A Non-Placebo Clinical Trial in Patients with Chronic Liver Disease to Test the Safety and Effect of N-003 on Liver Blood Pressure and Renal Function, as well as N-003 Levels in Blood

Phase 1

Conditions: decompensated liver cirrhosis
MedDRA version: 20.1Level: LLTClassification code 10064704Term: Decompensated cirrhosisSystem Organ Class: 100000004871
Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

Registration Number: EUCTR2018-002088-25-AT

Lead Sponsor: oorik Biopharmaceuticals AG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 24

Inclusion Criteria

1.Signed informed consent including data protection declaration prior to study participation
2.Subjects with confirmed cirrhosis (by biopsy, ultrasound, and/or laboratory examinations)
3.Ascites Grade II or Grade III at screening
4.Currently treated with at least one diuretic or the subject is considered intolerant to diuretics in the investigator’s opinion
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 12
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 12

Exclusion Criteria

1.Age <18 years of age
2.Any of the following laboratory findings at the time of screening
a.Serum creatinine level >1.5mg/dL (>132 µmol/L)
b.Serum Na+ < 125 meq/L
c.Serum K+ = 5.5 meq/L
d.Serum bilirubin = 5 mg/dL (85.5 µmol/L)
e.INR >3.0
3.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 ß-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 ß-hCG pregnancy tests at designated visits)
4.Pregnancy or lactation
5.Systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg
6.Sepsis and/or uncontrolled bacterial infection
7.Current or recent documented nephrotoxicity (within 4 weeks)
8.Hepatic Encephalopathy above grade 1
9.History of variceal bleeding in the last 2 months
10.Suspicion of active alcohol consumption in the last 3 months
11.History of liver or kidney transplantation
12.History of Transjugular Intrahepatic Portosystemic Shunt (TIPS)
13.Suspected occlusive portal vein or splenic vein thrombosis
14.Hepatocellular carcinoma (HCC) beyond the Milan criteria
15.Acute Liver Failure or superimposed acute liver injury due to drugs (e.g., acetaminophen), dietary supplements, herbal preparations, viral hepatitis, or toxins
16.Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary oedema, congestive heart failure
17.Current or recent (within 30 days) renal replacement therapy (RRT)
18.If on beta-blockers, a change in dose or drug within last 15 days prior to screening
19.Use of any other endothelin receptor antagonist, octreotide, midodrine, terlipressin in last 15 days prior to screening
20.Known hypersensitivity to contrast-media
21.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
22.Known sensitivity to ambrisentan or any of the excipients of the formulation
23.Participation in other clinical research involving investigational medicinal products within 30 days of enrolment
24.Subjects who have difficulties in understanding the language in which the study information is given
25.Subjects who do not agree to the transmission of their anonymous data within the liability of documentation and notification
26.Staff of the study centre, staff of the sponsor or CRO, the investigator himself or close relatives of the investigator.

Cardiac and Pulmonary Haemodynamic Study exclusion Criteria: For subjects enrolled in sites performing cardiac and pulmonary catheterisations, subjects fulfilling any of the exclusion criteria below may participate in the study, but will not undergo cardiac and pulmonary catheterisation:
1.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
2.Significant left ventricular outflow tract obstructions (e.g., severe valvular aortic stenosis, obstructive cardiomyopathy), severe mitral stenosis, restrictive amyloid

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of the study is to determine whether N-003 reduces portal pressure in patients with decompensated cirrhosis and a history of recurrent ascites.;Secondary Objective: •the effect of N-003 on weight<br>•the effect of N-003 on abdominal girth<br>•the effect of N-003 on liver disease severity scores (MELD and Child-Pugh scores)<br>•the effect of N-003 on cardiac and pulmonary haemodynamics<br>•the pharmacokinetic profile of N-003 in patients with liver impairment<br>•the effect of N-003 on plasma endothelin<br>•to assess the safety and tolerability of N-003 in this population;Primary end point(s): The primary efficacy endpoint is defined as the mean change in Hepatic Vein Pressure Gradient (HVPG) from baseline to Day 14.;Timepoint(s) of evaluation of this end point: Visit 1 - day 1 & visit 2 - day 14

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Secondary efficacy endpoints include:<br>•change in weight from baseline to each study visit <br>•change in abdominal girth from baseline to each study visit <br>•change in MELD score from baseline to each study visit<br>•change in Child-Pugh score from baseline to each study visit<br>•change in cardiac and pulmonary haemodynamic variables from baseline to 90 minutes post-drug administration, Day 14 (trough) and 90 minutes after last dose (Day 14). (evaluated only at investigational sites that perform cardiac and pulmonary catheterisation);Timepoint(s) of evaluation of this end point: at all visits starting from baseline

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