AstraZeneca_Zibotentan and Dapagliflozin combination, EvAluated in Liver cirrhosis (ZEAL study)

Summary

Part A Objectives Primary Objective: To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo. Secondary Objectives: - To evaluate the proportion of participants achieving HVPG < 10 mmHg or a reduction in HVPG of ? 1.5 mmHg on zibotentan and dapagliflozin versus placebo. - To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on change in body weight. - To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on accumulated additional loop-diuretic equivalents use. - To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on body water volumes and body fat mass. - in combination versus placebo on changes in office-based systolic and diastolic blood pressure. Safety Objective: To assess the safety and tolerability of zibotentan and dapagliflozin in combination versus placebo. Part B Objectives Primary Objective: To evaluate the proportion of participants achieving at least 20% decrease in HVPG or a reduction to or below 12 mmHg in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo. Secondary Objectives: - To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo. - To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on change in body weight. - To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on accumulated additional loop-diuretic equivalents use. - To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on body water volumes and body fat mass. - To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on changes in office-based systolic and diastolic blood pressure. Safety Objective: To assess the safety and tolerability of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.

Inclusion Criteria

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

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.
Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
Female participants 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 FSH levels in the post-menopausal range.
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 randomisation and must not be lactating
Part A participants who have the following:
Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness ≥ 21 kPa.
MELD score < 15.
Child-Pugh score ≤ 6.
No clinically evident ascites
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.
HVPG recording of good enough quality as judged by a central reader.
Part B participants who have the following:
Clinical and/or histological diagnosis of cirrhosis with features of portal hypertension.
MELD score < 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 and no paracentesis within the last month or planned paracentesis in the next 4 months at screening.
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.
HVPG recording of good enough quality as judged by a central reader.
Any evidence of a clinically significant disease which in the investigator's opinion makes it undesirable for the participant to participate in the study.
Liver cirrhosis caused by chronic cholestatic liver disease
ALT or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN
Acute liver injury caused by drug toxicity or by an infection.
Any history of hepatocellular carcinoma.
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.
Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year.
Participants with T1DM.
Medical Conditions (Part A only)
INR > 1.5.
Serum/plasma levels of albumin ≤ 35 g/L.
Platelet count < 75 × 109/L.
History of ascites
History of hepatic hydrothorax
History of portopulmonary syndrome
History of hepatic encephalopathy
History of variceal haemorrhage
History of acute kidney injury
History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget's disease)
Medical Conditions (Part B only)
INR > 1.7.
Serum/plasma levels of albumin ≤ 28 g/L.
Platelet count < 50 × /109L.
Acute kidney injury 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.
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.
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).
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.

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Study Location(s)

Beverly

More about this Clinical Trial

Full Title

A Two Part Phase IIa/b Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Dose-ranging Study to Assess Efficacy, Safety, and Tolerability of the Combination of Zibotentan and Dapagliflozin, and Dapagliflozin Monotherapy Versus Placebo in Participants with Cirrhosis with Features of Portal Hypertension

Details

Disease Type/Condition

Other

Principal Investigator

Kuo, Alexander

Co-Investigators

Ju Dong Yang, Walid Ayoub

Age Group

Adult

Phase

IRB Number

STUDY00002494