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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05516498




Registration number
NCT05516498
Ethics application status
Date submitted
24/08/2022
Date registered
25/08/2022
Date last updated
22/08/2024

Titles & IDs
Public title
Zibotentan and Dapagliflozin Combination, EvAluated in Liver Cirrhosis (ZEAL Study)
Scientific 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
Secondary ID [1] 0 0
2021-006577-30
Secondary ID [2] 0 0
D4326C00003
Universal Trial Number (UTN)
Trial acronym
ZEAL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Condition category
Condition code
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Inflammatory and Immune System 0 0 0 0
Connective tissue diseases
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)
Treatment: Drugs - Part A: zibotentan (dose B) + dapagliflozin
Treatment: Drugs - Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)
Treatment: Drugs - Part B: placebo (matching zibotentan capsule) + dapagliflozin
Treatment: Drugs - Part B: zibotentan (dose A) + dapagliflozin
Treatment: Drugs - Part B: zibotentan (dose B) + dapagliflozin
Treatment: Drugs - Part B: zibotentan (dose C) + dapagliflozin

Experimental: Part A: Treatment Group 1 - Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks.

Experimental: Part A: Treatment Group 2 - Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 6 weeks.

Experimental: Part B: Treatment Group 1 - Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 16 weeks.

Experimental: Part B: Treatment Group 2 - Participants will receive once daily dose of placebo matching zibotentan capsule + dapagliflozin tablet for 16 weeks.

Experimental: Part B: Treatment Group 3 - Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Experimental: Part B: Treatment Group 4 - Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.

Experimental: Part B: Treatment Group 5 - Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.


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

placebo tablet (matching dapagliflozin tablet)

Treatment: Drugs: Part A: zibotentan (dose B) + dapagliflozin
zibotentan capsule

dapagliflozin tablet

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

placebo tablet (matching dapagliflozin tablet)

Treatment: Drugs: Part B: placebo (matching zibotentan capsule) + dapagliflozin
placebo capsule (matching zibotentan capsule)

dapagliflozin tablet

Treatment: Drugs: Part B: zibotentan (dose A) + dapagliflozin
zibotentan capsule

dapagliflozin tablet

Treatment: Drugs: Part B: zibotentan (dose B) + dapagliflozin
zibotentan capsule

dapagliflozin tablet

Treatment: Drugs: Part B: zibotentan (dose C) + dapagliflozin
zibotentan capsule

dapagliflozin tablet
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part A: Absolute change in HVPG from baseline to Week 6.
Timepoint [1] 0 0
at Week 6
Primary outcome [2] 0 0
Part B: Absolute change in HVPG from baseline to Week 6.
Timepoint [2] 0 0
at Week 6
Secondary outcome [1] 0 0
Part A: Percent change in HVPG from baseline to Week 6.
Timepoint [1] 0 0
at Week 6
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
at Week 6
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
at Week 6
Secondary outcome [4] 0 0
Part A: Percentage and absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6.
Timepoint [4] 0 0
at Week 6
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
at Week 6
Secondary outcome [6] 0 0
Part A: Change in systolic and diastolic blood pressure from baseline to Week 6.
Timepoint [6] 0 0
at Week 6
Secondary outcome [7] 0 0
Part B: Percentage change in HVPG from baseline to Week 6.
Timepoint [7] 0 0
at Week 6
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
at Week 6
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
at Week 6 and Week 16
Secondary outcome [10] 0 0
Part B: Absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16.
Timepoint [10] 0 0
at Week 6 and Week 16
Secondary outcome [11] 0 0
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.
Timepoint [11] 0 0
at Week 6 and Week 16
Secondary outcome [12] 0 0
Part B: Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16.
Timepoint [12] 0 0
at Week 6 and Week 16

Eligibility
Key inclusion criteria
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.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Other
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
31/10/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
16/04/2025
Actual
Sample size
Target
195
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Clayton
Recruitment hospital [2] 0 0
Research Site - Heidelberg
Recruitment postcode(s) [1] 0 0
3168 - Clayton
Recruitment postcode(s) [2] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Louisiana
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Minnesota
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
South Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Texas
Country [10] 0 0
United States of America
State/province [10] 0 0
Virginia
Country [11] 0 0
United States of America
State/province [11] 0 0
Wisconsin
Country [12] 0 0
Austria
State/province [12] 0 0
Wien
Country [13] 0 0
Belgium
State/province [13] 0 0
Edegem
Country [14] 0 0
Canada
State/province [14] 0 0
Alberta
Country [15] 0 0
China
State/province [15] 0 0
Beijing
Country [16] 0 0
China
State/province [16] 0 0
Chengdu
Country [17] 0 0
China
State/province [17] 0 0
Guangzhou
Country [18] 0 0
China
State/province [18] 0 0
Hangzhou
Country [19] 0 0
Czechia
State/province [19] 0 0
Praha
Country [20] 0 0
Denmark
State/province [20] 0 0
Aarhus N
Country [21] 0 0
Denmark
State/province [21] 0 0
Esbjerg
Country [22] 0 0
Denmark
State/province [22] 0 0
Hvidovre
Country [23] 0 0
Denmark
State/province [23] 0 0
Køge
Country [24] 0 0
France
State/province [24] 0 0
Clichy
Country [25] 0 0
France
State/province [25] 0 0
Paris Cedex 13
Country [26] 0 0
France
State/province [26] 0 0
Toulouse
Country [27] 0 0
France
State/province [27] 0 0
TOURS Cedex 9
Country [28] 0 0
Germany
State/province [28] 0 0
Dresden
Country [29] 0 0
Germany
State/province [29] 0 0
Jena
Country [30] 0 0
Germany
State/province [30] 0 0
Landshut
Country [31] 0 0
Germany
State/province [31] 0 0
Leipzig
Country [32] 0 0
Germany
State/province [32] 0 0
Magdeburg
Country [33] 0 0
Germany
State/province [33] 0 0
Mainz
Country [34] 0 0
Germany
State/province [34] 0 0
Münster
Country [35] 0 0
Germany
State/province [35] 0 0
Wiesbaden
Country [36] 0 0
Netherlands
State/province [36] 0 0
Amsterdam
Country [37] 0 0
Spain
State/province [37] 0 0
Barcelona
Country [38] 0 0
Spain
State/province [38] 0 0
Madrid
Country [39] 0 0
Spain
State/province [39] 0 0
Majadahonda
Country [40] 0 0
Spain
State/province [40] 0 0
Santander
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Spain
State/province [41] 0 0
Sevilla
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Spain
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Zaragoza
Country [43] 0 0
Switzerland
State/province [43] 0 0
Bern
Country [44] 0 0
Switzerland
State/province [44] 0 0
Lugano
Country [45] 0 0
Switzerland
State/province [45] 0 0
Luzern
Country [46] 0 0
Switzerland
State/province [46] 0 0
St. Gallen
Country [47] 0 0
Taiwan
State/province [47] 0 0
Taipei
Country [48] 0 0
United Kingdom
State/province [48] 0 0
Birmingham
Country [49] 0 0
United Kingdom
State/province [49] 0 0
Cambridge
Country [50] 0 0
United Kingdom
State/province [50] 0 0
London
Country [51] 0 0
United Kingdom
State/province [51] 0 0
Nottingham

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT05516498
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
AstraZeneca Clinical Study Information Center
Address 0 0
Country 0 0
Phone 0 0
1-877-240-9479
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05516498