Clinical Research Studies

Are you eligible to participate in this study?

You may be eligible for this study if you meet the following criteria:

• Conditions:
  Liver Cirrhosis
  Portal Hypertension
• Age: Between 18 Year(s) - 80 Year(s)
• Gender: Male or Female

• Other Inclusion Criteria:
  

  Part A Inclusion Criteria:

  1. Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness = 21 kPa.
  2. MELD score < 15.
  3. Child-Pugh score = 6.
  4. No clinically evident ascites
  5. No evidence of worsening of hepatic function (e.g., no clinically significant change in signs, symptoms, or laboratory parameters of hepatic disease status) within the last month prior to dosing, as determined by the investigator or usual practitioner.
  6. No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or ERAs.
  7. On no or a stable dose of beta blockers, with no major dose changes within 1 month prior to the first dose of study intervention.
  8. Must agree to sex and contraceptive/barrier requirements

  Part B Inclusion Criteria:

  1. Clinical and/or histological diagnosis of cirrhosis with features of portal hypertension.
  2. MELD score < 15.
  3. Child-Pugh score < 10.
  4. No ascites or ascites up to grade 2 without change in diuretic treatment within the last month prior to first dose and no paracentesis within the last month or planned paracentesis in the next 4 months at screening.
  5. No evidence of worsening of hepatic function (e.g., no clinically significant change in signs, symptoms, or laboratory parameters of hepatic disease status) within the last month prior to dosing, as determined by the investigator or usual practitioner.
  6. No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or ERAs.
  7. On no or a stable dose of beta blockers, with no major dose changes within 1 month prior to the first dose of study intervention.
  8. Must agree to sex and contraceptive/barrier requirements

  
  

You may not be eligible for this study if the following are true:

• Exclusion Criteria (all participants):

  1. Liver cirrhosis caused by chronic cholestatic liver disease.
  2. Any history of hepatocellular carcinoma.
  3. Any history of portal venous thrombosis.
  4. Liver transplant or expected liver transplantation within 6 months of screening.
  5. History of TIPS or a planned TIPS within 6 months from enrolment into the study.
  6. Positive alcohol breath test or screen for drugs of abuse (excluding drugs prescribed by the participants’ usual physician) at screening.
  7. Ongoing or history of significant use of alcohol expected to preclude correct adherence to study procedures.
  8. Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year.
  9. Active urinary tract infection or genital infection
  10. Uncontrolled diabetes mellitus (HbA1c > 8% or >64 mmol/mol within the last month).
  11. Participants with T1DM.
  12. Renal transplant or chronic renal replacement therapy or short-term dialysis within the previous 6 months.
  13. Acute coronary syndrome events within 3 months prior to screening.
  14. Orthostatic hypotension or hypotension (systolic blood pressure < 95 mmHg or diastolic blood pressure < 60 mmHg).
  15. Participants treated with strong CYP3A4 inhibitor or strong or moderate CYP3A4 inducer within 14 days (St. John’s Wort 21 days) of study intervention administration; this includes grapefruit and grapefruit juice, if consumed more often than occasionally, or, in larger quantities.
  16. History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (e.g., dapagliflozin, empagliflozin), zibotentan, or drugs with a similar chemical structure to zibotentan.
  17. Any clinically significant chronic disease or disorder (e.g., cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) such as:
      1. Anaemia defined as haemoglobin (Hb) levels < 100 g/L or 10 g/dL.
      2. Wernicke’s encephalopathy or Korsakoff’s syndrome.
      3. History of HIV.
  18. Any of the following regarding COVID-19:
      1. Symptoms of COVID-19 infection or a recent positive test in the 14 days prior to enrolment in the study.
      2. Participants hospitalised with COVID-19 infection within the last 3 months who required in-hospital medical care (oxygen therapy, mechanical ventilation, intensive care unit admission, etc.).
  19. Acute liver injury caused by drug toxicity or by an infection.
  20. Participation in another clinical study with an investigational product administered in the last 3 months prior to randomisation.
  21. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study centre).
  22. Male participant in a sexually active relation with pregnant or breastfeeding partner.
  23. Hypersensitivity to contrast agents.
  24. Vulnerable participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

  Exclusion Criteria (Part A only)

  1. History of ascites
  2. History of hepatic hydrothorax
  3. History of portopulmonary syndrome
  4. History of hepatic encephalopathy
  5. History of variceal haemorrhage
  6. History of acute kidney injury
  7. History of heart failure, including high output heart failure (e.g., due to hyperthyroidism or Paget’s disease)

  Exclusion Criteria (Part B only)

  1. Acute kidney injury within 3 months of screening.
  2. History of encephalopathy of West Haven grade 2 or higher.
  3. History of variceal haemorrhage within 6 months prior to screening.
  4. 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.
  5. Heart failure due to cardiomyopathies that would primarily require specific other treatment: e.g., 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 (i.e., chemotherapy, infective myocarditis, septic cardiomyopathy).
  6. High output heart failure (e.g., due to hyperthyroidism or Paget’s disease).
  7. Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.