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

NCT06269484 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: D4326C000042023-506893-11-00
• Study Type: interventional
• Target: 73
• Locations: 10 countries
• Sites: 34

Brief 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.

Conditions

Liver Cirrhosis

Keywords

Cirrhosis

Outcome Measures

Primary Outcomes (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

  baseline to Week 6

Secondary Outcomes (10)

• Change From Baseline in Body Weight

  at Week 6

• Change From Baseline in Body Fat Mass

  at Week 6

• Change From Baseline in Total Body Water

  at Week 6

• Change From Baseline in Extracellular Water Volume

  at Week 6

• Change From Baseline in Intracellular Water Volume

  at Week 6

Study Arms (3)

Treatment Group 1

PLACEBO COMPARATOR

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

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

Treatment Group 2

EXPERIMENTAL

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

Drug: Zibotentan + placebo (placebo matching dapagliflozin tablet)

Treatment Group 3

EXPERIMENTAL

Participants will receive once daily zibotentan capsule + dapagliflozin tablet 10 mg for 6 weeks

Drug: Zibotentan + dapagliflozin

Interventions

Zibotentan + dapagliflozin DRUG

zibotentan capsule dapagliflozin 10 mg tablet

Treatment Group 3

Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet) DRUG

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

Treatment Group 1

Zibotentan + placebo (placebo matching dapagliflozin tablet) DRUG

zibotentan capsule placebo tablet (matching dapagliflozin tablet)

Treatment Group 2

Eligibility Criteria

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

You may qualify if:

• ≥ 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.
• 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.

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.
• 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.
• 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).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (34)

Research Site

Englewood, Colorado, 80113, United States

Location

Research Site

Charleston, South Carolina, 29425, United States

Location

Research Site

San Antonio, Texas, 78215, United States

Location

Research Site

Adelaide, 5000, Australia

Location

Research Site

Kogarah, 2217, Australia

Location

Research Site

Mitcham, 3132, Australia

Location

Research Site

Mechelen, 2800, Belgium

Location

Research Site

Liberec, 460 63, Czechia

Location

Research Site

Mladá Boleslav, 293 01, Czechia

Location

Research Site

Prague, 140 21, Czechia

Location

Research Site

Leipzig, 04103, Germany

Location

Research Site

Tübingen, 72076, Germany

Location

Research Site

Milan, 20122, Italy

Location

Research Site

Padua, 35128, Italy

Location

Research Site

Roma, 00168, Italy

Location

Research Site

Gifu, 500-8513, Japan

Location

Research Site

Kawasaki-shi, 215-0026, Japan

Location

Research Site

Kitakyusyu-shi, 806-8501, Japan

Location

Research Site

Nagaoka-shi, 940-2085, Japan

Location

Research Site

Niigata, 951-8520, Japan

Location

Research Site

Sapporo, 006-8555, Japan

Location

Research Site

Yokohama, 236-0004, Japan

Location

Research Site

Bydgoszcz, 85-794, Poland

Location

Research Site

Katowice, 40-081, Poland

Location

Research Site

Mysłowice, 41-400, Poland

Location

Research Site

Poznan, 61-848, Poland

Location

Research Site

Bratislava, 83104, Slovakia

Location

Research Site

Nitra, 950 01, Slovakia

Location

Research Site

Trnava, 91702, Slovakia

Location

Research Site

Aberdeen, AB25 2ZN, United Kingdom

Location

Research Site

Hull, HU3 2KZ, United Kingdom

Location

Research Site

Ipswich, IP4 5PD, United Kingdom

Location

Research Site

London, SE5 9RS, United Kingdom

Location

Research Site

Nottingham, NG7 2UH, United Kingdom

Location

Related Links

• D4326C00004 Clinical Study Protocol v3.0 EU Redacted
• D4326C00004 CSR Synopsis - Redacted
• D4326C00004 Statistical Analysis Plan v2.0 Redacted

MeSH Terms

Conditions

Liver Cirrhosis; Fibrosis

Interventions

ZD4054; dapagliflozin

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: February 2, 2024
• First Posted: February 21, 2024
• Study Start: February 15, 2024
• Primary Completion: December 11, 2024
• Study Completion: December 11, 2024
• Last Updated: January 20, 2026
• Results First Posted: January 20, 2026

Record last verified: 2026-01

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/PhRMA Data-Sharing Principles. For details of our timelines, please refer 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 anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Locations

GB (5); CZ (3); AU (3); IT (3); US (3); PL (4); SL (3); BE (1); DE (2); JP (7)