Endothelin Receptor Antagonism With Ambrisentan to Treat Hepatorenal Syndrome

Exclusion Criteria

• •Serum creatinine \> 5 mg/dL (442 µmol/L).
• •Mean arterial pressure (MAP) \< 60 mmHg.
• •Large Volume Paracentesis (LVP) 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 µmol/L).
• •Serum sodium \< 125 mmol/L.
• •International Normalised Ratio (INR) ≥ 3.5.
• •Proteinuria ≥ 1000 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.
• •Participation in a study of an investigational medical product or device within the last 30 days preceding screening.
• •Hepatic Encephalopathy with West Haven Grade III or IV.
• •Current or recent (30 days prior to enrolment) treatment with endothelin receptor antagonists, including ambrisentan.
• •Estimated life expectancy of less than 3 days.
• •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.