A Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Participants With Cirrhosis-ZEAL-UNLOCK
Summary
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Cumulative Number of Subjects With Any of the Components of the 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) |
14; 14; 6 | — |
| SECONDARY Change From Baseline in Body Weight |
-1.08; 0.64; -0.53 | — |
| SECONDARY Change From Baseline in Body Fat Mass |
-1.68; -0.23; -0.30 | — |
| SECONDARY Change From Baseline in Total Body Water |
0.36; 0.66; -0.36 | — |
| SECONDARY Change From Baseline in Extracellular Water Volume |
0.38; 0.38; -0.15 | — |
| SECONDARY Change From Baseline in Intracellular Water Volume |
0.08; 0.30; -0.19 | — |
| SECONDARY Change in Body Weight (kg) Over Time Course of Study |
-1.754; 0.021; -1.256 | — |
| SECONDARY Change in Total Dosage of Loop-diuretic Equivalents Use |
1.282; 6.340; 1.338 | — |
| SECONDARY Cumulative Number of Subjects With 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 |
7; 9; 2 | — |
| SECONDARY Absolute Change in Systolic Blood Pressure |
-12.0; -2.6; -0.1 | — |
| SECONDARY Absolute Change in Diastolic Blood Pressure |
-9.1; -2.5; 1.8 | — |
Eligibility Criteria
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 1.7.
Serum/plasma levels of albumin ≤ 28 g/L.
Platelet count 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.
Data sourced from ClinicalTrials.gov (NCT06269484). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.