A Multi-Centre, Randomised, Open-Label, Phase II Study of Ambrisentan in Patients with Hepatorenal Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 45
- 试验地点
- 8
- 主要终点
- The primary efficacy endpoint is defined as the change in eGFR from baseline to Day 4
研究概览
简要总结
The study is multi-center, randomised, open-label, interventional, proof-of-concept trial of parallel groups. For repurposing of Ambrisentan which is already approved in India since 2010 for Pulmonary Arterial Hypertension (PAH) at 5 and 10 mg strengths. In this trial, the microdose of Ambrisentan which is 80 folds less than the approved dose to be used in Hepatorenal Syndrome (HRS) subjects. Prior clinical studies have reported encouraging results with the microdose of Ambrisentan developed by Noorik Biopharmaceuticals. Therefore, this trial is being proposed in Indian subjects to potentially treat the HRS subjects.
Ambrisentan has a well-studied and understood safety and pharmacokinetic profile. It has been proven to be safe based on the various toxicity studies performed with Ambrisentan in various animal species. Phase I Clinical Trial with N-003 in healthy subjects to determine the pharmacokinetic profile. Two Phase II studies in liver cirrhosis and ascites patients shows that Ambrisentan is pharmacologically active at micro-doses and a reversal of the effects of endothelin in the liver and kidney have been observed.
This Phase II, Multi-Centre, Randomised, Open-Label, with N-003 in Patients with HRS is planned to be performed at 9 leading institutions in India. 45 subjects enrolled will be randomly assigned equally to one of three arms - Group AMB1: Low dose and Group AMB2 – High Dose, and Group T: Terlipressin. For AMB1 and AMB2 subjects will receive 60 days treatment and followed up 10 days post cessation of treatment. Group T treatment will be for 14 days as per standard practice.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Not Applicable
入排标准
- 年龄范围
- 18.00 Year(s) 至 60.00 Year(s)（—）
- 性别
- All
入选标准
- •Written Informed consent prior to any study-related procedures.
- •Age greater than or equal to 18 years and less than or equal to 60 years.
- •Male or non-pregnant, non-lactating female.
- •Women of child-bearing potential must have a confirmed negative serum pregnancy test at the time of screening and must use a highly effective contraceptive method throughout the study.
- •Men must use an effective contraception method, and should not donate semen during the study.
- •Men are considered to be fertile from the time of puberty, except for those men with permanent sterility secondary to bilateral orchiectomy.
- •Cirrhosis of the liver by laboratory examination, clinical history or biopsy.
- •History of ascites.
- •Increase in serum creatinine greater than or equal to 0.3 mg/dl (26.5 micro mol/L) from a value obtained in the 7 days prior to admission, OR a serum creatinine greater than or equal to 1.5 mg/dl (132.6 micro mol/L) and is greater than or equal to 1.5-fold above the most recent and lowest value obtained in the last 3 months.
- •Subject has completed 48 hours of diuretic withdrawal and plasma volume expansion with albumin prior to study inclusion (e.g., 1 g/kg for first 24 hours and not to exceed 100 g, followed by 20-40 g in second 24 hours).
- •No sustained improvement in renal function during 48 hours of both diuretic withdrawal and plasma volume expansion with albumin, defined as a decrease in serum creatinine of less than 20% from initial value.
排除标准
- •Serum creatinine > 5 mg/dL at the end of the 48-hour diuretic withdrawal and plasma volume expansion with albumin period.
- •Mean arterial pressure (MAP) < 60 mmHg, Large Volume Paracentesis in the 3 days prior to screening.
- •Sepsis, uncontrolled bacterial infection or less than 2 days anti-infective therapy for documented or suspected bacterial infection.
- •Total bilirubin > 8 mg/dL (137 micro mol/L).
- •Serum sodium < 130 mmol/L.
- •International Normalised Ratio (INR) greater than or equal to 3.
- •Proteinuria greater than or equal to 500 mg/dL.
- •Microhaematuria > 50 red blood cells per high power field.
- •Clinically significant casts on urinalysis, including granular casts.
- •History or evidence of obstructive uropathy or parenchymal renal disease on ultrasound or other imaging.
- •Subject with a recent history of circulatory shock defined as MAP < 60 mmHg within 5 days prior to screening requiring vasopressors or subjects requires circulatory support with vasopressors during screening.
- •Subject requiring oxygen supplementation or mechanical ventilation.
- •Recent exposure to nephrotoxic agents or exposure to radiographic contrast agents within 72 hrs prior to screening.
- •Superimposed acute liver failure/injury due to factors other than alcohol, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning).
- •Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary oedema, congestive heart failure (NYHA ≥ II), or persisting symptomatic peripheral vascular disease, myocardial infarction or stable chronic angina within the past 12 months, or any other cardiovascular disease judged by the Investigator to be severe.
- •Subject has a history of Transjugular Intrahepatic Portosystemic shunt (TIPS).
- •Subject with acute variceal bleeding at the time of screening who may undergo pre-emptive TIPS or is anticipated to be treated with terlipressin.
- •Current or recent Renal Replacement Therapy (RRT) within 30 days of enrolment, or anticipation of RRT in the next 3 days after screening.
- •Hepatocellular Carcinoma (HCC) beyond the Milan criteria or other malignancy affecting survival beyond 6 months.
- •Hepatic Encephalopathy with West Haven Grade III or IV.
- •Current or recent (30 days prior to enrolment) treatment with endothelin receptor antagonists, including ambrisentan.
- •Subjects receiving midodrine and/or octreotide may be enrolled.
- •Midodrine and octreotide treatment must be stopped prior to enrolment.
- •Known allergy or sensitivity to ambrisentan or propylene glycol.
- •History of Idiopathic Pulmonary Fibrosis.
- •Subject is unable or unwilling to follow instructions or comply with study procedures.
结局指标
主要结局
The primary efficacy endpoint is defined as the change in eGFR from baseline to Day 4
时间窗: From baseline to Day 4
次要结局
- Overall survival up to Day 60(Up to Day 60)
- Proportion of subjects experiencing HRS Recurrence up to Day 60
- Proportion of subjects achieving HRS Reversal up to Day 14(Up to Day 14)