This is a Phase IIb multicentre, randomised, double-blind, parallel-group, placebo-controlled study to evaluate the safety of zibotentan/dapagliflozin in combination as compared to zibotentan monotherapy as well as zibotentan/dapagliflozin and zibotentan monotherapy as compared to placebo in patients with cirrhosis.

The study is designed to evaluate the safety of zibotentan/dapagliflozin in combination as compared to zibotentan monotherapy as well as zibotentan/dapagliflozin in combination and zibotentan monotherapy as compared to placebo in patients with cirrhosis with or without a history of decompensation. The study will be conducted in approximately 52 study centers in North America, Asia and Europe.

Inclusion Criteria:

≥ 18 and ≤ 80 years of age at the time of signing the informed consent.

Clinical and/or histological diagnosis of cirrhosis.

Note: Either history of decompensation or compensated cirrhosis with signs of CSPH, including varices at endoscopy or collaterals at imaging (within 12 months prior to screening), and/or liver stiffness using vibration controlled elastography, liver stiffness > 25 kPa or > 21 kPa, and platelets < 150 × 10^99 (at time of screening).

Model for end stage liver disease score (MELD) < 15.

Child-Pugh score < 10.

No ascites or ascites up to grade 2 without change in diuretic treatment within the last month prior to first dose of study intervention and no paracentesis within the last month.

No evidence of worsening of hepatic function (eg, 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.

No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or endothelin receptor antagonist.

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.

Males or females of non-childbearing potential:

Male participants must be surgically sterile, abstinent, or must use in conjunction with their female partner a highly effective method of contraception from the time they sign the informed consent document and for 3 months after the last dose of study intervention to prevent pregnancy in a partner. In addition, the male participant should use a condom for the duration of the study and for 3 months after the last dose of study intervention. Male participants must not donate or bank sperm during the same period.

Highly effective birth control methods are defined as those that can achieve a failure rate of less than 1% per year when used consistently and correctly.

Female participants must be of non-childbearing potential confirmed at screening by fulfilling one of the following criteria:

Post-menopausal: defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments; and also FSH levels in the post-menopausal range by central laboratory (Note: The post-menopausal range must be checked against the specific FSH assay used). In the absence of 12 months of amenorrhoea, a single FSH measurement is insufficient to define post-menopausal criteria. In case of perimenopause or infrequent periods with variable levels of FSH, women should be considered of childbearing potential and, therefore, not eligible for participation in this study.

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

Female participants must have a negative pregnancy test at screening and must not be lactating.

Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

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

Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports Genomic Initiative.

Exclusion criteria:

Any evidence of a clinically significant disease, which in the investigator's opinion makes it undesirable for the participant to participate in the study.

Alanine aminotransferase/transaminase or AST ≥ 150 U/L and/or total bilirubin

≥ 3 × ULN.

International normalised ratio > 1.7.

Serum/plasma levels of albumin ≤ 28 g/L.

Platelet count < 50 × 109L.

Acute kidney injury (AKI) within 3 months of screening.

History of encephalopathy of West Haven Grade 2 or higher

History of variceal haemorrhage within 6 months prior to screening.

Any history of hepatocellular carcinoma.

Any history of portal venous thrombosis.

Liver transplant or expected liver transplantation within 6 months of screening.

History of TIPS or a planned TIPS within 6 months from enrolment into the study.

Positive alcohol breath test or screen for drugs of abuse (excluding drugs prescribed by the participants' usual physician) at screening.

Ongoing or history of significant use of alcohol expected to preclude correct adherence to study procedures (For details, refer to Section 5.3.2).

Active treatment for HCV within the last 1 year or HBV anti-viral therapy for less than 1 year.

Active urinary tract infection or genital infection.

Uncontrolled diabetes mellitus (HbA1c > 8.5% or > 69 mmol/mol within the last month).

Participants with T1DM.

Renal transplant or chronic renal replacement therapy or short-term dialysis within the previous 6 months.

eGFR < 60 mL/min/1.73m2 (eGFRcr[AS]).

Acute coronary syndrome events within 3 months prior to screening.

Orthostatic hypotension or hypotension (systolic blood pressure < 95 mmHg or diastolic blood pressure < 60 mmHg).

New York Heart Association functional heart failure Class III or IV or patients 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.

Heart failure due to cardiomyopathies that would primarily require specific other treatment.

High output heart failure (eg, due to hyperthyroidism or Paget's disease).

Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.

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.

History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin), zibotentan, or drugs with a similar chemical structure to zibotentan.

Any clinically significant chronic disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) which, as judged by the investigator, might put the participant at risk because of participation in the study, or probable alternative primary reason for participant's symptoms in judgment of investigator.

Acute liver injury caused by drug toxicity or by an infection.

Implanted electronic device such as pacemaker.

Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study centre).

Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

Male participant in a sexually active relation with pregnant or breastfeeding partner.

Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Exclusion Criteria for Participants Consenting to Optional Genetic Sampling:

Previous allogeneic bone marrow transplant.

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal

Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

"Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.