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

NCT ID: NCT05516498

Last Updated: 2025-08-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 205 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-31
• Study Completion Date: 2025-07-17

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.

Conditions

Liver Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SCREENING
• Blinding Strategy: TRIPLE

Study Groups

Part A: Treatment Group 1

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

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

placebo capsule (matching zibotentan capsule)

placebo tablet (matching dapagliflozin tablet)

Part A: Treatment Group 2

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

Group Type: EXPERIMENTAL

Part A: zibotentan (dose B) + dapagliflozin

Intervention Type: DRUG

zibotentan capsule

dapagliflozin tablet

Part B: Treatment Group 1

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

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

placebo capsule (matching zibotentan capsule)

placebo tablet (matching dapagliflozin tablet)

Part B: Treatment Group 2

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

Group Type: EXPERIMENTAL

Part B: placebo (matching zibotentan capsule) + dapagliflozin

Intervention Type: DRUG

placebo capsule (matching zibotentan capsule)

dapagliflozin tablet

Part B: Treatment Group 3

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

Group Type: EXPERIMENTAL

Part B: zibotentan (dose A) + dapagliflozin

Intervention Type: DRUG

zibotentan capsule

dapagliflozin tablet

Part B: Treatment Group 4

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

Group Type: EXPERIMENTAL

Part B: zibotentan (dose B) + dapagliflozin

Intervention Type: DRUG

zibotentan capsule

dapagliflozin tablet

Part B: Treatment Group 5

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

Group Type: EXPERIMENTAL

Part B: zibotentan (dose C) + dapagliflozin

Intervention Type: DRUG

zibotentan capsule

dapagliflozin tablet

Interventions

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

placebo capsule (matching zibotentan capsule)

placebo tablet (matching dapagliflozin tablet)

Intervention Type: DRUG

Part A: zibotentan (dose B) + dapagliflozin

zibotentan capsule

dapagliflozin tablet

Intervention Type: DRUG

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

placebo capsule (matching zibotentan capsule)

placebo tablet (matching dapagliflozin tablet)

Intervention Type: DRUG

Part B: placebo (matching zibotentan capsule) + dapagliflozin

placebo capsule (matching zibotentan capsule)

dapagliflozin tablet

Intervention Type: DRUG

Part B: zibotentan (dose A) + dapagliflozin

zibotentan capsule

dapagliflozin tablet

Intervention Type: DRUG

Part B: zibotentan (dose B) + dapagliflozin

zibotentan capsule

dapagliflozin tablet

Intervention Type: DRUG

Part B: zibotentan (dose C) + dapagliflozin

zibotentan capsule

dapagliflozin tablet

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or ERAs.

2. 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.

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

4. Female participants of non-childbearing potential confirmed at screening by fulfilling one of the following criteria:

1. 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.

2. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

5. Female participants must have a negative pregnancy test at screening and must not be lactating

Part A participants who have the following:

1. Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness ≥ 21 kPa.

2. MELD score < 15.

3. Child-Pugh score ≤ 6.

4. No clinically evident ascites.

5. 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.

6. HVPG recording of good enough quality as judged by a central reader.

Part B participants who have the following:

1. Clinical and/or histological diagnosis of cirrhosis and either history of decompensation or compensated cirrhosis with signs of clinically significant portal hypertension.

2. HVPG recording of good enough quality and HVPG > 10 mmHg, as judged by a central reader.

3. MELD score < 15.

4. Child-Pugh score < 10.

5. 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.

6. 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.

Exclusion Criteria

1. Any evidence of a clinically significant disease which in the investigator's opinion makes it undesirable for the participant to participate in the study.

2. Liver cirrhosis caused by chronic cholestatic liver disease

3. ALT or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN

4. Acute liver injury caused by drug toxicity or by an infection.

5. Any history of hepatocellular carcinoma.

6. Liver transplant or expected liver transplantation within 6 months of screening.

7. History of TIPS or a planned TIPS within 6 months from enrolment into the study.

8. Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year.

9. Participants with T1DM.

Medical Conditions (Part A only)

1. INR > 1.5.

2. Serum/plasma levels of albumin ≤ 35 g/L.

3. Platelet count < 75 × 109/L.

4. History of ascites

5. History of hepatic hydrothorax

6. History of portopulmonary syndrome

7. History of hepatic encephalopathy

8. History of variceal haemorrhage

9. History of acute kidney injury

10. History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget's disease)

Medical Conditions (Part B only)

1. INR > 1.7.

2. Serum/plasma levels of albumin ≤ 28 g/L.

3. Platelet count < 50 × /109L.

4. Acute kidney injury within 3 months of screening.

5. History of encephalopathy of West Haven grade 2 or higher within 6 months prior to screening.

6. History of variceal haemorrhage within 6 months prior to screening.

7. 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.

8. 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).

9. High output heart failure (eg, due to hyperthyroidism or Paget's disease).

10. Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Research Site

Birmingham, Alabama, United States

Research Site

Pasadena, California, United States

Research Site

San Francisco, California, United States

Research Site

West Hollywood, California, United States

Research Site

Rochester, Minnesota, United States

Research Site

The Bronx, New York, United States

Research Site

Charleston, South Carolina, United States

Research Site

Dallas, Texas, United States

Research Site

Charlottesville, Virginia, United States

Research Site

Richmond, Virginia, United States

Research Site

Milwaukee, Wisconsin, United States

Research Site

Heidelberg, , Australia

Research Site

Vienna, , Austria

Research Site

Edegem, , Belgium

Research Site

Beijing, , China

Research Site

Chengdu, , China

Research Site

Guangzhou, , China

Research Site

Hangzhou, , China

Research Site

Prague, , Czechia

Research Site

Prague, , Czechia

Research Site

Aarhus N, , Denmark

Research Site

Esbjerg, , Denmark

Research Site

Hvidovre, , Denmark

Research Site

Køge, , Denmark

Research Site

Angers, , France

Research Site

Clichy, , France

Research Site

Paris, , France

Research Site

Toulouse, , France

Research Site

Dresden, , Germany

Research Site

Landshut, , Germany

Research Site

Mainz, , Germany

Research Site

Münster, , Germany

Research Site

Wiesbaden, , Germany

Research Site

Amsterdam, , Netherlands

Research Site

Cluj-Napoca, , Romania

Research Site

Barcelona, , Spain

Research Site

Barcelona, , Spain

Research Site

Barcelona, , Spain

Research Site

Madrid, , Spain

Research Site

Madrid, , Spain

Research Site

Majadahonda, , Spain

Research Site

Santander, , Spain

Research Site

Bern, , Switzerland

Research Site

Lucerne, , Switzerland

Research Site

Lugano, , Switzerland

Research Site

Taipei, , Taiwan

Research Site

Taipei, , Taiwan

Research Site

Birmingham, , United Kingdom

Research Site

Cambridge, , United Kingdom

Research Site

London, , United Kingdom

Countries

United States; Australia; Austria; Belgium; China; Czechia; Denmark; France; Germany; Netherlands; Romania; Spain; Switzerland; Taiwan; United Kingdom

Other Identifiers

2021-006577-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D4326C00003

Identifier Type: -

Identifier Source: org_study_id