Zibotentan and Dapagliflozin Combination, EvAluated in Liver Cirrhosis (ZEAL Study)

Study Overview
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Brief Summary
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This is a two part Phase IIa/b multicentre, randomised, double-blind, placebo-controlled, parallel group dose-ranging study to assess the 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.

Detailed Description
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Part A will assess the efficacy, safety, and tolerability of the combination of B mg zibotentan and 10 mg dapagliflozin versus placebo in participants with Child-Pugh A cirrhosis with features of portal hypertension and with no history of decompensation events. If the safety profile is determined to be acceptable at the conclusion of Part A, Part B will investigate efficacy, safety, and tolerability of A mg, B mg, or C mg zibotentan combined with 10 mg dapagliflozin and of 10 mg dapagliflozin monotherapy versus placebo in participants with cirrhosis with features of portal hypertension. Part B will include a broader range of Child- Pugh A and Child-Pugh B cirrhosis participants, including those with more severe disease, a history of decompensation events, or current ascites. The study will be conducted in approximately 30 to 45 study centres in North America, Asia, and Europe.

Official Title
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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

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Drug: Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)
* Drug: Part A: zibotentan (dose B) + dapagliflozin
* Drug: Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)
* Drug: Part B: placebo (matching zibotentan capsule) + dapagliflozin
* Drug: Part B: zibotentan (dose A) + dapagliflozin
* Drug: Part B: zibotentan (dose B) + dapagliflozin
* Drug: Part B: zibotentan (dose C) + dapagliflozin


Participation Criteria
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Eligibility Criteria
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Study principal inclusion criteria For both Part A and Part B No current or prior (within 1 month of enrolment) medical treatment with an SGLT2 inhibitor or ERAs. 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. Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses. Female participants of non-childbearing potential confirmed at screening by fulfilling one of the following criteria: 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. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. Female participants must have a negative pregnancy test at screening and must not be lactating Part A participants who have the following: Clinical and/or histological diagnosis of cirrhosis with either (i) features of portal hypertension or (ii) liver stiffness ≥ 21 kPa. MELD score < 15. Child-Pugh score ≤ 6. No clinically evident ascites. 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. HVPG recording of good enough quality as judged by a central reader. Part B participants who have the following: Clinical and/or histological diagnosis of cirrhosis and either history of decompensation or compensated cirrhosis with signs of clinically significant portal hypertension. HVPG recording of good enough quality and HVPG > 10 mmHg, as judged by a central reader. MELD score < 15. Child-Pugh score < 10. 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. 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: Any evidence of a clinically significant disease which in the investigator's opinion makes it undesirable for the participant to participate in the study. Liver cirrhosis caused by chronic cholestatic liver disease ALT or AST ≥ 150 U/L and/or total bilirubin ≥ 3 × ULN Acute liver injury caused by drug toxicity or by an infection. Any history of hepatocellular carcinoma. Liver transplant or expected liver transplantation within 6 months of screening. History of TIPS or a planned TIPS within 6 months from enrolment into the study. Active treatment for HCV within the last 1 year or HBV antiviral therapy for less than 1 year. Participants with T1DM. Medical Conditions (Part A only) INR > 1.5. Serum/plasma levels of albumin ≤ 35 g/L. Platelet count < 75 × 109/L. History of ascites History of hepatic hydrothorax History of portopulmonary syndrome History of hepatic encephalopathy History of variceal haemorrhage History of acute kidney injury History of heart failure, including high output heart failure (eg, due to hyperthyroidism or Paget's disease) Medical Conditions (Part B only) INR > 1.7. Serum/plasma levels of albumin ≤ 28 g/L. Platelet count < 50 × /109L. Acute kidney injury within 3 months of screening. History of encephalopathy of West Haven grade 2 or higher. History of variceal haemorrhage within 6 months prior to screening. 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. 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Treatment Group 1<br>Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks. | Drug: Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)<br>* placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)<br>|
| Experimental: Part A: Treatment Group 2<br>Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 6 weeks. | Drug: Part A: zibotentan (dose B) + dapagliflozin<br>* zibotentan capsule dapagliflozin tablet<br>|
| Experimental: Part B: Treatment Group 1<br>Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 16 weeks. | Drug: Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet)<br>* placebo capsule (matching zibotentan capsule) placebo tablet (matching dapagliflozin tablet)<br>|
| Experimental: Part B: Treatment Group 2<br>Participants will receive once daily dose of placebo matching zibotentan capsule + dapagliflozin tablet for 16 weeks. | Drug: Part B: placebo (matching zibotentan capsule) + dapagliflozin<br>* placebo capsule (matching zibotentan capsule) dapagliflozin tablet<br>|
| Experimental: Part B: Treatment Group 3<br>Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks. | Drug: Part B: zibotentan (dose A) + dapagliflozin<br>* zibotentan capsule dapagliflozin tablet<br>|
| Experimental: Part B: Treatment Group 4<br>Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks. | Drug: Part B: zibotentan (dose B) + dapagliflozin<br>* zibotentan capsule dapagliflozin tablet<br>|
| Experimental: Part B: Treatment Group 5<br>Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks. | Drug: Part B: zibotentan (dose C) + dapagliflozin<br>* zibotentan capsule dapagliflozin tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Absolute change in HVPG from baseline to Week 6. | To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo. | at Week 6 | 
| Part B: Absolute change in HVPG from baseline to Week 6. | To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo. | at Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percent change in HVPG from baseline to Week 6. | To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo. | at Week 6 | 
| Part A: HVPG response, where a responder is defined as HVPG < 10 mmHg or a reduction in HVPG of ≥ 1.5 mmHg from baseline to Week 6. | To evaluate the proportion of participants achieving HVPG < 10 mmHg or a reduction in HVPG of ≥ 1.5 mmHg on zibotentan and dapagliflozin versus placebo. | at Week 6 | 
| Part A: Evaluation of change in body weight (kg) over time course of study. Percentage and absolute change from baseline in body weight at Week 6. | To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on change in body weight. | at Week 6 | 
| Part A: Percentage and absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6. | To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on total loop-diuretic equivalents use. | at Week 6 | 
| Part A: Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6. Change in total body fat mass from baseline to Week 6. | To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on body water volumes and body fat mass. | at Week 6 | 
| Part A: Change in systolic and diastolic blood pressure from baseline to Week 6. | To evaluate the effect of zibotentan and dapagliflozin in combination versus placebo on changes in office-based systolic and diastolic blood pressure. | at Week 6 | 
| Part B: Percentage change in HVPG from baseline to Week 6. | To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo. | at Week 6 | 
| Part B: HVPG response, where a responder is defined as at least 20% decrease or a reduction to or below 12 mmHg in HVPG from baseline to Week 6. | To evaluate the proportion of participants achieving at least 20% decrease in HVPG or a reduction to or below 12 mmHg in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo. | at Week 6 | 
| Part B: Evaluation of change in body weight (kg) over time course of study. Percentage and absolute change from baseline in body weight at Week 6 and Week 16. | To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on change in body weight. | at Week 6 and Week 16 | 
| Part B: Absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16. | To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on total loop-diuretic equivalents use. | at Week 6 and Week 16 | 
| Part B: Change in total body water, extracellular water and intracellular water volumes from baseline to Week 6 and Week 16. Change in total body fat mass from baseline to Week 6 and Week 16. | To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on body water volumes and body fat mass. | at Week 6 and Week 16 | 
| Part B: Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16. | To evaluate the effect of zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo on changes in office-based systolic and diastolic blood pressure. | at Week 6 and Week 16 |