Study to Investigate Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin in Participants With Chronic Kidney Disease and High Proteinuria (ZENITH High Proteinuria)

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Status and phase

Phase 3


Chronic Kidney Disease With High Proteinuria


Drug: Zibotentan/Dapagliflozin
Drug: Dapagliflozin

Study type


Funder types




Details and patient eligibility


This is a Phase III, randomised, multicentre, double-blinded study to evaluate efficacy, safety and tolerability of treatment with zibotentan/dapagliflozin and dapagliflozin alone in participants with chronic kidney disease (CKD) and high proteinuria.


1,500 estimated patients




18 to 95 years old


No Healthy Volunteers

Inclusion criteria

  • Participant must be ≥ 18 years of age and of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent.
  • Diagnosis of CKD, defined as eGFR ≥ 20 and < 90 mL/min/1.73 m2 and UACR > 700 mg/g (> 79 mg/mmol) or UPCR > 1000 mg/g (> 113 mg/mmoL).
  • All female participants must have a negative serum pregnancy test result at screening.

Female participants must be either

  • not of child-bearing potential or
  • women of child bearing potential (WOCBP) using at least one highly effective birth control method for at least 3 months prior to first dose of study intervention
  • Capable of giving signed informed consent
  • Provision of signed informed consent prior to any study specific procedure.
  • Provision of electronic informed consent prior to completion of the optional Study Participant Feedback Questionnaire (SPFQ).
  • Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics imitative research that supports the Genomic Initiative.
  • Receiving RAASi therapy (ACEi or ARB), and for the patient maximum tolerated labelled daily dose, that has been stable for at least 4 weeks.

Exclusion criteria

  • Participants with NYHA class III or class IV Congestive HF at the time of enrolment.
  • Participants hospitalised for HF during the last 6 month prior to screening.
  • Evidence of rales or jugular venous distention on physical examination.
  • Participants with type 1 diabetes mellitus.
  • History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).
  • Blood pressure above 160 mmHg systolic.
  • Blood pressure below 90 mmHg systolic.
  • Participants hospitalised for heart disease or cardiac procedures or for COVID-19 during the last 3 months prior to screening.
  • History of solid organ transplantation or bone marrow transplant.
  • History or ongoing allergy/hypersensitivity, as judged by the Investigator, to SGLT2i therapy (eg, dapagliflozin, canagliflozin, empagliflozin or other SGLT2 inhibitors) or Endothelin Receptor Antagonists (eg, ambrisentan, atrasentan, bosentan, or other).
  • Any condition with a life expectancy of less than 2 years based on investigator´s clinical judgment.
  • Malignancy within the past 5 years. Exceptions to this criterion include non-melanoma skin cancer and curatively treated cervical carcinoma in situ.
  • Significant liver disease as judged by the investigator or severe hepatic impairment with AST or ALT > 3 × ULN; or total bilirubin > 2 × ULN at time of screening. An isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion.
  • Known blood-borne diseases.
  • Clinically significant, unstable, or uncontrolled medical condition as assessed by the Investigator.
  • Participants on renal replacement therapy or previous kidney transplant.
  • Known history of drug or alcohol abuse within 12 months of screening.
  • Participants on treatment with strong or moderate CYP3A4 inducer.
  • Participants on systemic immunosuppression therapy other than stable maintenance therapy defined as prednisone 10 mg/day (or equivalent) or less, aziothioprine 100 mg/day or less; MMF 1000 mg/day or less for at least 3 months prior to Visit 1. Inhaled, nasal or dermatological steroids are also allowed.
  • Participants treated or expecting to be treated with tolvaptan, any other ERAs, or budesonide (where used to treat IBD or IgAN).
  • Participation in another clinical study with a study intervention administered in the last 3 months.

Trial design

Primary purpose




Interventional model

Parallel Assignment


Quadruple Blind

1,500 participants in 2 patient groups

Zibotentan/Dapagliflozin dose A or Zibotentan/Dapagliflozin dose B
Experimental group
Drug dose (dose A or B) are determined based on eGFR values. Participants will receive daily oral dose of zibotentan/dapagliflozin in fixed dose combination.
Drug: Zibotentan/Dapagliflozin
Dapagliflozin alone
Active Comparator group
Participants will receive daily oral dose of dapagliflozin.
Drug: Dapagliflozin

Trial contacts and locations



Central trial contact

AstraZeneca Clinical Study Information Center

Data sourced from

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