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    Summary
    EudraCT Number:2017-004890-15
    Sponsor's Protocol Code Number:EU-C-001-II-01
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-08-29
    Trial 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 ConcernedUK - MHRA
    A.2EudraCT number2017-004890-15
    A.3Full title of the trial
    A double-blind placebo-controlled study with an open-label pilot phase, assessing the efficacy, tolerability and safety of EU-C-001 in patients with moderate to severe traumatic brain injury
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the efficacy, tolerability and safety of EU-C-001 compared to placebo in patients with moderate to severe brain injury
    A.3.2Name or abbreviated title of the trial where available
    PANGEA
    A.4.1Sponsor's protocol code numberEU-C-001-II-01
    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 SponsorEustralis Pharmaceuticals Ltd.
    B.1.3.4CountryAustralia
    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 supportEustralis Pharmaceuticals Ltd.
    B.4.2CountryAustralia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEustralis Pharmaceuticals Ltd.
    B.5.2Functional name of contact pointKey Management
    B.5.3 Address:
    B.5.3.1Street AddressCompass Offices Level 26, 360 Collins Street
    B.5.3.2Town/ cityMelbourne, Victoria
    B.5.3.3Post code3000
    B.5.3.4CountryAustralia
    B.5.4Telephone number+61400414416
    B.5.6E-mailinfo@pressuraneuro.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 nameEU-C-001 di-hydrochloride
    D.3.2Product code EU-C-001
    D.3.4Pharmaceutical form Concentrate for 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 INNnot yet available
    D.3.9.1CAS number 290296-52-5
    D.3.9.2Current sponsor codeEU-C-001
    D.3.9.3Other descriptive nameEU-C-001 di-hydrochloride
    D.3.9.4EV Substance CodeSUB191224
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 placeboConcentrate for solution 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
    Traumatic brain injury
    E.1.1.1Medical condition in easily understood language
    Traumatic brain injury is a physical head injury that causes damage to the brain
    E.1.1.2Therapeutic area Body processes [G] - Bones and nerves physological processes [G11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level LLT
    E.1.2Classification code 10021665
    E.1.2Term Increased intracranial pressure
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • Double-blind phase: To assess the effect of EU-C-001 on intracranial pressure (ICP) in patients with moderate to severe traumatic brain injury (TBI) (area under the effect time curve [AUEC] 0 to 48 hours after the start of infusion of study medication [AUEC0 48 h])

    • Open-label pilot phase: To assess the safety of EU-C-001 in the target population of the highest dose to be tested in the double-blind phase
    E.2.2Secondary objectives of the trial
    • To assess the effect of EU-C-001 on ICP in patients with moderate to severe TBI (AUEC 0 to 120 hours after the start of infusion of study medication [AUEC 0-120 h] and measured values and index parameters)
    • To assess the effect of EU-C-001 on outcome in the Extended Glasgow Outcome Scale (GOS-E)
    • To assess the safety of EU-C-001 in patients with moderate to severe TBI
    • To assess the Therapy Intensity Level (TIL)
    • To assess the cerebral hypoperfusion
    • To assess the brain tissue oxygenation
    • To assess cognitive function after 12 weeks
    • To explore the effect of EU-C-001 on biomarkers of inflammation and neuronal injury in patients with severe TBI
    • To assess the PK/pharmacodynamic (PD) relationship of EU-C-001 in a TBI setting
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title:
    AN EXPLORATORY STUDY OF THE EFFECTS OF EU-C-001 ON INFLAMMATORY MARKERS IN MICRODIALYSIS FLUID AND ON CEREBRAL EDEMA EVALUATED BY MAGNETIC RESONANCE IMAGING IN PATIENTS WITH MODERATE TO SEVERE TRAUMATIC BRAIN INJURY

    Date: 13 November 2020

    Version: 3.0

    Objectives:
    • To explore the effect of EU-C-001 on markers of neuroinflammation and brain metabolism assessed by changes in biomarkers collected by microdialysis
    • To explore the effect of EU-C-001 on cerebral edema assessed by changes in edema visualized by MRI scanning
    E.3Principal inclusion criteria
    1. Male or female aged 18 to 65 years at the time the ICF is signed, or obtained remotely, by either the patient or the patient’s legally authorized representative
    2. Moderate to severe TBI due to blunt mechanism
    3. Abnormal CT scan result consistent with TBI due to blunt mechanism
    4. Intracranial pressure monitor in situ, ICP >20 mm Hg at screening in the absence of potential external ICP stimuli, e.g., suctioning, coughing, and turning. ICP at start of first infusion of study drug ≥ 18 mmHg. The preferred method of ICP measurement is either intraventricular, intraparenchymal, or subdural, where possible
    5. The GCS score at Screening is the most recent GCS score assessed at the hospital after resuscitation. If this is not available, the GCS score assessed by the ambulance personnel/paramedics prior to arrival at hospital will be used.
    a. If the Total Score is assessable (range 3 to 15), a patient is eligible for inclusion if their score is in the range 3 to 12
    b. If only the Eye and Motor scores are assessable (range 2 to 10), a patient is eligible for inclusion if their score is in the range 2 to 8
    c. If only the Motor score is assessable (range 1 to 6), a patient is eligible for inclusion if their score is in the range 1 to 5
    6. Onset of TBI within the last 72 hours
    E.4Principal exclusion criteria
    1. Documented continuously elevated ICP >20 mm Hg for >12 hours after elevated ICP was first measured/observed
    2.Use of an extraventricular drain (EVD) for ICP control
    3. Injury deemed non-survivable by study team
    4. Penetrating brain injury
    5. Bilateral dilated, unresponsive pupils
    6. Imminent cranial or extracranial surgery
    7. Concomitant use of thiopentone
    8. Cervical spinal cord injury
    9. Cardiopulmonary resuscitation performed
    10. Life-threatening systemic injuries, additional injuries, or conditions requiring medical treatment which would confound the assessment of the effects and/or safety of study medication
    11. Morbid obesity with body mass index ≥40 kg/m2
    12. Severe or unstable pre-existing respiratory and hemodynamic conditions
    13. Hypoxemia (oxygen saturation <80%, measured by pulse oximetry)
    14. Hypotension (sustained systolic blood pressure <70 mm Hg despite adequate volume resuscitation and vasopressors)
    15. Status epilepticus
    16. Pregnancy
    17. Clinically significant anemia (hemoglobin <7 g/dL)
    18. History of blood clotting disorder; exclude if international normalized ratio (INR) >1.5 and/or thrombocytes <50,000/µL
    19. Moderate to severe renal impairment with estimated glomerular filtration rate <60 mL/min
    20. Hepatic dysfunction with 1 or more of the following liver function test results: total bilirubin >2 x upper limit of normal (ULN), alanine aminotransferase >2.5 x ULN, or aspartate aminotransferase >2.5 x ULN, INR >1.5
    21. Any major neurological or psychiatric disorder associated with significant impairment of cognitive function or motor function e.g., Alzheimer’s disease with dementia, Parkinson’s disease, Huntington’s disease, alcohol or substance abuse
    22. Participating in or has participated in other investigational interventional studies (drug or device) within the last 30 days (or 5 times the half-life of the previously administered investigational compound, whichever is longer) prior to study treatment initiation
    23. Wearing an opt out bracelet or is known not to wish to participate in this type of study
    E.5 End points
    E.5.1Primary end point(s)
    Double-blind phase:
    comparison between active and placebo groups for:
    • AUEC 0-48 h for ICP

    Open-label pilot phase:
    • AEs
    E.5.1.1Timepoint(s) of evaluation of this end point
    Continuously over 48 hours after the start of infusion of study medication
    E.5.2Secondary end point(s)
    (Double-Blind Phase Only)
    Comparison between active and placebo group for:
    • AUEC 0-n h for ICP, where n = 8, 12, 16, 20, 24, 36, 48, and 120 hours post first dose (measured prior to respective dose)
    • Change from baseline in ICP at 0.5 hours post-dose and thereafter at 1, 2, 4, 8, 12, 16, 20, 24, 36, 48, and 120 hours post dose
    • AEs
    • Times during which ICP is above 20 mm Hg and 25 mm Hg during the 48 hours and 120 hours after the start of infusion of study medication
    • Intracranial hypertension index 20 during the 48 hours and 120 hours after the start of infusion of study medication (calculated by the total time [hours] where ICP >20 mm Hg divided by the total time [48 hours and 120 hours, respectively], multiplied by 100)
    • Intracranial hypertension index 25 during the 48 hours and 120 hours after the start of infusion of study medication (calculated by the total time [hours] where ICP >25 mm Hg divided by the total time [48 hours and 120 hours, respectively], multiplied by 100)
    • AUEC 0-48 h and AUEC 0-120 h of TIL
    • Maximal TIL
    • Product of AUEC 0-48 h for ICP and AUEC 0-48 h of TIL (exploratory endpoint)
    • AUEC 0-48 h for CPP
    • Cerebral hypoperfusion index (the number of end-hourly measures of CPP of <60 mm Hg divided by the total number of measurements, multiplied by 100) during the 48 hours and 120 hours after the start of infusion of study medication
    • AUEC 0-48 h and AUEC 0-120 h of brain tissue oxygenation (if Licox probe used routinely)
    • GOS-E scores
    • Safety evaluations including physical and neurological examination (Glasgow Coma Scale [GCS]), vital signs, ECGs, and hematological and biochemical parameters
    • Proportion of patients surviving at 28 days and 12 weeks
    • Time to completion of Trail Making Test (TMT) Parts A and B at Week 12
    • QoL assessed by the TBI – 36-Item Short Form Survey Instrument (SF 36) at Week 12
    • Length of ventilation/length of time in intensive care unit (ICU)/length of hospital stay
    • Mean change from baseline in:
    - Plasma tau/phosphorylated tau
    - Plasma substance P
    - Serum glial fibrillary acidic protein (GFAP)
    Additional secondary endpoint for patients in active groups:
    • PK of EU-C-001 in blood
    E.5.2.1Timepoint(s) of evaluation of this end point
    At different time points throughout the study. Please refer to study protocol for assessments schedule.
    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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    open-label pilot phase
    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 trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    United Kingdom
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 45
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    unconscious patients with head injury
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 45
    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)
    After study end, patients will be treated according to standard of care.
    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 Decision2018-10-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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