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

Study principal inclusion criteria For both Part A and Part B

1. No current or prior (within 1 month of enrolment) medical treatment with an SGLT2inhibitor or ERAs.

2. On no or a stable dose of beta blockers, with no major dose changes within 1 monthprior to the first dose of study intervention.

3. Provision of signed and dated, written ICF prior to any mandatory study-specificprocedures, sampling, and analyses.

4. Female participants of non-childbearing potential confirmed at screening byfulfilling one of the following criteria:

5. Post-menopausal: defined as amenorrhoea for at least 12 months or morefollowing cessation of all exogenous hormonal treatments; and also, FSH levelsin the post-menopausal range by central laboratory.

6. Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy or bilateral salpingectomy but not tubal ligation.

7. Female participants must have a negative pregnancy test at screening and must not belactating

Part A participants who have the following:

1. Clinical and/or histological diagnosis of cirrhosis with either (i) features ofportal 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 (eg, no clinically significant changein signs, symptoms, or laboratory parameters of hepatic disease status) within thelast month prior to dosing, as determined by the investigator or usual practitioner.

6. HVPG recording of good enough quality as judged by a central reader.

Part B participants who have the following:

1. Clinical and/or histological diagnosis of cirrhosis and either history ofdecompensation or compensated cirrhosis with signs of clinically significant portalhypertension.

2. HVPG recording of good enough quality and HVPG > 10 mmHg, as judged by a centralreader.

3. MELD score < 15.

4. Child-Pugh score < 10.

5. No ascites or ascites up to grade 2 without change in diuretic treatment within thelast month prior to first dose and no paracentesis within the last month or plannedparacentesis in the next 4 months at screening.

6. No evidence of worsening of hepatic function (eg, no clinically significant changein signs, symptoms, or laboratory parameters of hepatic disease status) within thelast month prior to dosing, as determined by the investigator or usual practitioner.

Study principal exclusion criteria:

1. Any evidence of a clinically significant disease which in the investigator's opinionmakes 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 lessthan 1 year.

9. Participants with T1DM.

Medical Conditions (Part A only)

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 tohyperthyroidism or Paget's disease)

Medical Conditions (Part B only)

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 within 6 months prior toscreening.

6. History of variceal haemorrhage within 6 months prior to screening.

7. NYHA functional heart failure class III or IV or with unstable heart failurerequiring hospitalisation for optimisation of heart failure treatment and who arenot yet stable on heart failure therapy within 6 months prior to screening.

8. Heart failure due to cardiomyopathies that would primarily require specific othertreatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or otherinfiltrative diseases, cardiomyopathy related to congenital heart disease, primaryhypertrophic 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 functionalmitral or tricuspid valve insufficiency, or planned cardiac valverepair/replacement.