Patients with advanced cirrhosis of the liver develop kidney problems occasionally. This condition is called Hepatorenal Syndrome, requires hospitalization and frequently results in death.

The goal of this clinical trial is to test whether the administration of low doses of ambrisentan can help patients with Hepatorenal Syndrome and to determine if it is safe. Ambrisentan is a drug that is approved for the treatment of high blood pressure in the lungs at higher doses.

This clinical trial will compare the safety and effects of ambrisentan to another drug called terlipressin, which is commonly used to treat patients with hepatorenal syndrome.

The main questions the clinical trial aims to answer are:

• Does ambrisentan help the kidney function of the patient?
• Does ambrisentan help prevent death in patients with Hepatorenal Syndrome?
• Does ambrisentan prevent Hepatorenal Syndrome from reappearing?

While in the hospital, trial participants will receive either one of two doses of ambrisentan or terlipressin. If in the first 4 days, ambrisentan is not helpful, the patient may be eligible to receive terlipressin. Patients assigned to receive ambrisentan will continue taking this medication at home after leaving the hospitals and until they complete 60 days of treatment.

Inclusion Criteria:

• Written Informed consent prior to any study-related procedures.
• Age ≥ 18 years and ≤ 70 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 such as combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tube occlusion, vasectomised partner, and sexual abstinence and until one month after completing treatment with the study medication. In the case of hormonal contraception, women should have been on a stable regimen for a minimum of three months before study enrolment. Women not of child-bearing potential include post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy). Men must use an effective contraception method (i.e., condom + diaphragm/spermicidal gel or foam, or vasectomy), 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 ≥ 0.3 mg/dl (26.5 µmol/L) from a value obtained in the 7 days prior to admission, OR a serum creatinine ≥ 1.5 mg/dl (132.6 µmol/L) and is ≥ 1.5-fold above the most recent and lowest value obtained in the last 3 months.
• The subject has no clinical and/or haemodynamic evidence of intravascular volume depletion; or has undergone at least 12 hours of diuretic withdrawal and fluid resuscitation to discard or treat intravascular volume depletion (such as difficulty in establishing volume status, volume status is assessed as equivocal, or there is clinical and/or haemodynamic evidence of intravascular volume depletion), and no significant improvement in serum creatinine has been observed.

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.