BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

Colorado Kidney Care Denver CO USA

Concord Clinical School University of Sydney Concord NSW Australia

Department of Cardiovascular Sciences University of Leicester General Hospital Leicester UK

Department of Clinical Pharmacy and Pharmacology University of Groningen Groningen Netherlands

Department of Internal Medicine Korea University Anam Hospital Korea University College of Medicine Seoul South Korea

Department of Internal Medicine Seoul Red Cross Hospital Seoul South Korea

Department of Laboratory Medicine and Pathology University of Washington Seattle WA USA

Department of Medicine Complutense University Madrid Spain

Department of Nephrology AZ Delta Roeselare Belgium

Department of Nephrology General University Hospital Charles University Prague Czechia

Department of Nephrology Międzyleski Specialist Hospital Warsaw Poland

Department of Renal Medicine Concord Repatriation General Hospital Concord NSW Australia

Division of Nephrology Columbia University Irving Medical Center New York NY USA

Division of Nephrology Department of Medicine School of Clinical Medicine The University of Hong Kong Hong Kong SAR China

Division of Nephrology Department of Pediatrics University of Michigan Ann Arbor MI USA

Division of Nephrology Ohio State University Wexner Medical Center Columbus OH USA

Division of Nephrology RWTH Aachen University Hospital Aachen Germany

Division of Nephrology School of Medicine University of Utah Health Salt Lake City UT USA

Division of Nephrology Stanford University Medical Center Stanford CA USA

Division of Nephrology University of Sao Paulo Sao Paulo Brazil

Division of Pediatric Nephrology University of Minnesota Medical School Minneapolis MN USA

Faculty of Medicine and Health University of New South Wales Sydney NSW Australia

JAMCO Pharma Consulting Stockholm Sweden

Nephrology Dialysis and Transplantation Unit University of Bari Aldo Moro Bari Italy

Nephrology Service British Hospital of Buenos Aires Buenos Aires Argentina

NephroNet Clinical Trials Consortium Atlanta GA USA

Renal Division Emory University Atlanta GA USA

Research Institute Hospital 12 de Octubre Madrid Spain

Royal Adelaide Hospital and University of Adelaide Adelaide SA Australia

The George Institute for Global Health University of New South Wales Sydney NSW Australia

Travere Therapeutics San Diego CA USA

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