Study to see if N-003 has an effect in helping a patient with a very sick liver to remove water from the body, a common cause of accumulation of water in the abdomen. Also, the study will see which dose of N-003 is more effective as determined by using several different tests and to examine the safety and tolerability of N-003 in these patients.

• Register: EUCTR
• Last refreshed on: 28 May 2018
• Main ID: EUCTR2016-002226-36-GR
• Date of registration: 16/11/2016
• Prospective Registration: No
• Primary sponsor: Noorik Biopharmaceuticals AG
• Public title: Study to see if N-003 has an effect in helping a patient with a very sick liver to remove water from the body, a common cause of accumulation of water in the abdomen. Also, the study will see which dose of N-003 is more effective as determined by using several different tests and to examine the safety and tolerability of N-003 in these patients.
• Scientific title: A double-blind, placebo-controlled, escalating-dose study of the effect of N-003 on renal function, pharmacodynamics, pharmacokinetics, safety and tolerability in patients with advanced liver disease. - N/A
• Date of first enrolment: 04/11/2016
• Target sample size: 32
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-002226-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Dose escalating; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Greece

Contacts

• Name: Head of Project Management
• Affiliation: Noorik Biopharmaceuticals AG

• Name: Head of Project Management
• Affiliation: Noorik Biopharmaceuticals AG

Key inclusion & exclusion criteria

Inclusion criteria:
• Signed informed consent including data protection declaration prior to study participation.
• Cirrhosis by biopsy and/or clinical/laboratory parameters.
• Paracentesis occurring between 7 and 30 days prior to baseline or patient is a candidate for Transjugular Intrahepatic Portosystemic Shunt (TIPS).
• Patient is on a stable regimen of diuretics for the last 15 days.
• Patient has a medical history of at least one previous paracentesis procedure being performed (total in medical history of at least two).
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 25
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 7

Exclusion criteria:
• Age less than 18 or more than 75 years of age.
• INR >2.5x.
• Total bilirubin >= 6 mg/dL or 100 µmol/L.
• Serum sodium <120 meq/L.
• Serum creatinine >1.5 mg/dL (>132.6 µmol/L).
• Recent change in serum creatinine >0.3 mg/dL or 27 µmol/L in the last 60 days (increase or decrease).
• Presence of organic renal disease or secondary causes of renal dysfunction (proteinuria >500mg/day, active urinary sediment, history of abnormal renal ultrasound or recent use of nephrotoxic medications).
• Causes of ascites other than cirrhosis and portal hypertension.
• Cause of cirrhosis is primary biliary cirrhosis or patient has hepatocellular carcinoma beyond the Milan criteria.
• History of TIPS or surgical shunt.
• Variceal bleeding, encephalopathy (Grade II or more), bacterial infection (positive blood, urine or ascites culture - above 250 cells / mm3) within 2 weeks from enrolment.
• Clinical signs of congestive heart failure as determined by the investigator.
• Acute alcoholic hepatitis.
• In the investigator’s opinion, the patient is likely to die in the next 3 months.
• 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 would preclude safe completion of the study or constrains pharmacokinetic assessment.
• History of Portal thrombosis secondary to malignancy.
• 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 pregnancy test at screening and baseline visits and must agree to use an effective contraceptive method (such as a hormonal contraceptive and barrier method) throughout the study.
• Presence of metabolites of illicit drugs in urine during screening procedures.
• Presence of a clinically significant anaemia, as judged by the Principal Investigator.
• Blood donation within 3 months prior to administration of the study medication.
• History of severe allergy or allergic reactions to the study drug or related drugs and products (including excipients of the formulation).
• Use of an investigational drug or participation in an investigational study within 30 days prior to administration of the study medication.
• 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 CRO, the investigator himself or close relatives of the investigator.
• Recent therapy with vasoactive drugs (octreotide, somatostatin, terlipressin, noradrenaline), antibiotics is not permitted except for antibiotics for the prevention of spontaneous bacterial peritonitis which are allowed throughout the study.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Decompensated cirrhosis of the liver
MedDRA version: 19.0 Level: PT Classification code 10019641 Term: Hepatic cirrhosis System Organ Class: 10019805 - Hepatobiliary disorders
MedDRA version: 19.0 Level: LLT Classification code 10038448 Term: Renal failure NOS System Organ Class: 100000004857

Intervention(s)

Product Name: N-003
Product Code: N-003
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: AMBRISENTAN
CAS Number: 177036-94-1
Current Sponsor code: N-003
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Primary end point(s): • Change in 24-hour urine volume (mL) for Day 1, 2, 3 and 4 and when compared to baseline and placebo.
• Change in hourly urinary rate (mL/h) at each urine collection period for Day 1, 2, 3 and 4 and when compared to baseline and placebo.

Timepoint(s) of evaluation of this end point: Day 1, 2, 3 and 4.

Main Objective: To evaluate the effect of intravenous administration of N-003 on renal function as determined by urinary volume.

Secondary Objective: • To evaluate the effect of N-003 on urinary sodium excretion.
• To evaluate the effect of N-003 on free water clearance.
• To evaluate the effect of N-003 on GFR (estimated by creatinine clearance).
• To evaluate the effect of N-003 on the ability to excrete a water load in 4 hours.
• To evaluate the effect of N-003 on plasma endothelin concentration.
• To evaluate the effect of N-003 on urine volume and urinary sodium.
• To characterize the pharmacokinetic (PK) profile of N-003 in plasma when given intravenously at different rates of infusion.

Secondary Outcome(s)

Secondary end point(s): • Change in creatinine clearance (ml/min) at each urine collection period for Day 1, 2, 3 and 4 and when compared to baseline and placebo.
• Change in the total urinary sodium rate (UNaV) (µmol/min) at each urine collection for Day 1, 2, 3 and 4 and when compared to baseline and placebo.
• Change in fractional excretion of sodium (FeNa) (%) at each urine collection for Day 1, 2, 3 and 4 and when compared to baseline and placebo.
• Change in free water clearance (FWC) (ml/min) at each urine collection for Day 1, 2, 3 and 4 and when compared to baseline and placebo.
• Change in creatinine clearance (ml/min) at each urine collection for Day 1, 2, 3, 4 and when compared to baseline and placebo.
• The plasma concentration at 4 hours, 24 hours and at the end of infusion and the area under the plasma concentration-time curve calculated from t0h to t4h (AUC0-4), t4h to t48h (AUC4-48) and from t48h to the last measurable concentration (AUC48-t) are chosen as the primary PK outcome measures to characterise the pharmacokinetic profile of total N-003 in patients with advanced liver disease when given intravenously.
• Calculation of Area Under the Curve (AUC) of N-003 during infusion at each dose.
• Change in ET-1 plasma concentration at each pharmacokinetic sampling timepoint compared to baseline and placebo.
• Correlation of N-003 plasma concentrations for each dose with ET-1 plasma concentrations at each timepoint.
Safety Endpoints:
The general safety and tolerability of N-003 in this study will be evaluated by:
• The results of the clinical examination.
• Description of frequency and severity of Adverse Events (AE) and Serious Adverse Events (SAE).
• Assessment of tolerability.
• Safety laboratory investigations (haematology, clinical chemistry, urinalysis) on the Day of Screening, Baseline, Visit 1 and Follow-up Visit.
• Vital Signs (blood pressure, pulse, body temperature, respiratory rate, ECG) throughout the study.

Timepoint(s) of evaluation of this end point: Day 1, 2, 3 and 4.

Secondary ID(s)

N-003-CRD002

Source(s) of Monetary Support

Noorik Biopharmaceuticals AG