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

This is an interventional treatment trial for Cirrhosis focused on measuring Cirrhosis, Portal Hypertension, Ambrisentan, N-003, Hepatic Vein Pressure Gradient, HVPG, Refractory Ascites, Varices, Esophageal, Variceal Hemorrhage, Hepatitis B, Hepatitis C, Non-Alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis, Ascites Read More

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