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

Liver Cirrhosis Clinical Trial

— ZEAL  

Official 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05516498
• Other study ID #: D4326C00003
• Secondary ID: 2021-006577-30
• Status: Recruiting
• Phase: Phase 2
• Start date: October 31, 2022
• Est. completion date: April 16, 2025

Study information

• Verified date: April 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 195
• Est. completion date: April 16, 2025
• Est. primary completion date: January 22, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Study principal inclusion criteria For both Part A and Part B

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.

Study principal 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.

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.

Related Conditions & MeSH terms

• Fibrosis
• Liver Cirrhosis

Intervention

Drug:
• Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)
placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)
• Part A: zibotentan (dose B) + dapagliflozin
zibotentan capsule dapagliflozin tablet
• Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)
placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)
• Part B: placebo (matching zibotentan capsule) + dapagliflozin
placebo capsule (matching zibotentan capsule) dapagliflozin tablet
• Part B: zibotentan (dose A) + dapagliflozin
zibotentan capsule dapagliflozin tablet
• Part B: zibotentan (dose B) + dapagliflozin
zibotentan capsule dapagliflozin tablet
• Part B: zibotentan (dose C) + dapagliflozin
zibotentan capsule dapagliflozin tablet

Locations

Country	Name	City	State
Australia	Research Site	Clayton
Australia	Research Site	Heidelberg
Austria	Research Site	Wien
Belgium	Research Site	Edegem
Canada	Research Site	Edmonton	Alberta
China	Research Site	Beijing
China	Research Site	Chengdu
China	Research Site	Chengdu
China	Research Site	Guangzhou
China	Research Site	Hangzhou
Czechia	Research Site	Praha
Czechia	Research Site	Praha
Denmark	Research Site	Aarhus N
Denmark	Research Site	Esbjerg
Denmark	Research Site	Hvidovre
Denmark	Research Site	Køge
France	Research Site	Clichy
France	Research Site	Paris Cedex 13
France	Research Site	Toulouse
France	Research Site	TOURS Cedex 9
Germany	Research Site	Dresden
Germany	Research Site	Jena
Germany	Research Site	Landshut
Germany	Research Site	Leipzig
Germany	Research Site	Magdeburg
Germany	Research Site	Mainz
Germany	Research Site	Münster
Germany	Research Site	Wiesbaden
Netherlands	Research Site	Amsterdam
Spain	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	Sevilla
Spain	Research Site	Zaragoza
Switzerland	Research Site	Bern
Switzerland	Research Site	Lugano
Switzerland	Research Site	Luzern
Switzerland	Research Site	St. Gallen
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Nottingham
United States	Research Site	Birmingham	Alabama
United States	Research Site	Boston	Massachusetts
United States	Research Site	Charleston	South Carolina
United States	Research Site	Charlottesville	Virginia
United States	Research Site	Dallas	Texas
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	New Orleans	Louisiana
United States	Research Site	New York	New York
United States	Research Site	Pasadena	California
United States	Research Site	Richmond	Virginia
United States	Research Site	Rochester	Minnesota
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Diego	California
United States	Research Site	San Francisco	California
United States	Research Site	West Hollywood	California

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  China,  Czechia,  Denmark,  France,  Germany,  Netherlands,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Part A: Percent 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
Secondary	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.	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.	at Week 6
Secondary	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.	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on change in body weight.	at Week 6
Secondary	Part A: Percentage and absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6.	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on total loop-diuretic equivalents use.	at Week 6
Secondary	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.	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on body water volumes and body fat mass.	at Week 6
Secondary	Part A: Change in systolic and diastolic blood pressure from baseline to Week 6.	To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on changes in office-based systolic and diastolic blood pressure.	at Week 6
Secondary	Part B: Percentage 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	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.	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.	at Week 6
Secondary	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.	To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on change in body weight.	at Week 6 and Week 16
Secondary	Part B: Absolute change in total dosage of loop-diuretic equivalents use from baseline to 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.	at Week 6 and Week 16
Secondary	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.	To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on body water volumes and body fat mass.	at Week 6 and Week 16
Secondary	Part B: Change in systolic and diastolic blood pressure from baseline to 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.	at Week 6 and Week 16