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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06269484




Registration number
NCT06269484
Ethics application status
Date submitted
2/02/2024
Date registered
21/02/2024

Titles & IDs
Public title
A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK
Scientific 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
Secondary ID [1] 0 0
D4326C00004
Universal Trial Number (UTN)
Trial acronym
ZEAL UNLOCK
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver Cirrhosis 0 0
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 - Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet)
Treatment: Drugs - Zibotentan + placebo (placebo matching dapagliflozin tablet)
Treatment: Drugs - Zibotentan + dapagliflozin

Placebo comparator: Treatment Group 1 - Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks

Experimental: Treatment Group 2 - Participants will receive once daily zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks

Experimental: Treatment Group 3 - Participants will receive once daily zibotentan capsule + dapagliflozin tablet 10 mg for 6 weeks


Treatment: Drugs: Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet)
placebo capsule (matching zibotentan capsule)

placebo tablet (matching dapagliflozin tablet)

Treatment: Drugs: Zibotentan + placebo (placebo matching dapagliflozin tablet)
zibotentan capsule

placebo tablet (matching dapagliflozin tablet)

Treatment: Drugs: Zibotentan + dapagliflozin
zibotentan capsule

dapagliflozin 10 mg tablet
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Occurence of any of the following components of this 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)
Timepoint [1] 0 0
baseline to Week 6
Primary outcome [2] 0 0
Occurence of any of the following components of this 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)
Timepoint [2] 0 0
baseline to Week 6
Secondary outcome [1] 0 0
Change in body weight (kg) over time course of study
Timepoint [1] 0 0
at Week 6
Secondary outcome [2] 0 0
Change in body weight (kg) over time course of study
Timepoint [2] 0 0
at Week 6
Secondary outcome [3] 0 0
Change in total dosage of loop-diuretic equivalents use
Timepoint [3] 0 0
from baseline to Week 6
Secondary outcome [4] 0 0
Change in total dosage of loop-diuretic equivalents use
Timepoint [4] 0 0
from baseline to Week 6
Secondary outcome [5] 0 0
Occurence of 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
Timepoint [5] 0 0
from baseline to Week 6
Secondary outcome [6] 0 0
Occurence of 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
Timepoint [6] 0 0
from baseline to Week 6
Secondary outcome [7] 0 0
Absolute change in systolic and diastolic blood pressure
Timepoint [7] 0 0
from baseline to Week 6
Secondary outcome [8] 0 0
Absolute change in systolic and diastolic blood pressure
Timepoint [8] 0 0
from baseline to Week 6
Secondary outcome [9] 0 0
Change from baseline in body weight
Timepoint [9] 0 0
at Week 6
Secondary outcome [10] 0 0
Change from baseline in total body water
Timepoint [10] 0 0
at Week 6
Secondary outcome [11] 0 0
Change from baseline in extracellular water volume
Timepoint [11] 0 0
at Week 6
Secondary outcome [12] 0 0
Change from baseline in intracellular water volume
Timepoint [12] 0 0
at Week 6
Secondary outcome [13] 0 0
Change from baseline in body fat mass
Timepoint [13] 0 0
at Week 6
Secondary outcome [14] 0 0
Change from baseline in body weight
Timepoint [14] 0 0
at Week 6
Secondary outcome [15] 0 0
Change from baseline in total body water
Timepoint [15] 0 0
at Week 6
Secondary outcome [16] 0 0
Change from baseline in extracellular water volume
Timepoint [16] 0 0
at Week 6
Secondary outcome [17] 0 0
Change from baseline in intracellular water volume
Timepoint [17] 0 0
at Week 6
Secondary outcome [18] 0 0
Change from baseline in body fat mass
Timepoint [18] 0 0
at Week 6

Eligibility
Key inclusion criteria
= 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.

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

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).

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.

Study design
Purpose of the study
Treatment
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
15/02/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
17/01/2025
Actual
Sample size
Target
66
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Adelaide
Recruitment hospital [2] 0 0
Research Site - Kogarah
Recruitment hospital [3] 0 0
Research Site - Mitcham
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
2217 - Kogarah
Recruitment postcode(s) [3] 0 0
3132 - Mitcham
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
South Carolina
Country [3] 0 0
United States of America
State/province [3] 0 0
Texas
Country [4] 0 0
Belgium
State/province [4] 0 0
Edegem
Country [5] 0 0
Belgium
State/province [5] 0 0
Mechelen
Country [6] 0 0
Czechia
State/province [6] 0 0
Liberec
Country [7] 0 0
Czechia
State/province [7] 0 0
Mladá Boleslav
Country [8] 0 0
Czechia
State/province [8] 0 0
Plzen
Country [9] 0 0
Czechia
State/province [9] 0 0
Praha 4
Country [10] 0 0
Germany
State/province [10] 0 0
Aachen
Country [11] 0 0
Germany
State/province [11] 0 0
Hannover
Country [12] 0 0
Germany
State/province [12] 0 0
Kiel
Country [13] 0 0
Germany
State/province [13] 0 0
Leipzig
Country [14] 0 0
Germany
State/province [14] 0 0
Tuebingen
Country [15] 0 0
Italy
State/province [15] 0 0
Milano
Country [16] 0 0
Italy
State/province [16] 0 0
Padova
Country [17] 0 0
Italy
State/province [17] 0 0
Roma
Country [18] 0 0
Japan
State/province [18] 0 0
Gifu-shi
Country [19] 0 0
Japan
State/province [19] 0 0
Iizuka-shi
Country [20] 0 0
Japan
State/province [20] 0 0
Kawasaki-shi
Country [21] 0 0
Japan
State/province [21] 0 0
Kitakyusyu-shi
Country [22] 0 0
Japan
State/province [22] 0 0
Nagaoka-shi
Country [23] 0 0
Japan
State/province [23] 0 0
Niigata-shi
Country [24] 0 0
Japan
State/province [24] 0 0
Sapporo-shi
Country [25] 0 0
Japan
State/province [25] 0 0
Yokohama-shi
Country [26] 0 0
Poland
State/province [26] 0 0
Bydgoszcz
Country [27] 0 0
Poland
State/province [27] 0 0
Katowice
Country [28] 0 0
Poland
State/province [28] 0 0
Kraków
Country [29] 0 0
Poland
State/province [29] 0 0
Myslowice
Country [30] 0 0
Poland
State/province [30] 0 0
Poznan
Country [31] 0 0
Poland
State/province [31] 0 0
Wroclaw
Country [32] 0 0
Slovakia
State/province [32] 0 0
Bratislava
Country [33] 0 0
Slovakia
State/province [33] 0 0
Nitra
Country [34] 0 0
Slovakia
State/province [34] 0 0
Trnava
Country [35] 0 0
United Kingdom
State/province [35] 0 0
Aberdeen
Country [36] 0 0
United Kingdom
State/province [36] 0 0
Hull
Country [37] 0 0
United Kingdom
State/province [37] 0 0
Ipswich
Country [38] 0 0
United Kingdom
State/province [38] 0 0
London
Country [39] 0 0
United Kingdom
State/province [39] 0 0
Nottingham

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

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
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

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP)
When will data be available (start and end dates)?
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
Available to whom?
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.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://vivli.org/


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT06269484