PROTECT Trial Explained: Sparsentan for IgA Nephropathy | Landmark Trials in Nephrology

PROTECT is the companion trial to NefIgArd — the other half of the 2023 IgA nephropathy revolution. Where Nefecon targets the immune source of the disease, sparsentan targets the downstream hemodynamic and inflammatory injury. Together they gave nephrologists two fundamentally different mechanistic tools for a disease that, for decades, had no disease-specific therapy. This video breaks down the trial in the NEJM QuickTake format — the companion trial narrative, the scientifically important active-controlled design (sparsentan vs maximally-titrated irbesartan, NOT placebo), the DEARA mechanism, the Week 36 proteinuria benefit that won accelerated FDA approval, the 2-year eGFR preservation data that won full approval in 2024, the real monitoring burden (boxed warning hepatotoxicity + REMS program), limitations, and how to choose between Nefecon and sparsentan in practice. CLINICAL PEARL EMBEDDED: sparsentan is NOT added on top of an angiotensin receptor blocker. Because sparsentan contains an angiotensin II receptor antagonist within its structure, combining it with a separate ARB is contraindicated. A patient optimized on an ARB transitions to sparsentan — the ARB is stopped. Third GN trial in the Landmark Trials arc. If you are a nephrology fellow, IM resident preparing for boards, or a practicing clinician managing IgA nephropathy — this is the video for you. 📋 CHAPTERS 00:00 Introduction 00:21 2023: The Year IgA Nephropathy Changed 01:24 Active-Controlled — Not Placebo 02:33 The DEARA Mechanism 03:54 Study Design 05:32 Week 36: Sparsentan Decisively Wins 06:55 2 Years: Kidney Function Preservation 08:44 Safety: The Monitoring Trade-Off 10:03 Board Pearl 11:53 Honest Limitations 13:12 Choosing Between Nefecon and Sparsentan 15:13 One-Sentence Summary and Closing 🔑 KEY NUMBERS N = 404 patients (202 vs 202), phase 3, active-controlled Sparsentan 400 mg/day vs irbesartan 300 mg/day (maximum ARB dose) Inclusion: eGFR ≥ 30, UPCR greater than 0.75 g/g or proteinuria ≥ 1 g/day, on max RAS blockade greater than 12 wk Study duration: 114 weeks double-blind + optional 156-week open-label extension Week 36 primary endpoint: UPCR −49.8% vs −15.1% (P less than 0.0001) FDA accelerated approval Feb 2023 based on Week 36 data → brand name FILSPARI® 2-year confirmatory endpoint: significantly slower eGFR slope with sparsentan 2-year UPCR: −42% vs −26% Composite endpoint (40% eGFR decline / ESKD / all-cause death): 3% vs 6% Complete remission OR 3.1; partial remission OR 4.5 (favoring sparsentan) FDA full approval 2024 based on 2-year data ⚠️ CRITICAL SAFETY NOTES Boxed warning for HEPATOTOXICITY — LFTs monthly × first 12 months, then every 3 months Dispensed only through FILSPARI REMS program in the US Contraindicated with ARBs, other endothelin receptor antagonists, or aliskiren Watch for hypotension, fluid retention, hyperkalemia 🎯 THE CLINICAL TAKEAWAY Sparsentan is the non-immunosuppressive disease-modifying option for IgA nephropathy. KDIGO 2025 lists both Nefecon AND sparsentan as options for moderate-to-high-risk patients. Patient selection depends on steroid contraindications, cardiovascular comorbidity, hepatic baseline, and willingness to commit to indefinite therapy. 📚 REFERENCES Rovin BH, Barratt J, Heerspink HJL, et al. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet 2023; 402: 2077-2090. https://www.thelancet.com/journals/la... Heerspink HJL, Radhakrishnan J, Alpers CE, et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet 2023; 401: 1584-1594. 📖 KDIGO 2025 IgA Nephropathy Guideline https://kdigo.org/guidelines/gd/ 🎓 LANDMARK TRIALS PLAYLIST ▶ CREDENCE: ▶ FIDELIO-DKD: ▶ FLOW: ▶ STARRT-AKI: ▶ AKIKI-2: ▶ EMPA-KIDNEY: ▶ DAPA-CKD: ▶ MENTOR: ▶ NefIgArd: ▶ PROTECT: (this video — third GN trial in the series) 👨‍⚕️ ABOUT Dr. Amit Kaushal, MD, FASN is Assistant Professor of Medicine and Medical Director of Dialysis Units in the Division of Nephrology & Hypertension at West Virginia University School of Medicine. 🔔 SUBSCRIBE for new landmark trial breakdowns — designed for nephrology fellows, IM residents, and practicing nephrologists who want the evidence without the 40-page read. 📧 For patient-facing kidney health content, check out my Substack: Kidney Health Explained https://kidneyhealthexplained.substac... #PROTECT #Sparsentan #Filspari #IgANephropathy #IgAN #DEARA #Nephrology #GlomerularDisease #BoardReview #KDIGO2025 #LandmarkTrials