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Liver CirrhosisPhase 2ZEAL UNLOCKNCT06269484

A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK

A Phase 2 study testing Zibotentan + dapagliflozin in people with Liver Cirrhosis, run by AstraZeneca at 34 sites in 10 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This is a Phase IIb multicentre, randomised, double-blind, parallel-group, placebo-controlled study to evaluate the safety of zibotentan/dapagliflozin in combination as compared to zibotentan monotherapy as well as zibotentan/dapagliflozin and zibotentan monotherapy as compared to placebo in patients with cirrhosis. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Liver Cirrhosis
What is being tested?
Zibotentan + dapagliflozin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
73 participants
Where
34 sitesin 10 countries
Study dates
15 Feb 2024to 11 Dec 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥ 18 and ≤ 80 years of age at the time of signing the informed consent.
  • Clinical and/or histological diagnosis of cirrhosis.
  • Note: Either history of decompensation or compensated cirrhosis with signs of CSPH, including varices at endoscopy or collaterals at imaging (within 12 months prior to screening), and/or liver stiffness using vibration controlled elastography, liver stiffness > 25 kPa or > 21 kPa, and platelets < 150 × 10^99 (at time of screening).
  • Model for end stage liver disease score (MELD) < 15.
  • Child-Pugh score < 10.
  • No ascites or ascites up to grade 2 without change in diuretic treatment within the last month prior to first dose of study intervention and no paracentesis within the last month.
Show all 19Show fewer
  • 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.
  • No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or endothelin receptor antagonist.
  • 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.
  • Males or females of non-childbearing potential:
  • Male participants must be surgically sterile, abstinent, or must use in conjunction with their female partner a highly effective method of contraception from the time they sign the informed consent document and for 3 months after the last dose of study intervention to prevent pregnancy in a partner. In addition, the male participant should use a condom for the duration of the study and for 3 months after the last dose of study intervention. Male participants must not donate or bank sperm during the same period.
  • Highly effective birth control methods are defined as those that can achieve a failure rate of less than 1% per year when used consistently and correctly.
  • Female participants must be 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 (Note: The post-menopausal range must be checked against the specific FSH assay used). In the absence of 12 months of amenorrhoea, a single FSH measurement is insufficient to define post-menopausal criteria. In case of perimenopause or infrequent periods with variable levels of FSH, women should be considered of childbearing potential and, therefore, not eligible for participation in this study.
  • 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.
  • Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
  • Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
  • Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports Genomic Initiative.

Who cannot join

  • Any evidence of a clinically significant disease, which in the investigator's opinion makes it undesirable for the participant to participate in the study.
  • Alanine aminotransferase/transaminase or AST ≥ 150 U/L and/or total bilirubin
  • ≥ 3 × ULN.
  • International normalised ratio > 1.7.
  • Serum/plasma levels of albumin ≤ 28 g/L.
  • Platelet count < 50 × 109L.
Show all 39Show fewer
  • Acute kidney injury (AKI) within 3 months of screening.
  • History of encephalopathy of West Haven Grade 2 or higher
  • History of variceal haemorrhage within 6 months prior to screening.
  • Any history of hepatocellular carcinoma.
  • Any history of portal venous thrombosis.
  • 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.
  • Positive alcohol breath test or screen for drugs of abuse (excluding drugs prescribed by the participants' usual physician) at screening.
  • Ongoing or history of significant use of alcohol expected to preclude correct adherence to study procedures (For details, refer to Section 5.3.2).
  • Active treatment for HCV within the last 1 year or HBV anti-viral therapy for less than 1 year.
  • Active urinary tract infection or genital infection.
  • Uncontrolled diabetes mellitus (HbA1c > 8.5% or > 69 mmol/mol within the last month).
  • Participants with T1DM.
  • Renal transplant or chronic renal replacement therapy or short-term dialysis within the previous 6 months.
  • eGFR < 60 mL/min/1.73m2 (eGFRcr[AS]).
  • Acute coronary syndrome events within 3 months prior to screening.
  • Orthostatic hypotension or hypotension (systolic blood pressure < 95 mmHg or diastolic blood pressure < 60 mmHg).
  • New York Heart Association functional heart failure Class III or IV or patients 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.
  • Heart failure due to cardiomyopathies that would primarily require specific other treatment.
  • High output heart failure (eg, due to hyperthyroidism or Paget's disease).
  • Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
  • Participants treated with strong CYP3A4 inhibitor or strong or moderate CYP3A4 inducer within 14 days (St. John's Wort: 21 days) of study intervention administration; this includes grapefruit and grapefruit juice, if consumed more often than occasionally, or, in larger quantities.
  • History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin), zibotentan, or drugs with a similar chemical structure to zibotentan.
  • Any clinically significant chronic disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) which, as judged by the investigator, might put the participant at risk because of participation in the study, or probable alternative primary reason for participant's symptoms in judgment of investigator.
  • Acute liver injury caused by drug toxicity or by an infection.
  • Implanted electronic device such as pacemaker.
  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study centre).
  • Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
  • Male participant in a sexually active relation with pregnant or breastfeeding partner.
  • Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
  • Exclusion Criteria for Participants Consenting to Optional Genetic Sampling:
  • Previous allogeneic bone marrow transplant.
  • Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.

Trial locations and contacts

34 sites in 10 countries.

34 sites in 10 countries

Japan7 sites

  • Research Site

    Gifu, 500-8513

  • Research Site

    Kawasaki-shi, 215-0026

  • Research Site

    Kitakyusyu-shi, 806-8501

  • Research Site

    Nagaoka-shi, 940-2085

  • Research Site

    Niigata, 951-8520

  • Research Site

    Sapporo, 006-8555

  • Research Site

    Yokohama, 236-0004

Other trials in Japan

United Kingdom5 sites

  • Research Site

    Aberdeen, AB25 2ZN

  • Research Site

    Hull, HU3 2KZ

  • Research Site

    Ipswich, IP4 5PD

  • Research Site

    London, SE5 9RS

  • Research Site

    Nottingham, NG7 2UH

Other trials in United Kingdom

Poland4 sites

  • Research Site

    Bydgoszcz, 85-794

  • Research Site

    Katowice, 40-081

  • Research Site

    Mysłowice, 41-400

  • Research Site

    Poznan, 61-848

Other trials in Poland

United States3 sites

  • Research Site

    Charleston, South Carolina, 29425

  • Research Site

    Englewood, Colorado, 80113

  • Research Site

    San Antonio, Texas, 78215

Other trials in United States

Australia3 sites

  • Research Site

    Adelaide, 5000

  • Research Site

    Kogarah, 2217

  • Research Site

    Mitcham, 3132

Other trials in Australia

Czechia3 sites

  • Research Site

    Liberec, 460 63

  • Research Site

    Mladá Boleslav, 293 01

  • Research Site

    Prague, 140 21

Other trials in Czechia

Italy3 sites

  • Research Site

    Milan, 20122

  • Research Site

    Padova, 35128

  • Research Site

    Roma, 00168

Other trials in Italy

Slovakia3 sites

  • Research Site

    Bratislava, 83104

  • Research Site

    Nitra, 950 01

  • Research Site

    Trnava, 91702

Other trials in Slovakia

Germany2 sites

  • Research Site

    Leipzig, 04103

  • Research Site

    Tübingen, 72076

Other trials in Germany

Belgium1 site

  • Research Site

    Mechelen, 2800

Other trials in Belgium

About this study

Official title: A Multicentre, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Combination Compared to Zibotentan Monotherapy, Zibotentan/Dapagliflozin and Zibotentan Monotherapy Compared to Placebo in Participants With Cirrhosis

This is a Phase IIb multicentre, randomised, double-blind, parallel-group, placebo-controlled study to evaluate the safety of zibotentan/dapagliflozin in combination as compared to zibotentan monotherapy as well as zibotentan/dapagliflozin and zibotentan monotherapy as compared to placebo in patients with cirrhosis.

Read the detailed description

The study is designed to evaluate the safety of zibotentan/dapagliflozin in combination as compared to zibotentan monotherapy as well as zibotentan/dapagliflozin in combination and zibotentan monotherapy as compared to placebo in patients with cirrhosis with or without a history of decompensation. The study will be conducted in approximately 52 study centers in North America, Asia and Europe.

Conditions
Liver Cirrhosis
Being tested
Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet), Zibotentan + placebo (placebo matching dapagliflozin tablet), Zibotentan + dapagliflozin
Keywords
Cirrhosis
Medical subject headings
Liver Cirrhosis, Fibrosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet)Drug

    placebo capsule (matching zibotentan capsule)

    placebo tablet (matching dapagliflozin tablet)

  • Zibotentan + placebo (placebo matching dapagliflozin tablet)Drug

    zibotentan capsule

    placebo tablet (matching dapagliflozin tablet)

  • Zibotentan + dapagliflozinDrug

    zibotentan capsule

    dapagliflozin 10 mg tablet

Study groups in NCT06269484
Study groupRoleWhat they receive
Treatment Group 1Placebo comparatorParticipants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks
Receives: Drug: Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet)
Treatment Group 2ExperimentalParticipants will receive once daily zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks
Receives: Drug: Zibotentan + placebo (placebo matching dapagliflozin tablet)
Treatment Group 3ExperimentalParticipants will receive once daily zibotentan capsule + dapagliflozin tablet 10 mg for 6 weeks
Receives: Drug: Zibotentan + dapagliflozin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Cumulative Number of Subjects With Any of the Components of the Composite Endpoint: >2kg Increase in Body Weight (Office-based), >2 L Increase in Total Body Water, Increase in 2 or More Loop-diuretic Equivalents, Fluid Retention Adverse Event (AE)

    Cumulative number of subjects with event of composite fluid retention endpoint

    Measured: baseline to Week 6

Secondary outcomes (10)

  1. Change From Baseline in Body Weight

    Change in site body weight

    Measured: at Week 6

  2. Change From Baseline in Body Fat Mass

    Measured: at Week 6

  3. Change From Baseline in Total Body Water

    Measured: at Week 6

  4. Change From Baseline in Extracellular Water Volume

    Measured: at Week 6

  5. Change From Baseline in Intracellular Water Volume

    Measured: at Week 6

  6. Change in Body Weight (kg) Over Time Course of Study

    Change in home body weight

    Measured: at Week 6

  7. Change in Total Dosage of Loop-diuretic Equivalents Use

    One loop-diuretic equivalent = 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg ethacrynic acid. In Japan, one loop-diuretic equivalent = 40 mg furosemide = 8 mg torsemide = 60 mg azosemide.

    Measured: at Week 6

  8. Cumulative Number of Subjects With Either of the Two Components of This Composite: 1. >3 L Increase in Total Body Water Volume From Baseline to Week 6 2. Increase in 3 or More Loop-diuretics Equivalents Use

    Cumulative number of subjects with event of composite and the components of total body water and total dosage of loop-diuretic equivalents

    Measured: from baseline to Week 6

  9. Absolute Change in Systolic Blood Pressure

    Measured: at Week 6

  10. Absolute Change in Diastolic Blood Pressure

    Measured: at Week 6

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Feb 2024
  2. Study start15 Feb 2024
  3. Primary completion11 Dec 2024
  4. Study completion11 Dec 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
73 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06269484
Sponsor's protocol ID
D4326C00004
Other IDs
2023-506893-11-00, 2023
Acronym
ZEAL UNLOCK
Status last verified
Jan 2026
First submitted
2 Feb 2024
Last updated
20 Jan 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. "Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Zibotentan + dapagliflozin in people with Liver Cirrhosis, run by AstraZeneca at 34 sites in 10 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 34 sites in Japan, United Kingdom, Poland, United States, Australia and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Jan 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cumulative Number of Subjects With Any of the Components of the Composite Endpoint: >2kg Increase in Body Weight (Office-based), >2 L Increase in Total Body Water, Increase in 2 or More Loop-diuretic Equivalents, Fluid Retention Adverse Event (AE) (time frame: baseline to Week 6). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06269484.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Jan 2026.

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