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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT06269484
Registration number
NCT06269484
Ethics application status
Date submitted
2/02/2024
Date registered
21/02/2024
Date last updated
25/03/2024
Titles & IDs
Public title
A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK
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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
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Secondary ID [1]
0
0
D4326C00004
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Universal Trial Number (UTN)
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Trial acronym
ZEAL UNLOCK
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Liver Cirrhosis
0
0
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Condition category
Condition code
Oral and Gastrointestinal
0
0
0
0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Inflammatory and Immune System
0
0
0
0
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Connective tissue diseases
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Inflammatory and Immune System
0
0
0
0
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Other inflammatory or immune system disorders
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Intervention/exposure
Study type
Interventional
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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
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Intervention code [1]
0
0
Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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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)
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Assessment method [1]
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To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on a composite endpoint of fluid retention
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Timepoint [1]
0
0
baseline to Week 6
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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)
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Assessment method [2]
0
0
To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on a composite endpoint of fluid retention
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Timepoint [2]
0
0
baseline to Week 6
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Secondary outcome [1]
0
0
Change in body weight (kg) over time course of study
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Assessment method [1]
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0
To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body weight
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Timepoint [1]
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at Week 6
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Secondary outcome [2]
0
0
Change in body weight (kg) over time course of study
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Assessment method [2]
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0
To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body weight
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Timepoint [2]
0
0
at Week 6
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Secondary outcome [3]
0
0
Change in total dosage of loop-diuretic equivalents use
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Assessment method [3]
0
0
To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on total loop-diuretic equivalents use
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Timepoint [3]
0
0
from baseline to Week 6
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Secondary outcome [4]
0
0
Change in total dosage of loop-diuretic equivalents use
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Assessment method [4]
0
0
To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on total loop-diuretic equivalents use
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Timepoint [4]
0
0
from baseline to Week 6
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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
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Assessment method [5]
0
0
To evaluate the effects of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on the composite of total body water and total dosage of loop-diuretic equivalents
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Timepoint [5]
0
0
from baseline to Week 6
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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
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Assessment method [6]
0
0
To evaluate the effects of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on the composite of total body water and total dosage of loop-diuretic equivalents
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Timepoint [6]
0
0
from baseline to Week 6
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Secondary outcome [7]
0
0
Absolute change in systolic and diastolic blood pressure
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Assessment method [7]
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To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on office-based systolic and diastolic blood pressure
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Timepoint [7]
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from baseline to Week 6
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Secondary outcome [8]
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Absolute change in systolic and diastolic blood pressure
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Assessment method [8]
0
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To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on office-based systolic and diastolic blood pressure
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Timepoint [8]
0
0
from baseline to Week 6
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Secondary outcome [9]
0
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Change from baseline in body weight
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Assessment method [9]
0
0
To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body weight
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Timepoint [9]
0
0
at Week 6
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Secondary outcome [10]
0
0
Change from baseline in total body water
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Assessment method [10]
0
0
To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on total body water
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Timepoint [10]
0
0
at Week 6
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Secondary outcome [11]
0
0
Change from baseline in extracellular water volume
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Assessment method [11]
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To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on extracellular water volume
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Timepoint [11]
0
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at Week 6
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Secondary outcome [12]
0
0
Change from baseline in intracellular water volume
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Assessment method [12]
0
0
To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on intracellular water volume
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Timepoint [12]
0
0
at Week 6
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Secondary outcome [13]
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Change from baseline in body fat mass
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Assessment method [13]
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To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body fat mass
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Timepoint [13]
0
0
at Week 6
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Secondary outcome [14]
0
0
Change from baseline in body weight
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Assessment method [14]
0
0
To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body weight
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Timepoint [14]
0
0
at Week 6
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Secondary outcome [15]
0
0
Change from baseline in total body water
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Assessment method [15]
0
0
To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on total body water
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Timepoint [15]
0
0
at Week 6
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Secondary outcome [16]
0
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Change from baseline in extracellular water volume
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Assessment method [16]
0
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To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on extracellular water volume
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Timepoint [16]
0
0
at Week 6
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Secondary outcome [17]
0
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Change from baseline in intracellular water volume
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Assessment method [17]
0
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To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on intracellular water volume
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Timepoint [17]
0
0
at Week 6
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Secondary outcome [18]
0
0
Change from baseline in body fat mass
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Assessment method [18]
0
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To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body fat mass
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Timepoint [18]
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at Week 6
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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.
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Minimum age
18
Years
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Maximum age
80
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
15/02/2024
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
17/01/2025
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Actual
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Sample size
Target
66
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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0
Research Site - Adelaide
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Recruitment hospital [2]
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Research Site - Kogarah
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Recruitment hospital [3]
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Research Site - Mitcham
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Recruitment postcode(s) [1]
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5000 - Adelaide
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Recruitment postcode(s) [2]
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2217 - Kogarah
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Recruitment postcode(s) [3]
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3132 - Mitcham
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Recruitment outside Australia
Country [1]
0
0
United States of America
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State/province [1]
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0
Colorado
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Country [2]
0
0
United States of America
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State/province [2]
0
0
South Carolina
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Country [3]
0
0
United States of America
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State/province [3]
0
0
Texas
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Country [4]
0
0
Belgium
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State/province [4]
0
0
Edegem
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Country [5]
0
0
Belgium
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State/province [5]
0
0
Mechelen
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Country [6]
0
0
Czechia
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State/province [6]
0
0
Liberec
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Country [7]
0
0
Czechia
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State/province [7]
0
0
Mladá Boleslav
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Country [8]
0
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Czechia
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State/province [8]
0
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Plzen
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Country [9]
0
0
Czechia
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State/province [9]
0
0
Praha 4
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Country [10]
0
0
Germany
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State/province [10]
0
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Aachen
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Country [11]
0
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Germany
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State/province [11]
0
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Kiel
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Country [12]
0
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Germany
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State/province [12]
0
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Leipzig
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Country [13]
0
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Germany
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State/province [13]
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Tuebingen
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Country [14]
0
0
Italy
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State/province [14]
0
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Milano
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Country [15]
0
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Italy
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State/province [15]
0
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Padova
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Country [16]
0
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Italy
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State/province [16]
0
0
Roma
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Country [17]
0
0
Japan
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State/province [17]
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Gifu-shi
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Country [18]
0
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Japan
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State/province [18]
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Iizuka-shi
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Country [19]
0
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Japan
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State/province [19]
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Kawasaki-shi
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Country [20]
0
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Japan
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State/province [20]
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Kitakyusyu-shi
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0
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Japan
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State/province [21]
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Nagaoka-shi
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0
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Japan
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State/province [22]
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Niigata-shi
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Country [23]
0
0
Japan
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State/province [23]
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Sapporo-shi
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Country [24]
0
0
Japan
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State/province [24]
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0
Yokohama-shi
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Country [25]
0
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Poland
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State/province [25]
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Bydgoszcz
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Country [26]
0
0
Poland
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State/province [26]
0
0
Katowice
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Country [27]
0
0
Poland
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State/province [27]
0
0
Kraków
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Country [28]
0
0
Poland
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State/province [28]
0
0
Myslowice
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0
0
Poland
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State/province [29]
0
0
Poznan
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0
0
Poland
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State/province [30]
0
0
Wroclaw
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0
0
Slovakia
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State/province [31]
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Bratislava
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0
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Slovakia
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State/province [32]
0
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Nitra
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Country [33]
0
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Slovakia
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State/province [33]
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Trnava
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Country [34]
0
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United Kingdom
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State/province [34]
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Aberdeen
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0
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United Kingdom
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State/province [35]
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Hull
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Country [36]
0
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United Kingdom
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State/province [36]
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Ipswich
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0
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United Kingdom
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0
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London
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Country [38]
0
0
United Kingdom
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State/province [38]
0
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Nottingham
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
AstraZeneca
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT06269484
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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0
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Address
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Country
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Phone
0
0
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Fax
0
0
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Email
0
0
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Contact person for public queries
Name
0
0
AstraZeneca Clinical Study Information Center
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Address
0
0
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Country
0
0
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Phone
0
0
1-877-240-9479
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Fax
0
0
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Email
0
0
[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT06269484
Download to PDF