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Study on Zibotentan and Dapagliflozin for Patients with Liver Cirrhosis and Portal Hypertension

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is focused on studying a condition known as liver cirrhosis, which is a disease where the liver becomes scarred and its function is impaired. The study specifically looks at liver cirrhosis with features of portal hypertension, a complication where there is increased blood pressure in the vein that carries blood from the digestive organs to the liver. The trial is investigating the effects of two medications, Zibotentan and Dapagliflozin, both individually and in combination, compared to a placebo. Zibotentan, also known by its code name ZD4054, is taken as a hard capsule, while Dapagliflozin is administered as a film-coated tablet.

The purpose of the study is to assess how these medications can affect the condition of patients with liver cirrhosis and portal hypertension. Participants will be randomly assigned to receive either the combination of Zibotentan and Dapagliflozin, Dapagliflozin alone, or a placebo. The study is designed to be double-blind, meaning neither the participants nor the researchers will know who is receiving which treatment, to ensure unbiased results. The trial will be conducted over a period of 16 weeks, during which the participants' health and response to the treatment will be closely monitored.

Throughout the study, the main focus will be on measuring changes in a specific pressure in the liver, known as hepatic venous pressure gradient (HVPG), from the start of the study to the end. This measurement helps to understand the severity of portal hypertension and the effectiveness of the treatment. The study will also look at other health indicators, such as body weight and blood pressure, to evaluate the overall safety and tolerability of the medications. Participants will be required to take the medications orally, and their progress will be assessed at regular intervals to gather comprehensive data on the treatment's impact.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Initial assessment

    Upon joining the study, an initial assessment is conducted to confirm eligibility. This includes reviewing medical history and current health status.

    Participants must have a clinical or histological diagnosis of liver cirrhosis with features of portal hypertension.

  2. Step 2

    Baseline measurements

    Baseline measurements are taken to establish a starting point for the study. This includes measuring the hepatic venous pressure gradient (HVPG), which is a key indicator of portal hypertension.

    Other baseline measurements may include body weight, blood pressure, and water volume in the body.

  3. Step 3

    Medication administration

    Participants are randomly assigned to receive either a combination of zibotentan and dapagliflozin, dapagliflozin alone, or a placebo. All medications are taken orally in the form of hard capsules.

    The dosage and frequency of administration are determined by the study protocol and are followed throughout the trial period.

  4. Step 4

    Ongoing monitoring

    Participants are monitored regularly to assess the effects of the medication. This includes repeated measurements of HVPG, body weight, blood pressure, and other relevant health indicators.

    Monitoring occurs at specified intervals, such as at week 6 and week 16, to track changes over time.

  5. Step 5

    Final assessment

    At the end of the study period, a final assessment is conducted to evaluate the overall impact of the treatment.

    This includes a final measurement of HVPG and other health indicators to determine any changes from the baseline.

Who can join the trial?

13 criteria

  • Age between 18 and 80 years old.
  • For Part A: Must have a clinical or tissue-based diagnosis of cirrhosis with either features of portal hypertension (increased blood pressure in the vein that carries blood to the liver) or liver stiffness of 21 kPa or more.
  • For Part B: Must have a clinical or tissue-based diagnosis of cirrhosis with features of portal hypertension.
  • For Part A: MELD score (a score that predicts the severity of liver disease) must be less than 15.
  • For Part B: MELD score must be less than 15.
  • For Part A: Child-Pugh score (a score to assess the prognosis of chronic liver disease) must be 6 or less.
  • For Part B: Child-Pugh score must be less than 10.
  • For Part A: No visible ascites (fluid buildup in the abdomen).
  • For Part B: No ascites or only mild to moderate ascites without changes in water pill treatment in the last month, and no fluid removal procedure in the last month or planned in the next 4 months.
  • For Part A: No signs of worsening liver function in the last month, as determined by a doctor.
  • For Part B: No signs of worsening liver function in the last month, as determined by a doctor.
  • For Part A: Must have a high-quality HVPG (a test measuring blood pressure in the liver) recording.
  • For Part B: Must have a high-quality HVPG recording and an HVPG measurement greater than 10 mmHg.

Who cannot join the trial?

1 criterion

  • Patients with **liver cirrhosis** that have features of **portal hypertension** cannot participate. Liver cirrhosis is a condition where the liver is severely scarred. Portal hypertension is increased blood pressure in the vein that carries blood to the liver.
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Investigated drugs

  • Zibotentan

    is a medication being studied for its potential to help people with cirrhosis, a liver condition, who also have signs of increased blood pressure in the veins that supply the liver. This medication works by blocking certain receptors in the body that can contribute to high blood pressure in these veins. The goal is to see if zibotentan can help reduce this pressure and improve liver health.

  • Dapagliflozin

    is a medication commonly used to help control blood sugar levels in people with diabetes. In this study, it is being tested to see if it can also help people with cirrhosis and high blood pressure in the liver veins. Dapagliflozin works by helping the kidneys remove sugar from the body through urine, and researchers are exploring if it has additional benefits for liver health in this context.

What is already known about the treatment

  • Zibotentan

    Zibotentan is administered orally in tablet form and is currently being studied in clinical trials for its potential use in treating liver cirrhosis with features of portal hypertension. It is not yet widely used in medicine, as it is still under investigation. The main therapeutic indication for zibotentan is to help reduce the pressure in the portal vein, which can be a complication of liver cirrhosis. At the molecular level, zibotentan works by blocking a specific receptor called the endothelin receptor, which is involved in the constriction of blood vessels. This medication is classified as an endothelin receptor antagonist.

  • Dapagliflozin

    Dapagliflozin is taken orally in tablet form and is currently being evaluated in clinical trials for its effectiveness in treating liver cirrhosis with features of portal hypertension. While it is already approved for use in managing type 2 diabetes, its role in liver conditions is still being researched. The main therapeutic indication in this trial is to help manage the complications associated with portal hypertension. Dapagliflozin works by inhibiting a protein in the kidneys called SGLT2, which helps lower blood sugar levels and may have beneficial effects on blood pressure and fluid balance. It is classified as an SGLT2 inhibitor.

Investigated diseases

Liver Cirrhosis with Features of Portal Hypertension – Liver cirrhosis is a condition where the liver becomes severely scarred, affecting its ability to function properly. This scarring is often the result of long-term damage from conditions like chronic alcohol use or hepatitis. As cirrhosis progresses, it can lead to portal hypertension, which is an increase in blood pressure within the portal vein system. This occurs because the scarred liver tissue obstructs normal blood flow through the liver. Over time, portal hypertension can cause complications such as varices, which are enlarged veins that can bleed, and ascites, which is the accumulation of fluid in the abdomen. The progression of liver cirrhosis and portal hypertension can lead to significant changes in the body's fluid balance and blood pressure.
Trial detailsLast updated 2 Oct 2026
Age18+ yearsPhasePhase IITrial ID2023-505405-17-00Protocol codeZealEstimated enrolment217 patientsSponsorAstraZeneca AB

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