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    Summary
    EudraCT Number:2016-002226-36
    Sponsor's Protocol Code Number:N-003-CRD002
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-11-16
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGreece - EOF
    A.2EudraCT number2016-002226-36
    A.3Full title of the trial
    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.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberN-003-CRD002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNoorik Biopharmaceuticals AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNoorik Biopharmaceuticals AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNoorik Biopharmaceuticals AG
    B.5.2Functional name of contact pointHead of Project Management
    B.5.3 Address:
    B.5.3.1Street AddressLange Gasse 15
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4052
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number0041(0)786246747
    B.5.5Fax number0041(0)613019104
    B.5.6E-mailpat.louie@noorik.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameN-003
    D.3.2Product code N-003
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMBRISENTAN
    D.3.9.1CAS number 177036-94-1
    D.3.9.2Current sponsor codeN-003
    D.3.9.4EV Substance CodeSUB25424
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Decompensated cirrhosis of the liver
    E.1.1.1Medical condition in easily understood language
    Renal failure in patients with advanced liver disease
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10019641
    E.1.2Term Hepatic cirrhosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10038448
    E.1.2Term Renal failure NOS
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of intravenous administration of N-003 on renal function as determined by urinary volume.
    E.2.2Secondary objectives of the trial
    • 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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).
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1, 2, 3 and 4.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 1, 2, 3 and 4.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Dose escalating
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days15
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state32
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No additional care will be provided to the subject following completion of the procedures and treatments of the study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-11-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-28
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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