Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Feb 28;39(3):414-425.
doi: 10.1093/ndt/gfad183.

Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial

Hiddo J L Heerspink  1   2 , Peter J Greasley  3 , Christine Ahlström  4 , Magnus Althage  5 , Jamie P Dwyer  6 , Gordon Law  7 , Emma Wijkmark  8 , Min Lin  9 , Anne-Kristina Mercier  10 , Mikael Sunnåker  10 , Michelle Turton  11 , David C Wheeler  12 , Philip Ambery  13
Affiliations
Clinical Trial

Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial

Hiddo J L Heerspink et al. Nephrol Dial Transplant. .

Abstract

Background: 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).

Methods: 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).

Results: 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.

Conclusion: 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.

Clinical trial registration number: NCT04724837.

Keywords: chronic kidney disease; dapagliflozin; efficacy; safety; zibotentan.

PubMed Disclaimer

Conflict of interest statement

H.J.L.H. reports grant funding and honoraria for consultancy as a member of the steering committee of the DAPA-CKD trial paid to their institution from AstraZeneca; research grants paid to his employer from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk for clinical trials; consulting fees, paid to his employer, from AbbVie, Boehringer Ingelheim, Travere Pharmaceuticals and Novo Nordisk; fees for steering committee membership, paid to his employer, from Bayer, Chinook, CSL Pharma, Dimerix, Gilead and Janssen; honoraria for lectures from AstraZeneca, Bayer, Mitsubishi Tanabe and Novo Nordisk; and honoraria for advisory board participation for Merck (paid to his employer), Mitsubishi Tanabe and Mundipharma. P.J.G. is an employee and shareholder of AstraZeneca. C.A. is an employee and shareholder of AstraZeneca. M.A. is an employee and shareholder of AstraZeneca. J.P.D. reports grant funding from AstraZeneca and Cincor, Inc.; received consulting fees from Akebia, Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim, Caladrius Biosciences, CSL Behring, Eli Lilly, Fibrogen, Inc., GlaxoSmithKline, LLC., Inversago, Novo Nordisk, ProKidney, LLC., Reata Inc., RenalytixAI, Inc., Sanofi and Tricida Inc.; has participated on a data safety monitoring board or advisory board for Eli Lilly and Novo Nordisk; has held a leadership or fiduciary role for BioRasi; and holds stock in Biorasi and Venostent. G.L. is an employee and shareholder of AstraZeneca. E.W. is an employee and shareholder of AstraZeneca. A.-K.M. is an employee of AstraZeneca. M.S. is an employee and shareholder of AstraZeneca. M.T. is an employee and shareholder of AstraZeneca. D.C.W. reports honoraria and/or consultancy fees from Amgen, AstraZeneca (ongoing), Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Merck Sharp, Napp, and Dohme, Takeda, Vifor Fresenius, and Zydus. P.A. is an employee and shareholder of AstraZeneca.

Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
Effect of SGLT2is and ETA receptor antagonists in combination.
Figure 2:
Figure 2:
ZENITH-CKD study design. aFollowing an ad hoc safety review, a protocol amendment was implemented on 5 April 2022. Owing to the rate of fluid-retention events in the zibotentan 5 mg QD and the zibotentan 5 mg/dapagliflozin 10 mg QD groups, randomization to these groups was closed. DAPA, dapagliflozin; R, randomization; ZIBO, zibotentan.
See this image and copyright information in PMC

References

    1. Xie Y, Bowe B, Mokdad AH et al. Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney Int 2018;94:567–81. 10.1016/j.kint.2018.04.011 - DOI - PubMed
    1. Currie CJ, Berni ER, Berni TR et al. Major adverse cardiovascular events in people with chronic kidney disease in relation to disease severity and diabetes status. PLoS One 2019;14:e0221044. 10.1371/journal.pone.0221044 - DOI - PMC - PubMed
    1. Ali I, Chinnadurai R, Ibrahim ST et al. Adverse outcomes associated with rapid linear and non-linear patterns of chronic kidney disease progression. BMC Nephrol 2021;22:82. 10.1186/s12882-021-02282-5 - DOI - PMC - PubMed
    1. Evans M, Lewis RD, Morgan AR et al. A narrative review of chronic kidney disease in clinical practice: current challenges and future perspectives. Adv Ther 2022;39:33–43. 10.1007/s12325-021-01927-z - DOI - PMC - PubMed
    1. National Institute for Health and Care Excellence . Dapagliflozin for Treating Chronic Kidney Disease. Available from: www.nice.org.uk/guidance/ta775 (23 May 2022, date last accessed).

Publication types

Associated data

Grants and funding