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Combination of zibotentan and dapagliflozin for liver cirrhosis

A Two Part Phase IIa/b Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Dose-ranging Study to Assess Efficacy, Safety, and Tolerability of the Combination of Zibotentan and Dapagliflozin, and Dapagliflozin Monotherapy Versus Placebo in Participants With Cirrhosis With Features of Portal Hypertension

Phase 2 Interventional AstraZeneca · NCT05516498

This study is testing if a combination of two medications, zibotentan and dapagliflozin, can help people with liver cirrhosis and high blood pressure in the liver feel better compared to a placebo.

Quick facts

PhasePhase 2
Study typeInterventional
Enrollment195 (estimated)
Ages18 Years to 80 Years
SexAll
SponsorAstraZeneca Industry-sponsored
Drugs / interventionschemotherapy
Locations66 sites (Birmingham, Alabama and 65 other locations)
Trial IDNCT05516498 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the efficacy, safety, and tolerability of zibotentan combined with dapagliflozin compared to placebo in patients with liver cirrhosis and portal hypertension. The study is divided into two parts: Part A focuses on patients with Child-Pugh A cirrhosis without decompensation events, while Part B includes a broader range of patients with Child-Pugh A and B cirrhosis, including those with more severe disease. The trial is multicenter, randomized, double-blind, and placebo-controlled, involving approximately 30 to 45 centers across North America, Asia, and Europe.

Who should consider this trial

Good fit: Ideal candidates are adults with Child-Pugh A or B liver cirrhosis and features of portal hypertension who have not received recent treatment with SGLT2 inhibitors or endothelin receptor antagonists.

Not a fit: Patients with recent treatment using SGLT2 inhibitors or endothelin receptor antagonists, or those with significant liver decompensation, may not benefit from this study.

Why it matters

Potential benefit: If successful, this combination therapy could improve treatment outcomes for patients with liver cirrhosis and portal hypertension.

How similar studies have performed: While this approach is novel in the context of liver cirrhosis, similar combination therapies have shown promise in other conditions, indicating potential for success.

Eligibility criteria

Show full inclusion / exclusion criteria 
Study principal inclusion criteria For both Part A and Part B

1. No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or ERAs.
2. 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.
3. Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
4. Female participants of non-childbearing potential confirmed at screening by fulfilling one of the following criteria:

   1. 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.
   2. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
5. Female participants must have a negative pregnancy test at screening and must not be lactating

Part A participants who have the following:

1. Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness ≥ 21 kPa.
2. MELD score \< 15.
3. Child-Pugh score ≤ 6.
4. No clinically evident ascites.
5. 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.
6. HVPG recording of good enough quality as judged by a central reader.

Part B participants who have the following:

1. Clinical and/or histological diagnosis of cirrhosis and either history of decompensation or compensated cirrhosis with signs of clinically significant portal hypertension.
2. HVPG recording of good enough quality and HVPG \> 10 mmHg, as judged by a central reader.
3. MELD score \< 15.
4. Child-Pugh score \< 10.
5. No ascites or ascites up to grade 2 without change in diuretic treatment within the last month prior to first dose and no paracentesis within the last month or planned paracentesis in the next 4 months at screening.
6. 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.

Study principal exclusion criteria:

1. Any evidence of a clinically significant disease which in the investigator's opinion makes it undesirable for the participant to participate in the study.
2. Liver cirrhosis caused by chronic cholestatic liver disease
3. ALT or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN
4. Acute liver injury caused by drug toxicity or by an infection.
5. Any history of hepatocellular carcinoma.
6. Liver transplant or expected liver transplantation within 6 months of screening.
7. History of TIPS or a planned TIPS within 6 months from enrolment into the study.
8. Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year.
9. Participants with T1DM.

Medical Conditions (Part A only)

1. INR \> 1.5.
2. Serum/plasma levels of albumin ≤ 35 g/L.
3. Platelet count \< 75 × 109/L.
4. History of ascites
5. History of hepatic hydrothorax
6. History of portopulmonary syndrome
7. History of hepatic encephalopathy
8. History of variceal haemorrhage
9. History of acute kidney injury
10. History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget's disease)

Medical Conditions (Part B only)

1. INR \> 1.7.
2. Serum/plasma levels of albumin ≤ 28 g/L.
3. Platelet count \< 50 × /109L.
4. Acute kidney injury within 3 months of screening.
5. History of encephalopathy of West Haven grade 2 or higher within 6 months prior to screening.
6. History of variceal haemorrhage within 6 months prior to screening.
7. NYHA functional heart failure class III or IV or 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.
8. Heart failure due to cardiomyopathies that would primarily require specific other treatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or other infiltrative diseases, cardiomyopathy related to congenital heart disease, primary hypertrophic cardiomyopathy, cardiomyopathy related to toxic or infective conditions (ie, chemotherapy, infective myocarditis, septic cardiomyopathy).
9. High output heart failure (eg, due to hyperthyroidism or Paget's disease).
10. Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.

Where this trial is running

Birmingham, Alabama and 65 other locations

+16 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Liver Cirrhosis
Last reviewed 2026-06-10 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.