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

Phase 2

Active, not recruiting

• Conditions: Liver Cirrhosis

• Registration Number: NCT05516498
• Lead Sponsor: AstraZeneca

Brief Summary

This is a two part Phase IIa/b multicentre, randomised, double-blind, placebo-controlled, parallel group dose-ranging study to assess the 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.

Detailed Description

Part A will assess the efficacy, safety, and tolerability of the combination of B mg zibotentan and 10 mg dapagliflozin versus placebo in participants with Child-Pugh A cirrhosis with features of portal hypertension and with no history of decompensation events.

If the safety profile is determined to be acceptable at the conclusion of Part A, Part B will investigate efficacy, safety, and tolerability of A mg, B mg, or C mg zibotentan combined with 10 mg dapagliflozin and of 10 mg dapagliflozin monotherapy versus placebo in participants with cirrhosis with features of portal hypertension. Part B will include a broader range of Child- Pugh A and Child-Pugh B cirrhosis participants, including those with more severe disease, a history of decompensation events, or current ascites.

The study will be conducted in approximately 30 to 45 study centres in North America, Asia, and Europe.

Study Timeline

• Study First Submitted: 2022-08-24
• Study First Submitted QC: 2022-08-24
• Study First Posted: 2022-08-25
• Study Start: 2022-10-31
• Primary Completion: 2025-05-22
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-03
• Last Update Posted: 2025-06-04
• Study Completion: 2025-08-15

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 205

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Part B: Absolute change in HVPG from baseline to Week 6.	at Week 6	To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
Part A: Absolute change in HVPG from baseline to Week 6.	at Week 6	To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo.

Secondary Outcome Measures

Name	Time	Method
Part A: Percent change in HVPG from baseline to Week 6.	at Week 6	To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo.
Part B: Absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16.	at Week 6 and Week 16	To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on total loop-diuretic equivalents use.
Part A: Evaluation of change in body weight (kg) over time course of study. Percentage and absolute change from baseline in body weight at Week 6.	at Week 6	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on change in body weight.
Part A: Percentage and absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6.	at Week 6	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on total loop-diuretic equivalents use.
Part A: 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.	at Week 6	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on body water volumes and body fat mass.
Part A: Change in systolic and diastolic blood pressure from baseline to Week 6.	at Week 6	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on changes in office-based systolic and diastolic blood pressure.
Part A: 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.	at Week 6	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.
Part B: Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16.	at Week 6 and Week 16	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.
Part B: Percentage change in HVPG from baseline to Week 6.	at Week 6	To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
Part B: Evaluation of change in body weight (kg) over time course of study. Percentage and absolute change from baseline in body weight at Week 6 and Week 16.	at Week 6 and Week 16	To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on change in body weight.
Part B: 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.	at Week 6	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.
Part B: 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.	at Week 6 and Week 16	To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on body water volumes and body fat mass.

Trial Locations

Locations (1)

Research Site; 🇬🇧 London, United Kingdom