Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPHEERSPINK, Hiddo J. L.RADHAKRISHNAN, JaiALPERS, Charles E.BARRATT, JonathanBIELER, StewartDIVA, UlyssesINRIG, JulaKOMERS, RadkoMERCER, AlexNORONHA, Irene L.RHEAULT, Michelle N.ROTE, WilliamROVIN, BradTRACHTMAN, HowardTRIMARCHI, HerninWONG, Muh GeotPERKOVIC, VladoPROTECT Investigators2023-08-162023-08-162023LANCET, v.401, n.10388, p.1584-1594, 20230140-6736https://observatorio.fm.usp.br/handle/OPI/54593Background Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety.Methods PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged >= 18 years) with biopsy-proven IgA nephropathy and proteinuria of 1 center dot 0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1 center dot 73 m2 and >= 60 mL/min per 1 center dot 73 m2) and urine protein excretion at screening (<= 1 center dot 75 g/day and >1 center dot 75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein- creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850.Findings Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49 center dot 8%) than the irbesartan group (-15 center dot 1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0 center dot 59; 95% CI 0 center dot 51-0 center dot 69; p<0 center dot 0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups.Interpretation Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan.engrestrictedAccessendothelin receptor antagonistskidneyalbuminuriairbesartanexpressionefficacydiseasesdesignarticleCopyright ELSEVIER SCIENCE INC10.1016/S0140-6736(23)00569-XMedicine, General & Internal1474-547X