinuria, but to varying degrees.

Kidney function outcomes followed a similar pattern, with data from trials reporting eGFR slope over > 12 months indicating benefits for all drug classes, but with some evidence that effects varied by class.

“What I'm really looking forward to seeing, and I think many others are looking forward to as well, is the safety data from ongoing phase 3 trials of the immunological therapies, particularly the B cell related therapies, APRIL and BAFF inhibitors, because of the tremendous potential that these agents have in preventing kidney function decline,” Neuen told 

. “If the safety data is as good as what is suggested in earlier phase studies, I think that will really help guide treatment selection in IgA nephropathy.”

However, in the absence of head-to-head data, the practical question of sequencing therapies remains unsettled, with Neuen referencing a 

recent episode of Kidney Compass on the VISIONARY trial

 with guest Vlado Perkovic, MBBS, PhD, dean and scientia professor of Medicine at UNSW Sydney.

“I think this is where cost, availability, and other practicalities are going to come into play,” Neuen said. “Of course, it's always going to be preferable to target the immunological basis of the disease. But in many health care settings around the world, these agents may not be available, or if they are, they may be available at considerable costs.”

From a practical perspective, he says clinicians will be accessing therapies readily available to them, likely meaning nonimmunological antiproteinuric therapies will be used first and additional therapies will be added later.

Looking ahead, Neuen says he sees a “great opportunity” to explore a more personalized approach to IgAN therapeutics, but notes there are challenges in doing so with so many therapies available and limited ability to determine which patients will respond to which treatment.

“We're obviously not there yet, but I think that's the great opportunity and a real call to arms in terms of mechanistic research to identify biomarkers so that we can sequence these therapies and prioritize individuals for whom these drugs may work better,” Neuen said.

Editors’ note: Relevant disclosures for

include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others.

Campbell P. Atrasentan (Vanrafia) Receives Accelerated Approval in IgA Nephropathy. HCPLive. April 3, 2025. Accessed September 24, 2025. 

https://www.hcplive.com/view/atrasentan-vanrafia-receives-accelerated-approval-in-igan

Brooks A. FDA Approves Travere Therapeutics’ Sparsentan to Slow Kidney Function Decline in Adult Primary IgAN. HCPLive. September 5, 2024. Accessed September 24, 2025. 

https://www.hcplive.com/view/fda-approves-travere-therapuetics-sparsentan-for-proteinuria-reduction-in-adult-primary-igan

Campbell C. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. HCPLive. August 8, 2024. Accessed September 24, 2025. 

https://www.hcplive.com/view/iptacopan-receives-accelerated-approval-for-reducing-proteinuria-in-iga-nephropathy

Kim D, Neuen BL, Perkovic V, Wong MG. Effects of Therapies on Proteinuria and Estimated Glomerular Filtration Rate in IgA Nephropathy: Meta-Analysis of Randomized Trials. Clin J Am Soc Nephrol. 

Videos

Neuen describes varying treatment effects with 4 different classes of IgAN therapeutics and future opportunities for personalized treatment.

Innovation in IgAN: Exploring New Therapies and Combination Approaches, With Brendon Neuen, MBBS, PhD

“Therapeutic options for IgA nephropathy have expanded so rapidly in the last few years, and we now have multiple agents approved by regulatory agencies like the US FDA to reduce proteinuria and reduce kidney function decline,” Brendon Neuen, MBBS, PhD, a senior research fellow with the George Institute for Global Health and director of the Kidney Trials Unit with Royal North Shore Hospital, told 

. “The question that is being asked by clinicians now and is increasingly relevant, is how do we use these drugs? Which ones should we preferentially use, and can we use them in combination?"

To clarify how available treatments compare, Neuen and a team of investigators conducted a systematic review and meta-analysis in which they pooled phase 2 and phase 3 trial data for nonimmunosuppressive antiproteinuric therapies, corticosteroids, B-cell modulating agents, and complement inhibitors. Treatment effects on proteinuria and eGFR slope were pooled overall and by drug class.

Findings showed all 4 therapeutic classes reduce proteinuria, but to varying degrees. Nonimmunosuppressive therapies achieved about a 34% reduction, while corticosteroids and B-cell modulating agents produced 45–50% reductions. Complement inhibitors also showed benefit with about a 35% reduction, though the available data are more limited.

Kidney function outcomes followed a similar pattern, with data from trials reporting eGFR slope over > 12 months indicating benefits for all drug classes, but with some evidence that effects varied by class. Specifically, nonimmunosuppressive therapies slowed eGFR decline by roughly 28%, corticosteroids by 52%, and B-cell–directed agents by as much as 73%.4

“We have to be a little bit careful about these indirect comparisons across trials because these are very different populations across the studies,” Neuen explained. “What it does suggest, or at least raise the possibility of, is that how we reduce proteinuria is at least as important as to what extent we reduce proteinuria. What this highlights is the really important role of targeting the underlying immunological basis of the disease, where we see that the rates of GFR decline are substantially improved, in particular with the B cell modulating agents.”

Looking ahead, Neuen points to the need for safety data on the B-cell modulating agents, citing a current lack of complete 2-year eGFR slope data and accompanying safety data. From a research perspective, he raises questions about how to best evaluate these therapies in combination and generate evidence supporting the potential role of combination therapy for IgAN.

 include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others.

Campbell P. Atrasentan (Vanrafia) Receives Accelerated Approval in IgA Nephropathy. HCPLive. April 3, 2025. Accessed September 22, 2025. 

Brooks A. FDA Approves Travere Therapeutics’ Sparsentan to Slow Kidney Function Decline in Adult Primary IgAN. HCPLive. September 5, 2024. Accessed September 22, 2025. 

Campbell C. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. HCPLive. August 8, 2024. Accessed September 22, 2025. 

Neuen reviews recent advances in IgAN treatment and findings from a systematic review and meta-analysis guiding their use in clinical practice.

Kidney Compass: NUDGE-CKD and the Power of Pragmatic Trials

, host Brendon Neuen, MBBS, PhD, is joined by Tor Biering-Sørensen, MD, MPH, PhD, and Kristoffer Skaarup, MD, to discuss the design, execution, and implications of the NUDGE-CKD trial—a landmark pragmatic study aimed at improving guideline-based care in 

The NUDGE-CKD trial tested whether low-cost digital “nudges”—letters sent to patients and their primary care physicians emphasizing evidence-based CKD therapies—could increase use of guideline-directed medical therapies (GDMT) for people with CKD. Using Denmark’s nationwide registries and E-box digital communication system, the team identified > 160,000 individuals with CKD and ultimately randomized nearly 20,000 patients into different trial arms.

Key findings showed a modest but meaningful increase in GDMT uptake among patients who received the nudges—particularly when both patients and GPs received communication. While the patient-only letters had little effect, the combined approach led to greater prescribing of key medications and improved risk factor control.

The episode also highlights how Denmark’s integrated national data systems make this kind of large-scale, fast, and cost-efficient research possible. Biering-Sørensen and Skaarup describe how trials like NUDGE-CKD can be designed and launched within weeks, thanks to the ability to rapidly identify target populations and deploy interventions nationwide with minimal burden on patients or clinicians.

Looking ahead, the team is applying this model to test continuous mailed treatments in a new decentralized heart failure trial and is preparing to launch their first fully remote phase 3 trial. They also share insights from an embedded recruitment experiment, showing that shorter invitation letters significantly improve trial participation—underscoring the value of optimizing every layer of the research process.

The episode closes with a call to action: as implementation science and pragmatic trials gain momentum, embedding randomization and leveraging real-world systems can offer causal answers to practical questions, helping close the evidence-practice gap in CKD and beyond.

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

 include Amgen, Boston Scientific, Sanofi Pasteur, Novartis, and others. 

Host Brendon Neuen is joined by guests Tor Biering-Sørensen and Kristoffer Skaarup to discuss NUDGE-CKD and implementation trial design.

Brendon Neuen, MBBS, PhD

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