A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK

Exclusion Criteria

• •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.
• •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.
• •Previous allogeneic bone marrow transplant.
• •Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.