A Study Evaluating the Utility of Ambrisentan in Lowering Portal Pressure in Patients With Liver Cirrhosis

A Phase II, Single-arm, Open-label Study to Characterise the Effect on Portal Pressure, the Effect on Renal Function and the Pharmacokinetic Profile of N-003 in Patients With Decompensated Cirrhosis

Endothelin is a human hormone which has been associated with increased portal pressure in patients with liver cirrhosis (also called portal hypertension). Ambrisentan blocks the effects of endothelin. The purpose of this study is to evaluate the effect of ambrisentan on portal pressure and renal function in patients with advanced liver cirrhosis and with portal hypertension. In this study, portal pressure will be determined at multiple times with the aid of a catheter inserted into the body of the patient. The effect of ambrisentan on the function of the kidney will also be investigated. This study will also evaluate the concentrations of ambrisentan in blood in patients with liver cirrhosis.

Inclusion Criteria:

• Signed informed consent including data protection declaration prior to study participation
• Subjects with confirmed cirrhosis (by biopsy, ultrasound, and/or laboratory examinations)
• Ascites Grade II or Grade III at screening currently treated with at least one diuretic or the subject is considered intolerant to diuretics in the investigator's opinion

Exclusion Criteria:

• Age <18 years of age

• Any of the following laboratory findings at the time of screening

  • Serum creatinine level >1.5mg/dL (>132 µmol/L)
  • Serum Na+ < 125 meq/L
  • Serum K+ ≥ 5.5 meq/L
  • Serum bilirubin ≥ 5 mg/dL (85.5 µmol/L)
  • INR >3.0

• Women of childbearing potential with no effective contraceptive method (women of childbearing potential [pre-menopausal, not surgically sterile for at least 3 months prior to the time of screening] must have a confirmed negative serum β-hCG pregnancy test prior to enrolment and at Baseline Visit. They must use an effective contraceptive method throughout the study, and agree to repeat serum β-hCG pregnancy tests at designated visits)

• Pregnancy or lactation

• Systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg

• Sepsis and/or uncontrolled bacterial infection

• Current or recent documented nephrotoxicity (within 4 weeks)

• Hepatic Encephalopathy above grade 1

• History of variceal bleeding in the last 2 months

• Suspicion of active alcohol consumption in the last 3 months

• History of liver or kidney transplantation

• History of Transjugular Intrahepatic Portosystemic Shunt (TIPS)

• Suspected occlusive portal vein or splenic vein thrombosis

• Hepatocellular carcinoma (HCC) beyond the Milan criteria

• Acute Liver Failure or superimposed acute liver injury due to drugs (e.g., acetaminophen), dietary supplements, herbal preparations, viral hepatitis, or toxins

• Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary oedema, congestive heart failure

• Current or recent (within 30 days) renal replacement therapy (RRT)

• If on beta-blockers, a change in dose or drug within last 15 days prior to screening

• Use of any other endothelin receptor antagonist, octreotide, midodrine, terlipressin in last 15 days prior to screening

• Known hypersensitivity to contrast-media

• Any clinically significant abnormality identified on physical examination, laboratory tests, ECG or vital signs at the time of screening that in the judgment of the investigator or any sub-investigator would preclude safe completion of the study or constrains the assessment of efficacy

• Known sensitivity to ambrisentan or any of the excipients of the formulation

• Participation in other clinical research involving investigational medicinal products within 30 days of enrolment

• Subjects who have difficulties in understanding the language in which the study information is given

• Subjects who do not agree to the transmission of their anonymous data within the liability of documentation and notification

• Staff of the study centre, staff of the sponsor or Clinical Research Organization (CRO), the investigator himself or close relatives of the investigator.

Cardiac and Pulmonary Haemodynamic Study exclusion Criteria: Subjects fulfilling any of the exclusion criteria below may participate in the study, but will not undergo cardiac and pulmonary catheterisation:

• Significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate < 45 beats per minute or atrial fibrillation/flutter with sustained ventricular response of > 90 beats per minute at rest, or Long QT syndrome or QTc > 450 ms
• Significant left ventricular outflow tract obstructions (e.g., severe valvular aortic stenosis, obstructive cardiomyopathy), severe mitral stenosis, restrictive amyloid myocardiopathy, acute myocarditis
• Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated
• Major neurologic event including cerebrovascular events, within 30 days prior to screening
• Clinical evidence of acute coronary syndrome currently or within 30 days prior to screening
• Permanent pacemaker, cardiac resynchronisation device or implantable cardioverter-defibrillator in situ