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

February 23, 2021 updated by: Noorik Biopharmaceuticals AG

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.

Study Overview

Status

Terminated

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

19

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Barcelona, Spain, 08041
        • Hospital de la Santa Creu i Sant Pau
      • Barcelona, Spain, 08035
        • Vall D'Hebron University Hospital
      • Madrid, Spain, 28034
        • Hospital Universitario Ramón y Cajal
      • Madrid, Spain, 28007
        • Hospital Universitario Gregorio Marañón
    • Catalunya
      • Barcelona, Catalunya, Spain, 08036
        • Hospital Clinic Barcelona
    • Madrid
      • Majadahonda, Madrid, Spain, 28222
        • Hospital Universitario Puerta de Hierro-Majadahonda

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ambrisentan
Ambrisentan will be administered subcutaneously at the Hospital on the days of HVPG deterination and taken orally at home between visits.
Other Names:
  • N-003

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean change in Hepatic Vein Pressure Gradient (HVPG) from Baseline to Day 14
Time Frame: 14 Days
Baseline HVPG is defined as the HVPG assessment performed prior to the first study drug administration. Day 14 HVPG is defined as the HVPG assessment prior to the last dose of study drug. The mean change in HVPG will be calculated as the difference between the HVPG assessment performed at Day 14 and the HVPG assessment performed at baseline
14 Days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in 24-hour Urinary Sodium Volume (UNaV)
Time Frame: 48 hours

The change in 24-hour Urinary Sodium Volume (UNaV) will be calculated as the difference in 24-hour UNaV at Baseline and the 24-hour UNaV at Day 1 (after the first study drug administration).

Urinary sodium volume collected in the 24 hours of baseline will be compared to the Urinary sodium volume collected in the 24 hours after the first dose of the drug. Collection of urine will be ongoing for 48 hours in total.

48 hours
Change in weight
Time Frame: 28 days
The change in weight will be calculated as the difference in weight at baseline and weight recorded throughout the study
28 days
Change in abdominal girth
Time Frame: 28 days
The change in abdominal girth will be calculated as the difference in abdominal girth at baseline and abdominal girth recorded throughout the study
28 days
Change in Model of End-Stage Liver Disease (MELD) score
Time Frame: 28 days

The change in MELD score will be calculated as the difference in MELD score at baseline and the MELD scores recorded throughout the study.

The MELD score is calculated according to the following formula:

MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43

The MELD score provides an indication of the anticipated mortality observed in previous studies when subjects were followed for 3-months, according to the following ranges:

71.3% mortality if score is 40 points or more

52.6% mortality if score between 30-39 points

19.6% mortality if score between 20-29 points

6.0% mortality if score between 10-19 points

1.9% mortality if score 9 points or less

The MELD score will be calculated at each visit during a 28 day period.

28 days
Change in Child-Pugh score
Time Frame: 28 days

The change in Child-Pugh score will be calculated as the difference in Child-Pugh score at baseline and the Child-Pugh scores recorded throughout the study

The Child-Pugh score provides information on the prognosis of a patient based on 5 clinical parameters which are individually graded. These parameters include laboratory values and other clinical information from the patient, such as the presence of ascites or hepatic encephalopathy. A lower score signifies a better chance and a higher score indicates a worse chance of survival at one year. Once the score is calculated it is further subclassified into three stages, depending on the score:

Child A - the score is between 5 and 6. The survival rate is 100%

Child B - the score is between 7 and 9. The survival rate is 80%

Child C - the score is between 10 and 15. The survival rate is 45%

28 days
Change in Cardiac Output
Time Frame: 14 days
The change in Cardiac Output will be calculated as the difference in Cardiac Output at baseline and the Cardiac Output recorded at Day 14
14 days
Change in Cardiac Index
Time Frame: 14 days
The change in Cardiac Index will be calculated as the difference in Cardiac Index at baseline and the Cardiac Index recorded at Day 14
14 days
Change in Pulmonary Capillary Wedge Pressure
Time Frame: 14 days
The change in Pulmonary Capillary Wedge Pressure will be calculated as the difference in Pulmonary Capillary Wedge Pressure at baseline and the Pulmonary Capillary Wedge Pressure recorded at Day 14
14 days
Change in Pulmonary Arterial Pressure
Time Frame: 14 days
The change in Pulmonary Arterial Pressure will be calculated as the difference in Pulmonary Arterial Pressure at baseline and the Pulmonary Arterial Pressure recorded at Day 14
14 days
Change in Central Venous Pressure
Time Frame: 14 days
The change in Central Venous Pressure will be calculated as the difference in Central Venous Pressure at baseline and the Central Venous Pressure recorded at Day 14
14 days

Other Outcome Measures

Outcome Measure
Time Frame
Proportion of patients achieving a 20% reduction in HVPG at Day 14 from baseline
Time Frame: 14 days
14 days
Proportion of patients achieving a 10% reduction in HVPG at Day 14 from baseline
Time Frame: 14 days
14 days
Proportion of patients achieving an HVPG of 10 mmHg or less at Day 14 from baseline
Time Frame: 14 days
14 days
Proportion of patients achieving an HVPG of 12 mmHg or less at Day 14 from baseline
Time Frame: 14 days
14 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 11, 2019

Primary Completion (Actual)

December 29, 2020

Study Completion (Actual)

January 21, 2021

Study Registration Dates

First Submitted

January 25, 2019

First Submitted That Met QC Criteria

January 31, 2019

First Posted (Actual)

February 1, 2019

Study Record Updates

Last Update Posted (Actual)

February 26, 2021

Last Update Submitted That Met QC Criteria

February 23, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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