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

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 - ZEAL

Status

Active, not recruiting

Phases

Phase 2

Study type

Interventional

Source

EU CTR

Registry ID

EUCTR2021-006577-30-AT

Enrollment

140

Registered

2022-07-12

Start date

2022-11-04

Completion date

Unknown

Last updated

2024-03-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Liver cirrhosis with features of portal hypertension. MedDRA version: 20.0 Level: LLT Classification code 10024667 Term: Liver cirrhosis System Organ Class: 100000004871

Interventions

Trade Name: Forxiga Product Name: Dapagliflozin Pharmaceutical Form: Film-coated tablet INN or Proposed INN: Dapagliflozin propanediol CAS Number: 960404-48-2 Current Sponsor code: Dapagliflozin propa

Eligibility

Sex/Gender

All

Inclusion criteria

Inclusion criteria: Study principal inclusion criteria: Participant must be aged 18 years and = 80 years of age at the time of signing the informed consent. Part A participants who have the following: (a) Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness = 21 kPa. (b) MELD score =65 years) yes F.1.3.1 Number of subjects for this age range 40

Exclusion criteria

Exclusion criteria: Study principal exclusion criteria: a) Any evidence of a clinically significant disease which in the investigator’s opinion makes it undesirable for the participant to participate in the study. b) Liver cirrhosis caused by chronic cholestatic liver disease c) ALT or AST = 150 U/L and/or total bilirubin = 3 × ULN d) Acute liver injury caused by drug toxicity or by an infection. e) Any history of hepatocellular carcinoma. f) Liver transplant or expected liver transplantation within 6 months of screening. g) History of TIPS or a planned TIPS within 6 months from enrolment into the study. h) Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year. i) Participants with T1DM. Medical Conditions (Part A only) a) INR > 1.5. b) Serum/plasma levels of albumin = 35 g/L. c) Platelet count 1.7. b) Serum/plasma levels of albumin = 28 g/L. c) Platelet count < 50 × /109L. d) Acute kidney injury within 3 months of screening. e) History of encephalopathy of West Haven grade 2 or higher. f) History of variceal haemorrhage within 6 months prior to screening. g) 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. h) 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). i) High output heart failure (eg, due to hyperthyroidism or Paget’s disease). j) Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.

Design outcomes

Primary

Measure	Time frame
Main Objective: Part A main objective: To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo. Part B main 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 Objective: Part A secondary objectives- to evaluate: •the change from baseline in HVPG • the proportion of participants achieving HVPG < 10 mmHg or a reduction in HVPG of = 1.5 mmHg •the effect on change in body weight •the effect on accumulated additional loop-diuretic equivalents use •the effect on body water volumes and body fat mass •the effect on changes in office-based systolic and diastolic blood pressure Of zibotentan and dapagliflozin in combination versus placebo Part B secondary objectives- to evaluate: •the change from baseline in HVPG •the effect on change in body weight •the effect on accumulated additional loop-diuretic equivalents use •the effect on body water volumes and body fat mass •the effect on changes in office-based systolic and diastolic blood pressure Of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.;Primary end point(s): Part A Primary End Point: Absolute change in HVPG from baseline to Week 6. Part B Primary End Point: HVPG response, where a responder is defined as at least 20% decrease or a reduction to or below 12 mmHg in HVPG from baseline to Week 6.;Timepoint(s) of evaluation of this end point: Part A Primary End Point Week 6 Part B Primary End Point: Week 6	—

Measure

Time frame

Main Objective: Part A main objective: To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo. Part B main 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 Objective: Part A secondary objectives- to evaluate: •the change from baseline in HVPG • the proportion of participants achieving HVPG < 10 mmHg or a reduction in HVPG of = 1.5 mmHg •the effect on change in body weight •the effect on accumulated additional loop-diuretic equivalents use •the effect on body water volumes and body fat mass •the effect on changes in office-based systolic and diastolic blood pressure Of zibotentan and dapagliflozin in combination versus placebo Part B secondary objectives- to evaluate: •the change from baseline in HVPG •the effect on change in body weight •the effect on accumulated additional loop-diuretic equivalents use •the effect on body water volumes and body fat mass •the effect on changes in office-based systolic and diastolic blood pressure Of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.;Primary end point(s): Part A Primary End Point: Absolute change in HVPG from baseline to Week 6. Part B Primary End Point: HVPG response, where a responder is defined as at least 20% decrease or a reduction to or below 12 mmHg in HVPG from baseline to Week 6.;Timepoint(s) of evaluation of this end point: Part A Primary End Point Week 6 Part B Primary End Point: Week 6

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Secondary

Measure	Time frame
Secondary end point(s): Part A Secondary End Points: 1 Percent change in HVPG from baseline to Week 6. 2 HVPG response, where a responder is defined as HVPG < 10 mmHg or a reduction in HVPG of = 1.5 mmHg from baseline to Week 6. 3 Evaluation of change in body weight (kg) over time course of study (Home-based balance) Percentage and absolute change from baseline in body weight at Week 6. (Office balance) 4 Percentage and absolute change in accumulated dosage of loop-diuretic equivalents use from baseline to Week 6. 5 Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6. Change in total body fat mass from baseline to Week 6. 6 Change in systolic and diastolic blood pressure from baseline to Week 6. Part B Secondary End Points: 1 Percentage and absolute change in HVPG from baseline to Week 6. 2 Evaluation of change in body weight (kg) over time course of study. (Home-based balance) Percentage and absolute change from baseline in body weight at Week 6 and Week 16. (Office balance) 3 Percentage and absolute change in accumulated dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16. 4 Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6 and Week 16. Change in total body fat mass from baseline to Week 6 and Week 16 5 Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16.;Timepoint(s) of evaluation of this end point: Part A Secondary End Points: 1 Week 6 2 Week 6 3 Week 6 4 Week 6 5 Week 6 6 Week 6 Part B Secondary End Points: 1 Week 6 2 Week 6 and Week 16 3 Week 6 and Week 16 4 Week 6 and Week 16 5 Week 6 and Week 16	—

Measure

Time frame

Secondary end point(s): Part A Secondary End Points: 1 Percent change in HVPG from baseline to Week 6. 2 HVPG response, where a responder is defined as HVPG < 10 mmHg or a reduction in HVPG of = 1.5 mmHg from baseline to Week 6. 3 Evaluation of change in body weight (kg) over time course of study (Home-based balance) Percentage and absolute change from baseline in body weight at Week 6. (Office balance) 4 Percentage and absolute change in accumulated dosage of loop-diuretic equivalents use from baseline to Week 6. 5 Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6. Change in total body fat mass from baseline to Week 6. 6 Change in systolic and diastolic blood pressure from baseline to Week 6. Part B Secondary End Points: 1 Percentage and absolute change in HVPG from baseline to Week 6. 2 Evaluation of change in body weight (kg) over time course of study. (Home-based balance) Percentage and absolute change from baseline in body weight at Week 6 and Week 16. (Office balance) 3 Percentage and absolute change in accumulated dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16. 4 Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6 and Week 16. Change in total body fat mass from baseline to Week 6 and Week 16 5 Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16.;Timepoint(s) of evaluation of this end point: Part A Secondary End Points: 1 Week 6 2 Week 6 3 Week 6 4 Week 6 5 Week 6 6 Week 6 Part B Secondary End Points: 1 Week 6 2 Week 6 and Week 16 3 Week 6 and Week 16 4 Week 6 and Week 16 5 Week 6 and Week 16

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Countries

Austria, Belgium, Denmark, Germany, Netherlands, Spain, Switzerland, United States

Contacts

Public ContactClinical Study Information Center

AstraZeneca

information.center@astrazeneca.com

Outcome results

None listed

Source: EU CTR (via WHO ICTRP) · Data processed: Feb 4, 2026