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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- AstraZeneca
- 入组人数
- 205
- 试验地点
- 51
- 主要终点
- Absolute Change in HVPG From Baseline to Week 6, Part A
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Screening
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 <
- •Child-Pugh score ≤
- •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 <
- •Child-Pugh score <
- •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
排除标准
- •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)
- •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)
- •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 within 6 months prior to screening.
- •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.
研究组 & 干预措施
Part A: Treatment Group 2
Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 6 weeks.
干预措施: Part A: zibotentan (dose B) + dapagliflozin (Drug)
Part B: Treatment Group 3
Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.
干预措施: Part B: zibotentan (dose A) + dapagliflozin (Drug)
Part B: Treatment Group 5
Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.
干预措施: Part B: zibotentan (dose C) + dapagliflozin (Drug)
Part B: Treatment Group 4
Participants will receive once daily dose of zibotentan capsule + dapagliflozin tablet for 16 weeks.
干预措施: Part B: zibotentan (dose B) + dapagliflozin (Drug)
Part B: Treatment Group 1
Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 16 weeks.
干预措施: Part B: Placebo (matching zibotentan capsule & matching dapagliflozin tablet) (Drug)
Part B: Treatment Group 2
Participants will receive once daily dose of placebo matching zibotentan capsule + dapagliflozin tablet for 16 weeks.
干预措施: Part B: placebo (matching zibotentan capsule) + dapagliflozin (Drug)
Part A: Treatment Group 1
Participants will receive once daily dose of placebo matching zibotentan capsule + placebo matching dapagliflozin tablet for 6 weeks.
干预措施: Part A: Placebo (matching zibotentan capsule & matching dapagliflozin tablet) (Drug)
结局指标
主要结局
Absolute Change in HVPG From Baseline to Week 6, Part A
时间窗: From Baseline to Week 6
Absolute change in Hepatic venous pressure gradient from baseline to week 6.
Absolute Change in HVPG From Baseline to Week 6, Part B
时间窗: From Baseline to Week 6
Absolute change in Hepatic venous pressure gradient from baseline to week 6.
Part B: Absolute change in HVPG from baseline to Week 6.
时间窗: at Week 6
To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination and dapagliflozin monotherapy versus placebo.
Part A: Absolute change in HVPG from baseline to Week 6.
时间窗: at Week 6
To evaluate the change from baseline in HVPG on zibotentan and dapagliflozin in combination versus placebo.
次要结局
- HVPG Percentage Change From Baseline to Week 6, Part A(From Baseline to Week 6)
- HVPG Percentage Change From Baseline to Week 6, Part B(From baseline to week 6)
- Number of Participants With HVPG Response at Week 6, Part A(From baseline to week 6)
- Number of Participants With HVPG Response at Week 6, Part B(From baseline to Week 6)
- Change in Body Weight (kg) Over Time Course of Study, Part A(From baseline to Week 6)
- Change in Body Weight (kg) Over Time Course of Study, Part B(From baseline to Week 6 and Week 16)
- Change in Total Dosage of Loop-diuretic Equivalents Use From Baseline to Week 6, Part A(From baseline to Week 6)
- Change in Total Dosage of Loop-diuretic Equivalents Use From Baseline to Week 6 and Week 16, Part B(From Baseline to Week 6 and Week 16)
- Change in Total Body Water From Baseline to Week 6, Part A(From Baseline to Week 6)
- Change in Total Body Water From Baseline to Week 6 and Week 16, Part B(From Baseline to Week 6 and Week 16)
- Change in Extracellular Water From Baseline to Week 6, Part A(From baseline to Week 6)
- Change in Extracellular Water From Baseline to Week 6 and Week 16, Part B(From Baseline to Week 6 and to Week 16)
- Change in Intracellular Water From Baseline to Week 6, Part A(From Baseline to Week 6)
- Change in Intracellular Water From Baseline to Week 6 and Week 16, Part B(From Baseline to Week 6 and Week 16)
- Change in Total Body Fat Mass From Baseline to Week 6, Part A(From baseline to Week 6)
- Change in Total Body Fat Mass From Baseline to Week 6 and Week 16, Part B(From Baseline to Week 6 and Week 16)
- Change in Systolic Blood Pressure From Baseline to Week 6, Part A(From Baseline to Week 6)
- Change in Systolic Blood Pressure From Baseline to Week 6 and Week 16, Part B(From baseline to Week 6 and Week 16)
- Change in Diastolic Blood Pressure From Baseline to Week 6, Part A(From Baseline to Week 6)
- Change in Diastolic Blood Pressure From Baseline to Week 6 and Week 16, Part B(From baseline to Week 6 and Week 16)
- Part A: Percent change in HVPG from baseline to Week 6.(at Week 6)
- Part B: Absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6 and Week 16.(at Week 6 and Week 16)
- 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.(at Week 6)
- Part A: Percentage and absolute change in total dosage of loop-diuretic equivalents use from baseline to Week 6.(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.(at Week 6)
- Part A: Change in systolic and diastolic blood pressure from baseline to Week 6.(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.(at Week 6)
- Part B: Change in systolic and diastolic blood pressure from baseline to Week 6 and Week 16.(at Week 6 and Week 16)
- Part B: Percentage change in HVPG from baseline to Week 6.(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.(at Week 6 and Week 16)
- 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.(at Week 6)
- 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.(at Week 6 and Week 16)