Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

초록

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 , 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 , Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1 center dot 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 center dot 7 mL/min per 1 center dot 73 m2 per year versus -3 center dot 8 mL/min per 1 center dot 73 m2 per year (difference 1 center dot 1 mL/min per 1 center dot 73 m2 per year, 95% CI 0 center dot 1 to 2 center dot 1; p=0 center dot 037); total 2-year slope (day 1-week 110) was -2 center dot 9 mL/min per 1 center dot 73 m2 per year versus -3 center dot 9 mL/min per 1 center dot 73 m2 per year (difference 1 center dot 0 mL/min per 1 center dot 73 m2 per year, 95% CI -0 center dot 03 to 1 center dot 94; p=0 center dot 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 center dot 8%, 95% CI -49 center dot 8 to -35 center dot 0, with sparsentan versus -4 center dot 4%, -15 center dot 8 to 8 center dot 7, with irbesartan; geometric least-squares mean ratio 0 center dot 60, 95% CI 0 center dot 50 to 0 center dot 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 center dot 7, 95% CI 0 center dot 4 to 1 center dot 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.

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