A Study to Investigate the Effects of Zibotentan/Dapagliflozin Combination Compared to Dapagliflozin Alone in Adult Participants With Chronic Kidney Disease and High Proteinuria

Inclusion criteria

• ≥ 18 years of age at the time of signing the informed consent.
• Diagnosis of CKD with eGFR ≥ 20 and \< 90 mL/min/1.73m2 AND UACR \> 700 mg/g (\> 79 mg/mmol) or UPCR \> 1000 mg/g (\> 113 mg/mmol).
• Body mass index (BMI) within the range ≤40 kg/m2.
• Female participants must be either - not of child-bearing potential or - women of childbearing potential (WOCBP) using at least one highly effective birth control method for at least 3 months prior to first dose of study intervention.
• All WOCBP must have a negative serum pregnancy test result at screening.
• 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

• Clinically significant, unstable, or uncontrolled medical condition which in the Investigator's opinion makes it undesirable for the participant to participate in the study.
• Known hypersensitivity to dapagliflozin or zibotentan or any of the excipients of the investigational product. History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i therapy or ERAs.
• NYHA class III or class IV HF.
• Participants hospitalised for HF and/or who have not been stable on HF therapy during the last 6 months prior to screening.
• HF due to cardiomyopathies that would primarily require other specific treatment.
• High output HF (eg, due to hyperthyroidism or Paget's disease).
• HF due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
• Evidence of rales or jugular venous distention on physical examination.
• Type 1 diabetes mellitus.
• History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).
• 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.
• Any condition with a life expectancy of less than 1 year 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.
• Renal replacement therapy or previous kidney transplant.
• Known history of significant drug or alcohol abuse within 12 months of screening.
• On treatment with strong or moderate CYP3A4 inducer.
• On systemic immunosuppression therapy other than prespecified stable maintenance therapy.
• Participants treated or expecting to be treated with tolvaptan (including as part of participation in a clinical trial), any other ERAs, or budesonide (where used to treat IBD or IgAN).
• Systolic blood pressure above 160 mmHg and/or below 90 mmHg.
• Significant impairment of liver function defined as AST or ALT \>3 x upper limit of normal (ULN) or Total serum bilirubin \>2 x ULN (an isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion).
• NT-proBNP ≥ 600 pg/mL (or NT-proBNP ≥ 1200 pg/mL, if associated with atrial fibrillation) measured by local laboratory at screening.
• Any of the following results of echocardiography at screening:
• left ventricular ejection fraction (LVEF) \< 50%
• significant ventricular wall motion abnormality or severe cardiac valve abnormalities
• isolated pulmonary arterial hypertension (as defined by local clinical practice) or right ventricular failure; in the absence of left-sided HF
• Women who are pregnant, breast-feeding, or women with intent of getting pregnant.
• Women who are not willing to use adequate contraception or cannot, in the opinion of the Investigator, understand and/or comply with the study requirements regarding contraception.