Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial

Background In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin.Methods ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (>= 18 to <= 90 years) with an estimated GFR (eGFR) of 20 mL/min per 173 m(2) or greater and a urinary albumin-to-creatinine ratio (UACR) of 150-5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 15 mg plus dapagliflozin 10 mg, zibotentan 025 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 15 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 25% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed.Findings Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 628 years [SD 121], 138 [31%] female, 309 [69%] male, 305 [68%] White, mean eGFR 467 mL/min per 173 m(2) [SD 224], and median UACR 5655 mg/g [IQR 2430-12126]) received treatment with zibotentan 15 mg plus dapagliflozin (n=179 [40%]), zibotentan 025 mg plus dapagliflozin (n=91 [20%]), or dapagliflozin plus placebo (n=177 [40%]). Zibotentan 15 mg plus dapagliflozin and zibotentan 025 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was -337% (90% CI -425 to -235; p<00001) for zibotentan 15 mg plus dapagliflozin and -270% (90% CI -384 to -136; p=00022) for zibotentan 025 mg plus dapagliflozin. Fluid-retention events were observed in 33 (18%) of 179 participants in the zibotentan 15 mg plus dapagliflozin group, eight (9%) of 91 in the zibotentan 025 mg plus dapagliflozin group, and 14 (8%) of 177 in the dapagliflozin plus placebo group.Interpretation Zibotentan combined with dapagliflozin reduced albuminuria with an acceptable tolerability and safety profile and is an option to reduce chronic kidney disease progression in patients already receiving currently recommended therapy.