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

NCT05516498 | Terminated Phase 2 DMC FDA Drug

• 2 other identifiers: D4326C000032021-006577-30
• Study Type: interventional
• Target: 205
• Locations: 14 countries
• Sites: 49

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.

Conditions

Liver Cirrhosis

Outcome Measures

Primary Outcomes (2)

• Part A: Absolute change in HVPG from baseline to Week 6.

  To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo.

  at Week 6

• Part B: Absolute change in HVPG from baseline to Week 6.

  To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.

  at Week 6

Secondary Outcomes (12)

• Part A: Percent change in HVPG from baseline to Week 6.

  at Week 6

• 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

• 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

• Part A: Percentage and absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6.

  at Week 6

• 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

Study Arms (7)

Part A: Treatment Group 1

EXPERIMENTAL

Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks.

Drug: Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)

Part A: Treatment Group 2

EXPERIMENTAL

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 6 weeks.

Drug: Part A: zibotentan (dose B) + dapagliflozin

Part B: Treatment Group 1

EXPERIMENTAL

Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 16 weeks.

Drug: Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)

Part B: Treatment Group 2

EXPERIMENTAL

Participants will receive once daily dose of placebo matching zibotentan capsule + dapagliflozin tablet for 16 weeks.

Drug: Part B: placebo (matching zibotentan capsule) + dapagliflozin

Part B: Treatment Group 3

EXPERIMENTAL

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Drug: Part B: zibotentan (dose A) + dapagliflozin

Part B: Treatment Group 4

EXPERIMENTAL

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Drug: Part B: zibotentan (dose B) + dapagliflozin

Part B: Treatment Group 5

EXPERIMENTAL

Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Drug: Part B: zibotentan (dose C) + dapagliflozin

Interventions

Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet) DRUG

placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)

Part A: Treatment Group 1

Part A: zibotentan (dose B) + dapagliflozin DRUG

zibotentan capsule dapagliflozin tablet

Part A: Treatment Group 2

Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet) DRUG

placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)

Part B: Treatment Group 1

Part B: placebo (matching zibotentan capsule) + dapagliflozin DRUG

placebo capsule (matching zibotentan capsule) dapagliflozin tablet

Part B: Treatment Group 2

Part B: zibotentan (dose A) + dapagliflozin DRUG

zibotentan capsule dapagliflozin tablet

Part B: Treatment Group 3

Part B: zibotentan (dose B) + dapagliflozin DRUG

zibotentan capsule dapagliflozin tablet

Part B: Treatment Group 4

Part B: zibotentan (dose C) + dapagliflozin DRUG

zibotentan capsule dapagliflozin tablet

Part B: Treatment Group 5

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or ERAs.
• 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 also, FSH levels in the post-menopausal range by central laboratory.
• 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
• 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:

You may not qualify if:

• 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (50)

Research Site

Birmingham, Alabama, 35233, United States

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Pasadena, California, 91105, United States

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San Francisco, California, 94115, United States

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West Hollywood, California, 90048, United States

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Rochester, Minnesota, 55905, United States

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The Bronx, New York, 10467, United States

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Charleston, South Carolina, 29425, United States

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Dallas, Texas, 75246, United States

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Charlottesville, Virginia, 22903, United States

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Richmond, Virginia, 23249, United States

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Milwaukee, Wisconsin, 53226, United States

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Heidelberg, 3084, Australia

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Vienna, 1090, Austria

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Edegem, 2650, Belgium

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Beijing, 100057, China

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Chengdu, 610000, China

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Guangzhou, 510515, China

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Hangzhou, 310000, China

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Prague, 128 00, Czechia

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Prague, 169 02, Czechia

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Aarhus N, 8200, Denmark

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Esbjerg, 6700, Denmark

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Hvidovre, 2650, Denmark

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Køge, 4600, Denmark

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Angers, 49933, France

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Clichy, 92110, France

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Paris, 75651, France

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Toulouse, 31059, France

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Dresden, 01307, Germany

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Landshut, 84034, Germany

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Mainz, 55131, Germany

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Münster, 48149, Germany

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Wiesbaden, 65189, Germany

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Amsterdam, 1081 HV, Netherlands

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Cluj-Napoca, 400162, Romania

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Barcelona, 08035, Spain

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Barcelona, 08036, Spain

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Barcelona, 08041, Spain

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Madrid, 28007, Spain

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Madrid, 28034, Spain

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Majadahonda, 28222, Spain

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Santander, 39008, Spain

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Bern, 3010, Switzerland

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Lucerne, 6000, Switzerland

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Lugano, 6900, Switzerland

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Taipei, 10002, Taiwan

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Taipei, 112, Taiwan

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Birmingham, B9 5SS, United Kingdom

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Cambridge, CB2 0XY, United Kingdom

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London, SE5 9RS, United Kingdom

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MeSH Terms

Conditions

Liver Cirrhosis

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 24, 2022
• First Posted: August 25, 2022
• Study Start: October 31, 2022
• Primary Completion: May 22, 2025
• Study Completion: July 17, 2025
• Last Updated: August 15, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Locations

ES (7); NL (1); TW (2); CH (3); US (11); CZ (2); CN (4); FR (4); DK (4); DE (5); AU (1); BE (1); GB (3); RO (1)