Zibotentan and Dapagliflozin, and Dapagliflozin Monotherapy in Cirrhosis

What is the Purpose of this Study?

The purpose of this study is to learn more about the effects of 2 drugs, zibotentan and dapagliflozin, in people with liver disease (cirrhosis) with features of increased pressure in portal veins (portal hypertension). The study also aims to better understand this disease and associated health problems. Cirrhosis is the end-stage of chronic liver disease and slows the blood flow through the liver, which causes increased pressure in portal veins known as portal hypertension. Zibotentan works by blocking the effect of the hormone that causes the narrowing of blood vessels, which may thereby prevent complications of liver disease. Dapagliflozin reduces water accumulating in the body, which helps to maintain the overall health of the body. Researchers aim to measure the effect of zibotentan in combination with dapagliflozin on lowering blood pressure in the liver veins in these patients, in addition to assessing the drugs’ safety and tolerability. Participants will be randomly assigned to receive the combination of zibotentan with dapagliflozin or placebo (inactive substance). Zibotentan is an experimental drug; dapagliflozin is approved by the U.S. Food and Drug Administration (FDA) to treat various conditions, but its use in this study is investigational.

Eligibility

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. 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.
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.
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.

Show less

Where can I participate?

Beverly

More about this Clinical Trial

What is the full name of this clinical trial?

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

Study Details

Disease Type/Condition

Liver cirrhosis, Portal hypertension

Principal Investigator

Kuo, Alexander

Co-Investigators

Ju Dong Yang, Walid Ayoub

Age Group

Adult

Phase

IRB Number

STUDY00002494

ClinicalTrials.gov ID

NCT05516498

Key Eligibility

ClinicalTrials.gov

How do I learn more about this study?

clinicaltrials@cshs.org