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

Liver Cirrhosis Clinical Trial

— ZEAL UNLOCK  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06269484
• Other study ID #: D4326C00004
• Status: Recruiting
• Phase: Phase 2
• Start date: February 15, 2024
• Est. completion date: January 17, 2025

Study information

• Verified date: March 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. completion date: January 17, 2025
• Est. primary completion date: January 17, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

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.

Related Conditions & MeSH terms

• Fibrosis
• Liver Cirrhosis

Intervention

Drug:
• Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet)
placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)
• Zibotentan + placebo (placebo matching dapagliflozin tablet)
zibotentan capsule placebo tablet (matching dapagliflozin tablet)
• Zibotentan + dapagliflozin
zibotentan capsule dapagliflozin 10 mg tablet

Locations

Country	Name	City	State
Australia	Research Site	Adelaide
Australia	Research Site	Kogarah
Australia	Research Site	Mitcham
Belgium	Research Site	Edegem
Belgium	Research Site	Mechelen
Czechia	Research Site	Liberec
Czechia	Research Site	Mladá Boleslav
Czechia	Research Site	Plzen
Czechia	Research Site	Praha 4
Germany	Research Site	Aachen
Germany	Research Site	Kiel
Germany	Research Site	Leipzig
Germany	Research Site	Tuebingen
Italy	Research Site	Milano
Italy	Research Site	Padova
Italy	Research Site	Roma
Japan	Research Site	Gifu-shi
Japan	Research Site	Iizuka-shi
Japan	Research Site	Kawasaki-shi
Japan	Research Site	Kitakyusyu-shi
Japan	Research Site	Nagaoka-shi
Japan	Research Site	Niigata-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Yokohama-shi
Poland	Research Site	Bydgoszcz
Poland	Research Site	Katowice
Poland	Research Site	Kraków
Poland	Research Site	Myslowice
Poland	Research Site	Poznan
Poland	Research Site	Wroclaw
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Nitra
Slovakia	Research Site	Trnava
United Kingdom	Research Site	Aberdeen
United Kingdom	Research Site	Hull
United Kingdom	Research Site	Ipswich
United Kingdom	Research Site	London
United Kingdom	Research Site	Nottingham
United States	Research Site	Charleston	South Carolina
United States	Research Site	Englewood	Colorado
United States	Research Site	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czechia,  Germany,  Italy,  Japan,  Poland,  Slovakia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on a composite endpoint of fluid retention	baseline to Week 6
Primary	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)	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on a composite endpoint of fluid retention	baseline to Week 6
Secondary	Change in body weight (kg) over time course of study	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body weight	at Week 6
Secondary	Change in body weight (kg) over time course of study	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body weight	at Week 6
Secondary	Change in total dosage of loop-diuretic equivalents use	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on total loop-diuretic equivalents use	from baseline to Week 6
Secondary	Change in total dosage of loop-diuretic equivalents use	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on total loop-diuretic equivalents use	from baseline to Week 6
Secondary	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	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	from baseline to Week 6
Secondary	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	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	from baseline to Week 6
Secondary	Absolute change in systolic and diastolic blood pressure	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on office-based systolic and diastolic blood pressure	from baseline to Week 6
Secondary	Absolute change in systolic and diastolic blood pressure	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on office-based systolic and diastolic blood pressure	from baseline to Week 6
Secondary	Change from baseline in body weight	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body weight	at Week 6
Secondary	Change from baseline in total body water	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on total body water	at Week 6
Secondary	Change from baseline in extracellular water volume	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on extracellular water volume	at Week 6
Secondary	Change from baseline in intracellular water volume	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on intracellular water volume	at Week 6
Secondary	Change from baseline in body fat mass	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body fat mass	at Week 6
Secondary	Change from baseline in body weight	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body weight	at Week 6
Secondary	Change from baseline in total body water	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on total body water	at Week 6
Secondary	Change from baseline in extracellular water volume	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on extracellular water volume	at Week 6
Secondary	Change from baseline in intracellular water volume	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on intracellular water volume	at Week 6
Secondary	Change from baseline in body fat mass	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body fat mass	at Week 6