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

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.

Study Overview

• Status: Recruiting
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Drug: Placebo (placebo matching zibotentan capsule and placebo matching dapagliflozin tablet); Drug: Zibotentan + placebo (placebo matching dapagliflozin tablet); Drug: Zibotentan + dapagliflozin

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.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Not yet recruiting
    • Research Site
  • Kogarah, Australia, 2217
    • Not yet recruiting
    • Research Site
  • Mitcham, Australia, 3132
    • Not yet recruiting
    • Research Site
• Belgium
  • Edegem, Belgium, 2650
    • Not yet recruiting
    • Research Site
  • Mechelen, Belgium, 2800
    • Not yet recruiting
    • Research Site
• Czechia
  • Liberec, Czechia, 460 63
    • Not yet recruiting
    • Research Site
  • Mladá Boleslav, Czechia, 293 01
    • Not yet recruiting
    • Research Site
  • Plzeň, Czechia, 323 00
    • Not yet recruiting
    • Research Site
  • Praha 4, Czechia, 140 21
    • Not yet recruiting
    • Research Site
• Germany
  • Aachen, Germany, 52074
    • Not yet recruiting
    • Research Site
  • Kiel, Germany, 24146
    • Not yet recruiting
    • Research Site
  • Leipzig, Germany, 04103
    • Not yet recruiting
    • Research Site
  • Tuebingen, Germany, 72076
    • Not yet recruiting
    • Research Site
• Italy
  • Milano, Italy, 20122
    • Not yet recruiting
    • Research Site
  • Padova, Italy, 35128
    • Not yet recruiting
    • Research Site
  • Roma, Italy, 00168
    • Not yet recruiting
    • Research Site
• Japan
  • Gifu-shi, Japan, 500-8513
    • Not yet recruiting
    • Research Site
  • Iizuka-shi, Japan, 820-8505
    • Recruiting
    • Research Site
  • Kawasaki-shi, Japan, 215-0026
    • Not yet recruiting
    • Research Site
  • Kitakyusyu-shi, Japan, 806-8501
    • Not yet recruiting
    • Research Site
  • Nagaoka-shi, Japan, 940-2085
    • Recruiting
    • Research Site
  • Niigata-shi, Japan, 951-8520
    • Recruiting
    • Research Site
  • Sapporo-shi, Japan, 006-8555
    • Not yet recruiting
    • Research Site
  • Yokohama-shi, Japan, 236-0004
    • Not yet recruiting
    • Research Site
• Poland
  • Bydgoszcz, Poland, 85-794
    • Not yet recruiting
    • Research Site
  • Katowice, Poland, 40-081
    • Not yet recruiting
    • Research Site
  • Kraków, Poland, 31-513
    • Not yet recruiting
    • Research Site
  • Mysłowice, Poland, 41-400
    • Not yet recruiting
    • Research Site
  • Poznań, Poland, 61-848
    • Not yet recruiting
    • Research Site
  • Wrocław, Poland, 52-210
    • Not yet recruiting
    • Research Site
• Slovakia
  • Bratislava, Slovakia, 83104
    • Not yet recruiting
    • Research Site
  • Nitra, Slovakia, 950 01
    • Not yet recruiting
    • Research Site
  • Trnava, Slovakia, 91702
    • Not yet recruiting
    • Research Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Not yet recruiting
    • Research Site
  • Hull, United Kingdom, HU3 2KZ
    • Not yet recruiting
    • Research Site
  • Ipswich, United Kingdom, IP4 5PD
    • Not yet recruiting
    • Research Site
  • London, United Kingdom, SE5 9RS
    • Not yet recruiting
    • Research Site
  • Nottingham, United Kingdom, NG7 2UH
    • Not yet recruiting
    • Research Site
• United States
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Not yet recruiting
      • Research Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Not yet recruiting
      • Research Site
  • Texas
    • San Antonio, Texas, United States, 78215
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Treatment Group 1; 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); placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)
Experimental: Treatment Group 2; Participants will receive once daily zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks	Drug: Zibotentan + placebo (placebo matching dapagliflozin tablet); zibotentan capsule placebo tablet (matching dapagliflozin tablet)
Experimental: Treatment Group 3; Participants will receive once daily zibotentan capsule + dapagliflozin tablet 10 mg for 6 weeks	Drug: Zibotentan + dapagliflozin; zibotentan capsule dapagliflozin 10 mg tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
Change from baseline in body weight	To evaluate the effect of zibotentan/dapagliflozin versus corresponding zibotentan monotherapy on body weight	at Week 6
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
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
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
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
Change from baseline in body weight	To evaluate the effect of zibotentan/dapagliflozin and zibotentan monotherapy versus placebo on body weight	at Week 6
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
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
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
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

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2024
• Primary Completion (Estimated): January 17, 2025
• Study Completion (Estimated): January 17, 2025

Study Registration Dates

• First Submitted: February 2, 2024
• First Submitted That Met QC Criteria: February 13, 2024
• First Posted (Actual): February 21, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D4326C00004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing 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
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No