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    Summary
    EudraCT Number:2012-000756-34
    Sponsor's Protocol Code Number:2012.001
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-09-20
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2012-000756-34
    A.3Full title of the trial
    Copenhagen Head Injury Ciclosporin (CHIC) Study:

    An open-label, uncontrolled Phase II -study to investigate pharmacokinetics, safety and biomarkers of effectiveness of NeuroSTAT® (ciclosporin) in patients with severe Traumatic Brain Injury (TBI).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Copenhagen Head Injury Ciclosporin (CHIC) Study:
    An open-label, uncontrolled Phase II-study to investigate pharmacokinetics, safety and biomarkers of effectiveness of NeuroSTAT® (ciclosporin) in patients with severe Traumatic Brain Injury (TBI).
    Et åbent, ukontrolleret fase II-forsøg for at undersøge farmakokinetik, sikkerhed og biomarkører for virkningen af NeuroSTAT® (ciclosporin) hos patienter med svær traumatisk hjerneskade.

    A.3.2Name or abbreviated title of the trial where available
    Copenhagen Head Injury Ciclosporin (CHIC) Study.
    Copenhagen Head Injury Ciclosporin (CHIC) Studie.
    A.4.1Sponsor's protocol code number2012.001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01825044
    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 SponsorNeuroVive Pharmaceutical AB
    B.1.3.4CountrySweden
    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 supportNeuroVive Pharmaceutical AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNeuroVive Pharmaceutical AB
    B.5.2Functional name of contact pointDep. Clinical Trials & Reg. Affairs
    B.5.3 Address:
    B.5.3.1Street AddressMedicon Village, Scheelevägen 2
    B.5.3.2Town/ cityLund
    B.5.3.3Post codeSE-223 81
    B.5.3.4CountrySweden
    B.5.4Telephone number+46763393147
    B.5.5Fax number+46(0)46888 83 48
    B.5.6E-mailmatilda.hugerth@neurovive.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/791
    D.3 Description of the IMP
    D.3.1Product nameNeuroSTAT
    D.3.4Pharmaceutical form Emulsion 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 INNciclosporin
    D.3.9.1CAS number 59865-13-3
    D.3.9.3Other descriptive namecyclosporine, cyclosporin A
    D.3.9.4EV Substance CodeSUB06250MIG
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe Traumatic Brain Injury
    svær traumatisk hjerneskade.
    E.1.1.1Medical condition in easily understood language
    Brain damage caused by a head injury, such as a blow to the head in a traffic accident or a fall.
    E.1.1.2Therapeutic area Diseases [C] - Injuries, poisonings, and occupational diseases [C21]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish safety and to characterise the pharmacokinetic profile of two dosing regimens of ciclosporin in severe Traumatic Brain Injury (TBI) patients.
    E.2.2Secondary objectives of the trial
    •To gain preliminary insight into the risk of over - or underdosing of specified dosing schedules in patients with severe traumatic brain injury.

    In patients where it is possible:
    •To study the effect of ciclosporin on the secondary cascade of biochemical events after a brain injury, defined as changes in microdialysis biochemistry and mitochondrial dysfunction and further clinical deterioration of the injury.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients, age between 18 and 75 years, inclusive.
    2. Requirement for Intensive Care Unit (ICU) admission and clinical indication for External Ventricular Drainage (EVD) and Intracranial Pressure (ICP) monitoring.
    3. Evidence of non-penetrating severe TBI, confirmed by history and abnormalities consistent with a non-penetrating trauma on computerised tomography (CT) scan upon admission.
    4. Clinical examination with post-resuscitation Glasgow Coma Scale (GCS) of 4-8, inclusive.
    5. Hemodynamically stable after resuscitation (systolic blood pressure (SBP) >100 mm Hg).
    6. Informed consent for participation waived: obtained by two independent physicians and subsequently, the patient’s Legally Acceptable Representative (LAR) and General Practitioner (GP). If GP is unavailable, the Danish Health and Medicines Authority can give consent together with the LAR.
    E.4Principal exclusion criteria
    1. Bilaterally fixed dilated pupils.
    2. Penetrating traumatic brain injury.
    3. Spinal cord injury.
    4. Pure epidural haematoma.
    5. Currently developed, known or a medical history of renal disorder, significant renal failure, or high risk renal failure, defined as:
    a. Serum creatinine ≥ 1.5 x upper limit of normal (ULN).
    b. Pre-existing chronic renal failure with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 estimated by the simplified Modification of Diet in Renal Disease (MDRD) Study formula.
    c. Major rhabdomyolysis with serum creatine kinase > 5,000 IU/L.
    d. Renal injury resulting in loss of a kidney (either due to direct trauma or ischaemia).
    e. Vascular injury with renal ischaemia likely to cause an episode of acute renal failure.
    f. Any history of renal replacement therapy.

    6. Known or a medical history of hepatic disease.
    7. Prolonged and/or uncorrectable hypoxia, as judged by the investigator (PaO< 60 mmHg) or hypotension (SBP< 90 mmHg) upon admission.
    8. Suspected or confirmed pregnancy (positive urine sample, followed by confirmational serum human chorionic gonadotropin (HCG) pregnancy test).
    9. Immunosuppression due to drugs (for ex. ciclosporin) or disease (e.g. human immunodeficiency virus (HIV), malignancy).
    10. Known or a medical history of serious chronic viral or fungal infection.
    11. Known or a medical history of active mycobacterial infection or antituberculous treatment.
    12. Known or a medical history of any allergic reactions and/or anaphylactic reactions towards ciclosporin, egg, peanuts or soya-bean proteins.
    13. Ongoing preinjury therapy with any of these drugs:
    rosuvastatin, tacrolimus, Hypericum perforatum (St.John´s Wort; a herbal dietary supplement), stiripentol, aliskiren, bosentan, diltiazem, verapamil and antiepileptics.
    14. Participation in other clinical trials.
    15. Any significant disease or disorder including abnormal laboratory tests which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or may influence the results of the study.
    E.5 End points
    E.5.1Primary end point(s)
    • Non-compartmental analysis (NCA) of pharmacokinetics of ciclosporin in whole blood.
    • Safety parameters and adverse events, including:
    1. Ciclosporin levels in whole blood.
    2. Markers of nephrotoxicity: plasma creatinine, plasma Cystatin-C and blood urea nitrogen.
    3. Markers of hepatotoxicity: prothrombin time (PT), aspartate transaminase (AST), alanine transaminase (ALT) and bilirubin.
    4. Intracranial Pressure (ICP)
    5. Assessment of infections: according to standard procedures at intensive care unit.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At database lock N#1, when data has been obtained from 10 evaluable patients on first dosing step, then consecutively at the final database lock, when data has been obtained for additonal 10 evaluable patients on the second dosing step.
    E.5.2Secondary end point(s)
    • Ciclosporin levels in cerebrospinal fluid (CSF).
    • Safety biomarkers for nephrotoxicity: Kidney Injury Molecule (KIM)-1, creatinine and Cystatin-C in urine samples.
    The following only if available:
    • Biomarkers of brain injury in brain tissue, measured using microdialysis in the most and least traumatised side.
    • Brain tissue oxygen (BrTiO2) measured directly using probe.
    • Biomarkers of brain injury in CsA and/or blood, if possible


    The below explorative endpoint will be reported separately:

    • Electroencephalography (EEG).

    E.5.2.1Timepoint(s) of evaluation of this end point
    -The secondary endpoint: Biomarkers of brain injury in brain tissue, measured using microdialysis, will be included, and the data accessible at database lock N=#1 (after 10 patients in the first dosing Group). These data will not be part of the IDSMB interimanalysis assessment. Also, these data (from the 10 patients) will not be evaluated until after the final database lock: (after 20 patients; after both dosing groups).

    -All secondary endpoints will be evaluated at the final database lock , when results have been obtained from 20 evaulable patients.

    -For the secondary exploratory endpoint this will be reported separately, after the final database lock.
    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 Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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
    Consecutively dose-response
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 Yes
    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
    Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    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: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-09-20. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women Yes
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients with severe traumatic brain injury (GCS score 4-8) are comatose (unconscious)and they are temporarily incapacitated due to impaired consciousness. Patients will be treated at an Intensive Care Unit, acute clinical trial.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    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)
    The continued treatment for the patients after day 8, will be in accordance with the normal standard routine medical treatment at the ICU.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-02
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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