{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T22:24:08Z","timestamp":1787264648371,"version":"build-2736575974"},"reference-count":34,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","award":["NCT06087835"],"award-info":[{"award-number":["NCT06087835"]}],"id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>A low dose of the selective endothelin A receptor antagonist zibotentan in combination with the sodium\u2212glucose co-transporter 2 inhibitor dapagliflozin reduced urinary albumin-to-creatinine ratio (UACR) by \u223c30% compared with dapagliflozin alone in a phase 2b study without increasing the risk of fluid retention. These findings supported the design and conduct of the ZENITH High Proteinuria trial (NCT06087835) to assess the long-term efficacy and safety of a fixed-dose combination zibotentan\/dapagliflozin in delaying the progression of chronic kidney disease (CKD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ZENITH High Proteinuria is an ongoing randomized, double-blind, placebo-controlled phase 3 trial enrolling participants with CKD [defined as UACR &amp;gt;700 mg\/g or urinary protein-to-creatinine ratio &amp;gt;1000 mg\/g and estimated glomerular filtration rate (eGFR) \u226520\u2013&amp;lt;90 ml\/min\/1.73 m2] with and without type 2 diabetes. Eligible participants were randomized 1:1 to zibotentan\/dapagliflozin 0.25\/10 mg (if eGFR&amp;lt;45 ml\/min\/1.73 m2)\/0.75\/10 mg (if eGFR \u226545 ml\/min\/1.73 m2) or placebo\/dapagliflozin on top of standard of care, including maximum tolerated renin\u2013angiotensin-system blockade. The primary efficacy outcome is the mean eGFR change from baseline to Month 24. Secondary efficacy outcomes include time to the composite of end-stage kidney disease, sustained \u226540% decrease in eGFR, or renal death. Adverse events are collected to assess safety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Participants were enrolled from November 2023 to November 2024 from 30 countries. Overall, 2910 patients were screened, of whom 1833 were randomized and treated. Mean age at baseline was 61 years and 28% were female. Mean (standard deviation) eGFR was 44.0 (18.2) ml\/min\/1.73 m2, median (interquartile range) UACR was 1262 (801\u20132097) mg\/g, and median (interquartile range) B-type natriuretic peptide was 44 (23\u201386) ng\/l.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>To evaluate the effect of zibotentan and dapagliflozin combination therapy, the ZENITH High Proteinuria study has successfully recruited a population at high risk of CKD progression for whom novel therapies remain necessary. Results are expected in 2027.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ndt\/gfag172","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:21:38Z","timestamp":1785756098000},"source":"Crossref","is-referenced-by-count":0,"title":["Design and baseline characteristics of the ZENITH high proteinuria trial testing zibotentan\/dapagliflozin efficacy on CKD progression"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3126-3730","authenticated-orcid":false,"given":"Hiddo J L","family":"Heerspink","sequence":"first","affiliation":[{"name":"The George Institute for Global Health, University of New South Wales Sydney , Sydney, NSW ,","place":["Australia"]},{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen 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