Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
The George Institute for Global Health, Sydney, New South Wales, Australia.
Nephrol Dial Transplant. 2024 Feb 28;39(3):414-425. doi: 10.1093/ndt/gfad183.
Sodium-glucose co-transporter 2 inhibitors (SGLT2is) are part of the standard of care for patients with chronic kidney disease (CKD), both with and without type 2 diabetes. Endothelin A (ETA) receptor antagonists have also been shown to slow progression of CKD. Differing mechanisms of action of SGLT2 and ETA receptor antagonists may enhance efficacy. We outline a study to evaluate the effect of combination zibotentan/dapagliflozin versus dapagliflozin alone on albuminuria and estimated glomerular filtration rate (eGFR).
We are conducting a double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ETA receptor antagonist zibotentan and SGLT2i dapagliflozin in a planned 415 adults with CKD (Zibotentan and Dapagliflozin for the Treatment of CKD; ZENITH-CKD). Participants are being randomized (1:2:2) to zibotentan 0.25 mg/dapagliflozin 10 mg once daily (QD), zibotentan 1.5 mg/dapagliflozin 10 mg QD and dapagliflozin 10 mg QD alone, for 12 weeks followed by a 2-week off-treatment wash-out period. The primary endpoint is the change in log-transformed urinary albumin-to-creatinine ratio (UACR) from baseline to Week 12. Other outcomes include change in blood pressure from baseline to Week 12 and change in eGFR the study. The incidence of adverse events will be monitored. Study protocol-defined events of special interest include changes in fluid-related measures (weight gain or B-type natriuretic peptide).
A total of 447 patients were randomized and received treatment in placebo/dapagliflozin (n = 177), zibotentan 0.25 mg/dapagliflozin (n = 91) and zibotentan 1.5 mg/dapagliflozin (n = 179). The mean age was 62.8 years, 30.9% were female and 68.2% were white. At baseline, the mean eGFR of the enrolled population was 46.7 mL/min/1.73 m2 and the geometric mean UACR was 538.3 mg/g.
This study evaluates the UACR-lowering efficacy and safety of zibotentan with dapagliflozin as a potential new treatment for CKD. The study will provide information about an effective and safe zibotentan dose to be further investigated in a Phase 3 clinical outcome trial.
NCT04724837.
钠-葡萄糖协同转运蛋白 2 抑制剂（SGLT2is）是慢性肾脏病（CKD）患者的标准治疗方法，无论是否患有 2 型糖尿病。内皮素 A（ETA）受体拮抗剂也已被证明可减缓 CKD 的进展。SGLT2 和 ETA 受体拮抗剂的作用机制不同，可能会增强疗效。我们概述了一项评估 SGLT2 联合 ETA 受体拮抗剂（ETA）佐匹坦/达格列净与达格列净单药治疗对白蛋白尿和估计肾小球滤过率（eGFR）影响的研究。
我们正在进行一项双盲、活性对照、2b 期研究，以评估 ETA 受体拮抗剂佐匹坦和 SGLT2i 达格列净在计划的 415 名 CKD 患者（佐匹坦和达格列净治疗 CKD；ZENITH-CKD）中的疗效和安全性。参与者被随机分为 1:2:2 组，分别接受佐匹坦 0.25mg/达格列净 10mg 每日一次（QD）、佐匹坦 1.5mg/达格列净 10mg QD 和达格列净 10mg QD 单药治疗，持续 12 周，然后进行为期 2 周的停药洗脱期。主要终点是从基线到第 12 周时对数转换的尿白蛋白与肌酐比值（UACR）的变化。其他结果包括从基线到第 12 周时的血压变化和研究期间的 eGFR 变化。将监测不良事件的发生率。研究方案定义的特别关注事件包括与液体相关的指标变化（体重增加或 B 型利钠肽）。
共有 447 名患者被随机分配并接受安慰剂/达格列净（n=177）、佐匹坦 0.25mg/达格列净（n=91）和佐匹坦 1.5mg/达格列净（n=179）治疗。平均年龄为 62.8 岁，30.9%为女性，68.2%为白人。入组人群的基线 eGFR 平均为 46.7ml/min/1.73m2，几何均数 UACR 为 538.3mg/g。
本研究评估了佐匹坦联合达格列净降低 UACR 的疗效和安全性，作为 CKD 的一种潜在新治疗方法。该研究将提供有关佐匹坦有效和安全剂量的信息，以进一步在 3 期临床结局试验中进行研究。
NCT04724837。
