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    Summary
    EudraCT Number:2013-003368-29
    Sponsor's Protocol Code Number:VAS203/III/1/04
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-03-09
    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 ConcernedAustria - BASG
    A.2EudraCT number2013-003368-29
    A.3Full title of the trial
    EFFICACY OF VAS203 IN PATIENTS WITH MODERATE AND SEVERE
    TRAUMATIC BRAIN INJURY. A confirmatory, placebo-controlled, randomised, double blind, multi-centre study.
    Wirksamkeit von VAS203 bei Patienten mit moderatem oder schwerem Schädel Hirn-Trauma (NOSTRA Phase-III-Studie) - eine konfirmatorische, placebokontrollierte, randomisierte, doppelblinde, multizentrische Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    EFFICACY OF VAS203 IN PATIENTS WITH MODERATE AND SEVERE
    TRAUMATIC BRAIN INJURY. A confirmatory, placebo-controlled, randomised, double blind, multi-centre study.
    A.3.2Name or abbreviated title of the trial where available
    NOSTRA Phase III Trial
    A.4.1Sponsor's protocol code numberVAS203/III/1/04
    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 Sponsorvasopharm GmbH
    B.1.3.4CountryGermany
    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 supportvasopharm GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationvasopharm GmbH
    B.5.2Functional name of contact pointFrank Tegtmeier
    B.5.3 Address:
    B.5.3.1Street AddressFriedrich-Bergius-Ring 15
    B.5.3.2Town/ cityWuerzburg
    B.5.3.3Post code97076
    B.5.3.4CountryGermany
    B.5.4Telephone number499313590990
    B.5.5Fax number4993135909912
    B.5.6E-mailtegtmeier@vasopharm.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/3/06/390 //EMEA/OD/035/06
    D.3 Description of the IMP
    D.3.1Product nameVAS203
    D.3.2Product code VAS203
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrauterine use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRonopterin
    D.3.9.1CAS number 206885-38-3
    D.3.9.2Current sponsor codeVAS203
    D.3.9.3Other descriptive name4-AMINO-(6R,S)-5,6,7,8-TETRAHYDRO-L-BIOPTERIN
    D.3.9.4EV Substance CodeSUB33337
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 placeboLyophilisate 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
    Moderate and severe traumatic brain injury
    E.1.1.1Medical condition in easily understood language
    Moderate and severe traumatic brain injury
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10060690
    E.1.2Term Traumatic brain injury
    E.1.2System Organ Class 100000004863
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate efficacy of VAS203 on clinical outcome at 6 months (extended Glasgow Outcome Scale Interview, eGOS-I) in patients suffering from moderate and severe traumatic brain injury (TBI)
    E.2.2Secondary objectives of the trial
    To demonstrate efficacy on
    • Quality of Life after Brain Injury (QOLIBRI) at 6 months after TBI
    • QOLIBRI overall scale (QOLIBRI-OS) at 6 months after TBI
    • eGOS-I at 3 months after TBI
    • QOLIBRI-OS at 3 months after TBI
    • 24-hours value of Therapy Intensity Level (TIL) over 14 days after start of treatment
    • number of craniectomies (one or both hemispheres)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria
    1. Written informed consent from patient’s legal guardian or legal representative or deferred consent procedure, according to local requirements
    2. 18 - 60 years of age, inclusive
    3. Expected to survive more than 24 hours after admission
    4. Traumatic Brain Injury (TBI) within the last 18 hours (infusion must not start earlier than 6 hours after the injury)
    5. TBI with Glasgow Coma Score (GCS) ≥ 3 requiring intracranial pressure (ICP) monitoring according to the assessment of the treating physician.
    6. Catheter placement (intraventricular or intraparenchymal, only) for monitoring and management of increased ICP
    7. Systolic blood pressure ≥ 100 mmHg
    8. Females of child-bearing potential must have a negative pregnancy test
    E.4Principal exclusion criteria
    Exclusion criteria
    1. Penetrating head injury (e.g. missile, stab wound)
    2. Concurrent, but not pre-existing, spinal cord injury
    3. Bilateral fixed and dilated pupil (> 4 mm). However, inclusion with unilateral fixed and dilated pupil (> 4 mm) is possible when there are no signs of herniation in transtentorial or temporal brain area.
    4. Cardiopulmonary resuscitation performed post injury, or extracranial injuries causing continuing bleeding likely to require multiple transfusions (> 4 units red blood cells)
    5. Coma due to an exclusive epidural hematoma (lucid interval and absence of structural brain damage on CT scan)
    6. Coma suspected to be primarily due to other causes than head injury (e.g. drug overdose intoxication, drowning/near drowning)
    7. Known or CT scan evidence of pre-existing major cerebral damage
    8. Patients who cannot be monitored with regard to their recovery (eGOS-I and QOLIBRI)
    9. Patients and relatives of patients who don´t understand/speak Spanish, or English, or French, or German (if Israel is included: Hebrew, Russian, Arabic).
    10. Decompressive craniectomy, planned prior to randomisation
    Note:enrolment is possible, when osteoplastic craniectomy is performed for hematoma evacuation, only
    11. Polytraumatic patients with Injury Severity Score non-head > 18
    12. Rhabdomyolysis with CK > 5000 IU/L
    13. Injuries to ascending aorta and/or carotid arteries and vertebral arteries
    14. Serum creatinine values > 1.2 mg/dL (106 µmol/L) (women), or > 1.5 mg/dL (133 µmol/L) (men)
    15. Estimated glomerular filtration rate (eGFR) < 60 mL/min as calculated by Chronic Kidney Disease Epidemiology Collaboration Formula
    16. BMI < 18.5 kg/m2 and > 40 kg/m2, Body weight > 110 kg
    17. Any severe concomitant condition (cancer; hematologic, renal, hepatic,
    coronary disease; major psychiatric disorder; alcohol or drug abuse), that
    can be ascertained at admission
    18. Known to have received an experimental drug within 4 weeks prior to
    current injury
    E.5 End points
    E.5.1Primary end point(s)
    Clinical outcome eGOS-I at 6 months after the TBI will be evaluated face to face with the patient and or a proxy by means of a standardized questionnaire in an interview
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    E.5.2Secondary end point(s)
    Secondary efficacy assessments
    • QOLIBRI at 6 months after the TBI will be evaluated face to face with the patient and or
    a proxy by means of a standardized questionnaire in an interview form












    • QOLIBRI OS at 6 months after TBI will be evaluated face to face with the patient or a
    proxy by means of a standardized questionnaire in an interview form (Appendix z)
    • eGOS-I at 3 months after TBI will be evaluated face to face with the patient and/or a proxy by means of a standardized questionnaire in an interview form (Appendix x)
    • QOLIBRI OS at 3 months after TBI will be evaluated face to face with the patient or a proxy by means of a standardized questionnaire in an interview form (Appendix z)
    • 24-hours value of TIL on a daily base over 14 days after start of treatment
    • Number of decompressive craniectomies (one or both hemispheres)
    E.5.2.1Timepoint(s) of evaluation of this end point
    14 days, 3 months and 6 months
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    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 visit of last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    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: 232
    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 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 2016-03-09. Yes
    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
    Patients with moderate and severe traumatic brain injury.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 232
    F.4.2.2In the whole clinical trial 232
    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)
    Continuation of Standard of Care procedures as per the treating facility.
    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 Decision2016-05-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-17
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