Phase IIb Evaluation of Zibotentan and Dapagliflozin Safety in Cirrhosis: Monotherapy and Combination Versus Placebo
- Trial ID
- 2023-506893-11-00
- Protocol
- ZEAL-UNLOCK
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase IIb study is to evaluate the effect of **zibotentan**/**dapagliflozin** combination therapy compared to zibotentan monotherapy and placebo on a composite endpoint of fluid retention in participants with cirrhosis. This is clinically relevant as fluid retention is a common complication in cirrhosis, leading to significant morbidity. The study also aims to assess the impact of these treatments on body weight, body water volumes, body fat mass, total loop-diuretic equivalents use, and office-based systolic and diastolic blood pressure. These parameters are critical in managing cirrhosis, as they can influence patient outcomes and quality of life.
Secondary objectives include assessing the safety and tolerability of zibotentan/dapagliflozin and zibotentan compared to placebo. Understanding the safety profile is essential for determining the therapeutic viability of these treatments in clinical practice.
Participants
The clinical trial involves a total of **30 participants** diagnosed with **cirrhosis of the liver**, a condition characterized by scarring and damage to the liver. The study population includes both male and female subjects, aged between **18 and 80 years**. Participants are required to be in a stable health condition, with no significant changes in hepatic function or treatment regimens within the month prior to the study. The selection criteria ensure that participants have a Model for End-Stage Liver Disease (MELD) score of less than 15 and a Child-Pugh score of less than 10, indicating a specific range of liver function. Lifestyle considerations include the requirement for participants to be on no or stable doses of beta blockers, with no recent use of SGLT2 inhibitors or endothelin receptor antagonists. The trial excludes vulnerable populations and focuses on individuals who meet the specified health and treatment stability criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** Phase IIb study to evaluate the safety and efficacy of **zibotentan** and **dapagliflozin** in combination, compared to zibotentan monotherapy, as well as both treatments compared to placebo in participants with **cirrhosis of the liver**. The trial aims to assess the impact on fluid retention, body weight, body water volumes, body fat mass, and the use of loop-diuretics. The study will also evaluate the effects on systolic and diastolic blood pressure. The trial is expected to last for approximately 42 days, with participant involvement beginning from the screening visit and continuing through to the end-of-study visit.
Participants will undergo a series of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, sex, and medical history, including a diagnosis of cirrhosis. The screening will ensure participants are not currently or have not recently been treated with an SGLT2 inhibitor or endothelin receptor antagonist. Following successful screening, participants will be randomized to receive either the combination therapy, monotherapy, or placebo. The trial will include regular follow-up visits to monitor safety and efficacy endpoints, such as changes in body weight, total body water, and blood pressure, as well as to record any adverse events.
The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints. Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as significant adverse events or non-compliance with the study protocol. The trial is scheduled to commence recruitment in February 2024, with an estimated completion date in January 2025.
Treatment
The clinical trial involves the administration of **Zibotentan**, an experimental medication provided in the form of a hard capsule. The active substance, **zibotentan**, is of chemical origin and is manufactured by AstraZeneca AB. The medication is administered orally. The trial does not specify a maximum daily dose, but the treatment period is set for a maximum of 42 days. Participants' compliance with the dosing schedule will be monitored throughout the study.
**Dapagliflozin** is another experimental medication used in this trial, provided as a film-coated tablet. The active substance, **dapagliflozin**, is also of chemical origin. The maximum daily dose for dapagliflozin is 10 mg, with a total maximum dose of 420 mg over the 42-day treatment period. This medication is administered orally, and participant adherence to the dosing regimen will be closely monitored.
The study also includes the use of a **Zibotentan placebo**, which serves as a comparator treatment. The placebo is designed to mimic the appearance of the zibotentan capsules but does not contain any active pharmaceutical ingredients. The placebo is administered orally, and its use is intended to maintain the double-blind nature of the trial.
Similarly, a **Dapagliflozin placebo** is utilized in the trial. This placebo is intended to resemble the dapagliflozin tablets in appearance but lacks any active substances. The administration of the placebo is oral, and it is used to ensure the integrity of the study's blinding process.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on evaluating the occurrence of specific components from baseline to Week 6, including a greater than 2 kg increase in body weight, a greater than 2 L increase in total body water, an increase in two or more loop-diuretic equivalents, and the occurrence of fluid retention adverse events. Additionally, changes in body weight, total body water, extracellular and intracellular water volumes, and body fat mass will be monitored at Week 6. The total dosage of loop-diuretic equivalents used from baseline to Week 6 will also be assessed, along with the absolute change in systolic and diastolic blood pressure.
Secondary endpoints will include the assessment of adverse events (AEs), serious adverse events (SAEs), and discontinuations due to adverse events (DAEs). Other secondary measures will involve adverse events of special interest (AESIs) such as new or worsening heart failure, signs of fluid retention, orthostatic hypotension, urinary tract infections, gastrointestinal issues, and acute kidney injury. Vital signs, safety laboratory tests, and electrocardiogram (ECG) assessments will also be part of the secondary efficacy evaluations. These parameters will be measured and collected at specified time points throughout the study to ensure comprehensive analysis of the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age: Participant must be aged ≥ 18 years and ≤ 80 years of age at the time of signing the informed consent.
- Participants who have the following: a) 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 × 109 (at time of screening).
- Participants who have the following: b) Model for end stage liver disease score (MELD) < 15.
- Participants who have the following: c) Child-Pugh score < 10.
- Participants who have the following: d) 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.
- Participants who have the following: e) 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.
- Medical Treatment: No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or endothelin receptor antagonist.
- Medical Treatment: 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.
- Sex and Contraceptive/Barrier Requirements: 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 See sections 5.3.5 and 8.4.9.2.
- Sex and Contraceptive/Barrier Requirements: Males or females of non-childbearing potential. Female participants must be of non-childbearing potential confirmed at screening by fulfilling one of the following criteria: o 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. o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
- Sex and Contraceptive/Barrier Requirements: Female participants must have a negative pregnancy test at screening and must not be lactating.
- Informed Consent: 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.
- Informed Consent: Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
- Informed Consent: 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
- Medical Condition: Any evidence of a clinically significant disease, which in the investigator’s opinion makes it undesirable for the participant to participate in the study.
- Medical Condition: Alanine aminotransferase/transaminase or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN.
- Medical Condition: International normalised ratio > 1.7.
- Medical Condition: Serum/plasma levels of albumin ≤ 28 g/L.
- Medical Condition: Platelet count < 50 × 109L.
- Medical Condition: Acute kidney injury (AKI) within 3 months of screening.
- Medical Condition: History of encephalopathy of West Haven Grade 2 or higher.
- Medical Condition: History of variceal haemorrhage within 6 months prior to screening.
- Medical Condition: Any history of hepatocellular carcinoma.
- Medical Condition: Any history of portal venous thrombosis.
- Medical Condition: Liver transplant or expected liver transplantation within 6 months of screening.
- Medical Condition: History of TIPS or a planned TIPS within 6 months from enrolment into the study.
- Medical Condition: Positive alcohol breath test or screen for drugs of abuse (excluding drugs prescribed by the participants’ usual physician) at screening.
- Medical Condition: Ongoing or history of significant use of alcohol expected to preclude correct adherence to study procedures (For details, refer to Section 5.3.2).
- Medical Condition: Active treatment for HCV within the last 1 year or HBV anti-viral therapy for less than 1 year.
- Medical Condition: Active urinary tract infection or genital infection.
- Medical Condition: Uncontrolled diabetes mellitus (HbA1c > 8.5% or > 69 mmol/mol within the last month).
- Medical Condition: Participants with T1DM.
- Medical Condition: Renal transplant or chronic renal replacement therapy or short-term dialysis within the previous 6 months.
- Medical Condition: eGFR < 60 mL/min/1.73m2 (eGFRcr[AS]).
- Medical Condition: Acute coronary syndrome events within 3 months prior to screening.
- Medical Condition: Orthostatic hypotension or hypotension (systolic blood pressure < 95 mmHg or diastolic blood pressure < 60 mmHg).
- Medical Condition: 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.
- Medical Condition: Heart failure due to cardiomyopathies that would primarily require specific other treatment.
- Medical Condition: High output heart failure (eg, due to hyperthyroidism or Paget’s disease).
- Medical Condition: Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.
- Medical Condition: 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.
- Medical Condition: 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.
- Medical Condition: 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.
- Medical Condition: Acute liver injury caused by drug toxicity or by an infection.
- Prior/Concurrent Clinical Study Experience: Participation in another clinical study with a study intervention administered in the last 3 months prior to randomisation.
- Other Exclusions: Implanted electronic device such as pacemaker.
- Other Exclusions: Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study centre).
- Other Exclusions: 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.
- Other Exclusions: Male participant in a sexually active relation with pregnant or breastfeeding partner.
- Other Exclusions: 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. The following participants are not eligible to consent to the optional genetic sampling: Previous allogeneic bone marrow transplant.
- Exclusion Criteria for Participants Consenting to Optional Genetic Sampling. The following participants are not eligible to consent to the optional genetic sampling: Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 15 Feb 2024 | 4 |
 Czechia | Not Recruiting | 15 Feb 2024 | 6 |
 Germany | Not Recruiting | 15 Feb 2024 | 7 |
 Italy | Not Recruiting | 15 Feb 2024 | 6 |
 Poland | Not Recruiting | 15 Feb 2024 | 8 |
 Slovakia | Not Recruiting | 15 Feb 2024 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zibotentan | Test | CAPSULE, HARD | ORAL | 0 | 42 | PRD10433114 |
DAPAGLIFLOZIN | Test | — | ORAL | 10 | 42 | SUB31650 |
Zibotentan placebo | Placebo | N/A | — | — | — | N/A |
Dapagliflozin placebo | Placebo | N/A | — | — | — | N/A |