Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active- controlled clinical trial
Carregando...
Citações na Scopus
54
Tipo de produção
article
Data de publicação
2023
Título da Revista
ISSN da Revista
Título do Volume
Editora
ELSEVIER SCIENCE INC
Autores
HEERSPINK, Hiddo J. L.
RADHAKRISHNAN, Jai
ALPERS, Charles E.
BARRATT, Jonathan
BIELER, Stewart
DIVA, Ulysses
INRIG, Jula
KOMERS, Radko
MERCER, Alex
Citação
LANCET, v.401, n.10388, p.1584-1594, 2023
Resumo
Background 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.
Palavras-chave
Referências
- Barratt J, 2023, KIDNEY INT REP, V8, P1043, DOI 10.1016/j.ekir.2023.02.1086
- Barratt J, 2019, KIDNEY INT REP, V4, P1633, DOI 10.1016/j.ekir.2019.08.007
- Benigni A, 2021, PEDIATR NEPHROL, V36, P763, DOI 10.1007/s00467-020-04518-2
- Boels MGS, 2016, DIABETES, V65, P2429, DOI 10.2337/db15-1413
- COPPO R, 1993, AM J KIDNEY DIS, V21, P593, DOI 10.1016/S0272-6386(12)80031-X
- De Miguel C, 2016, CURR OPIN NEPHROL HY, V25, P35, DOI 10.1097/MNH.0000000000000185
- de Zeeuw D, 2014, J AM SOC NEPHROL, V25, P1083, DOI 10.1681/ASN.2013080830
- Dhaun N, 2012, BRIT J PHARMACOL, V167, P720, DOI 10.1111/j.1476-5381.2012.02070.x
- Dhaun N, 2011, HYPERTENSION, V57, P772, DOI 10.1161/HYPERTENSIONAHA.110.167486
- Heerspink HJL, 2019, LANCET, V393, P1937, DOI 10.1016/S0140-6736(19)30772-X
- Heerspink HL, 2019, LANCET DIABETES ENDO, V7, P128, DOI 10.1016/S2213-8587(18)30314-0
- Herrington WG, 2022, NEPHROL DIAL TRANSPL, V37, P1317, DOI 10.1093/ndt/gfac040
- Inker LA, 2021, AM J KIDNEY DIS, V78, P1
- Kohan DE, 2014, KIDNEY INT, V86, P896, DOI 10.1038/ki.2014.143
- Komers R, 2020, KIDNEY INT REP, V5, P494, DOI 10.1016/j.ekir.2019.12.017
- Komers R, 2017, KIDNEY INT REP, V2, P654, DOI 10.1016/j.ekir.2017.02.019
- Komers R, 2016, AM J PHYSIOL-REG I, V310, pR877, DOI 10.1152/ajpregu.00425.2015
- Lehrke I, 2001, J AM SOC NEPHROL, V12, P2321, DOI 10.1681/ASN.V12112321
- Levey AS, 2020, AM J KIDNEY DIS, V75, P84, DOI 10.1053/j.ajkd.2019.06.009
- Maisonneuve P, 2000, AM J KIDNEY DIS, V35, P157, DOI 10.1016/S0272-6386(00)70316-7
- Martinez-Diaz I, 2023, INT J MOL SCI, V24, DOI 10.3390/ijms24043427
- NAKAMURA T, 1993, LANCET, V342, P1147, DOI 10.1016/0140-6736(93)92126-E
- Reich HN, 2007, J AM SOC NEPHROL, V18, P3177, DOI 10.1681/ASN.2007050526
- Rovin BH, 2021, KIDNEY INT, V100, pS1, DOI 10.1016/j.kint.2021.05.021
- Smeijer JD, 2021, CURR OPIN NEPHROL HY, V30, P456, DOI 10.1097/MNH.0000000000000716
- Thompson A, 2019, CLIN J AM SOC NEPHRO, V14, P469, DOI 10.2215/CJN.08600718
- Trachtman H, 2020, DRUG FUTURE, V45, P79, DOI 10.1358/dof.2020.45.2.3058863
- Trachtman H, 2018, J AM SOC NEPHROL, V29, P2745, DOI 10.1681/ASN.2018010091
- Travere Therapeutics, FILSPARITM SPARS TAB
- Wheeler DC, 2021, KIDNEY INT, V100, P215, DOI 10.1016/j.kint.2021.03.033
- Wyatt RJ, 2013, NEW ENGL J MED, V368, P2402, DOI 10.1056/NEJMra1206793