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 Hypertensio

Phase 2

• Conditions: end-stage liver disease; hypertension of the portal vein of the liver; 10057166; 10019654

• Registration Number: NL-OMON51672
• Lead Sponsor: Astra Zeneca

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Last Update Posted: 9 April 2024

Recruitment & Eligibility

• Status: Pending
• Sex: Not specified
• Target Recruitment: 4

Inclusion Criteria

Participant must be aged 18 years and <= 80 years of age at the time of signing
theinformed consent.

Part A participants who have the following:
(a) Clinical and/or histological diagnosis of cirrhosis with either (i)
features of portalhypertension or (ii) liver stiffness >= 21 kPa.
(b) MELD score < 15.
(c) Child-Pugh score <= 6.
(d) No clinically evident ascites
(e) No evidence of worsening of hepatic function (eg, no clinically significant
change insigns, symptoms, or laboratory parameters of hepatic disease status)
within the lastmonth prior to dosing, as determined by the investigator or
usual practitioner.
(f) HVPG recording of good enough quality as judged by a central reader.

Part B participants who have the following:
(a) Clinical and/or histological diagnosis of cirrhosis with features of
portalhypertension.
(b) MELD score < 15.
(c) Child-Pugh score < 10.
(d) No ascites or ascites up to grade 2 without change in diuretic treatment
within the lastmonth prior to first dose and no paracentesis within the last
month or plannedparacentesis in the next 4 months at screening.
(e) No evidence of worsening of hepatic function (eg, no clinically significant
change insigns, symptoms, or laboratory parameters of hepatic disease status)
within the lastmonth prior to dosing, as determined by the investigator or
usual practitioner.
(f) HVPG recording of good enough quality as judged by a central reader.

Exclusion Criteria

Study principal exclusion criteria:
a) Any evidence of a clinically significant disease which in the investigator's
opinion makes it undesirable for the participant to participate in the study.
b) Liver cirrhosis caused by chronic cholestatic liver disease
c) ALT or AST >= 150 U/L and/or total bilirubin >= 3 × ULN
d) Acute liver injury caused by drug toxicity or by an infection.
e) Any history of hepatocellular carcinoma.
f) Liver transplant or expected liver transplantation within 6 months of
screening.
g) History of TIPS or a planned TIPS within 6 months from enrolment into the
study.
h) Active treatment for HCV within the last 1 year or HBV antiviral therapy for
less than 1 year.
i) Participants with T1DM.

Medical Conditions (Part A only)
a) INR > 1.5.
b) Serum/plasma levels of albumin <= 35 g/L.
c) Platelet count < 75 × 109/L.
d) History of ascites
e) History of hepatic hydrothorax
f) History of portopulmonary syndrome
g) History of hepatic encephalopathy
h) History of variceal haemorrhage
i) History of acute kidney injury
j) History of heart failure, including high output heart failure (eg, due to
hyperthyroidism or Paget's disease)

Medical Conditions (Part B only)
a) INR > 1.7.
b) Serum/plasma levels of albumin <= 28 g/L.
c) Platelet count < 50 × /109L.
d) Acute kidney injury within 3 months of screening.
e) History of encephalopathy of West Haven grade 2 or higher.
f) History of variceal haemorrhage within 6 months prior to screening.
g) 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.
h) 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).
i) High output heart failure (eg, due to hyperthyroidism or Paget's disease).
j) Heart failure due to primary cardiac valvular disease/dysfunction, severe
functional mitral or tricuspid valve insufficiency, or planned cardiac valve
repair/replacement.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>PART A:<br /><br>Obj: To evaluate the change from baseline in HVPG on zibotentan and<br /><br>dapagliflozin in combination versus placebo.<br /><br><br /><br>endpoint: Absolute change in HVPG from baseline to Week 6.<br /><br><br /><br><br /><br><br /><br>PART B:<br /><br>Obj: To evaluate the proportion of participants achieving at least 20% decrease<br /><br>in HVPG or a reduction to or below 12mmHg in HVPG on zibotentan and<br /><br>dapagliflozin in combination and dapagliflozin monotherapy versus placebo.<br /><br><br /><br>endpoint: HVPG response, where a responder is defined as at least 20% decrease<br /><br>or a reduction to or below 12 mmHgin HVPG from baseline to Week6.</p><br>