Zibotentan and Dapagliflozin Combination, EvAluated in Liver Cirrhosis (ZEAL Study)

Eligibility Criteria

• 1. Any evidence of a clinically significant disease which in the investigator's opinion makes it undesirable for the participant to participate in the study.
• 2. Liver cirrhosis caused by chronic cholestatic liver disease
• 3. ALT or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN
• 4. Acute liver injury caused by drug toxicity or by an infection.
• 5. Any history of hepatocellular carcinoma.
• 6. Liver transplant or expected liver transplantation within 6 months of screening.
• 7. History of TIPS or a planned TIPS within 6 months from enrolment into the study.
• 8. Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year.
• 9. Participants with T1DM.
• 1. INR \> 1.5.
• 2. Serum/plasma levels of albumin ≤ 35 g/L.
• 3. Platelet count \< 75 × 109/L.
• 4. History of ascites
• 5. History of hepatic hydrothorax
• 6. History of portopulmonary syndrome
• 7. History of hepatic encephalopathy
• 8. History of variceal haemorrhage
• 9. History of acute kidney injury
• 10. History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget's disease)
• 1. INR \> 1.7.
• 2. Serum/plasma levels of albumin ≤ 28 g/L.
• 3. Platelet count \< 50 × /109L.
• 4. Acute kidney injury within 3 months of screening.
• 5. History of encephalopathy of West Haven grade 2 or higher.
• 6. History of variceal haemorrhage within 6 months prior to screening.
• 7. NYHA functional heart failure class III or IV or with unstable heart failure requiring hospitalisation for optimisation of heart failure treatment and who are not yet stable on heart failure therapy within 6 months prior to screening.
• 8. Heart failure due to cardiomyopathies that would primarily require specific other treatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or other infiltrative diseases, cardiomyopathy related to congenital heart disease, primary hypertrophic cardiomyopathy, cardiomyopathy related to toxic or infective conditions (ie, chemotherapy, infective myocarditis, septic cardiomyopathy).
• 9. High output heart failure (eg, due to hyperthyroidism or Paget's disease).
• 10. Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.