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    Summary
    EudraCT Number:2013-003368-29
    Sponsor's Protocol Code Number:VAS203/III/1/04
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-04-18
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2013-003368-29
    A.3Full title of the trial
    EFFICACY OF VAS203 IN PATIENTS WITH MODERATE AND SEVERE
    TRAUMATIC BRAIN INJURY (NOSTRA Phase III trial). A confirmatory, placebo-controlled, randomised, double blind, multi-centre study.
    EFICACIA DE VAS203 EN PACIENTES CON TRAUMATISMO CRANEOENCEFÁLICO DE MODERADO A INTENSO (ensayo NOSTRA de fase III). Estudio multicéntrico, doble ciego, aleatorizado, controlado con placebo y de confirmación.
    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.
    Eficacia de VAS203 en pacientes con traumatismo craneoencefálico de moderado a intenso. Estudio multicéntrico, doble ciego, aleatorizado, controlado con placebo y de confirmación.
    A.3.2Name or abbreviated title of the trial where available
    NOSTRA Phase III Trial
    NOSTRA Ensayo Fase III
    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 number34934893515
    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 IMPIntravenous 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 mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Moderate and severe traumatic brain injury
    Traumatismo craneoencefálico de moderado a intenso
    E.1.1.1Medical condition in easily understood language
    Moderate and severe traumatic brain injury
    Traumatismo craneoencefálico de moderado a intenso
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    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)
    Demostrar la eficacia de VAS203 en el resultado clínico a los 6 meses (entrevista de la escala de resultados de Glasgow ampliada, extended Glasgow Outcome Scale Interview, eGOS-I) en pacientes con traumatismo craneoencefálico (TCE) de moderado a intenso
    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 TBI
    ? number of craniectomies (one or both hemispheres)
    Demostrar eficacia en
    ? calidad de vida tras un TCE (QOLIBRI) 6 meses después del TCE
    ? escala global QOLIBRI (QOLIBRI-OS) 6 meses después del TCE
    ? eGOS-I 3 meses después del TCE
    ? QOLIBRI-OS 3 meses después del TCE
    ? valor de 24 horas del nivel de intensidad del tratamiento (TIL) en los 14 días siguientes al TCE
    ? número de cranectomías (en un hemisferio o en los dos)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria
    1. Written informed consent from patients 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
    Criterios de inclusión
    1. Consentimiento informado por escrito del tutor o del representante legal del paciente, o procedimiento de consentimiento diferido, según los requisitos locales
    2. De 18 a 60 años de edad, inclusive
    3. Esperanza de vida superior a 24 horas después del ingreso
    4. Traumatismo craneoencefálico (TCE) en las últimas 18 horas (la infusión no empezará hasta pasadas al menos 6 horas del TCE)
    5. TCE con puntuación del coma de Glasgow (GCS) ? 3 que precise monitorización de la presión intracraneal (PIC), según la evaluación de médico a cargo del tratamiento
    6. Implantación de catéter (intraventricular o intraparenquimatoso, exclusivamente) para la monitorización y el tratamiento del aumento de la PIC
    7. Presión arterial sistólica ? 100 mmHg
    8. Las mujeres en edad fértil deberán dar resultado negativo en una prueba de embarazo
    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
    Criterios de exclusión
    1. Traumatismo craneoencefálico penetrante (p. ej., proyectil, herida por arma blanca)
    2. Lesión medular concurrente, pero no preexistente
    3. Pupilas fijas y dilatadas (> 4 mm). Pero se permite la inclusión si solo hay una pupila fija y dilatada (> 4 mm), si el paciente no presenta signos de herniación de las zonas cerebrales transtentorial o temporal
    4. Reanimación cardiopulmonar después del TCE, o lesiones extracraneales que provocan hemorragia ininterumpida que probablemente precisará de múltiples transfusiones (> 4 unidades de eritrocitos)
    5. Coma debido a hematoma epidural exclusivo (intervalo de lucidez y ausencia de lesión cerebral estructural en la TC)
    6. Sospecha de que el coma se debe principalmente a causas distintas del TCE (p. ej., sobredosis, ahogamiento o casi ahogamiento)
    7. Constancia de TCE mayor anterior, o demostración por TC de este
    8. Pacientes cuya recuperación no se pueda monitorizar (eGOS-I y QOLIBRI)
    9. Pacientes y parientes que no entiendan o hablen español, inglés, francés o alemán (en Israel: hebreo, ruso, árabe)
    10. Cranectomía descompresora, prevista antes de la aleatorización
    Nota: se podrá inscribir al paciente si la única finalidad de la cranectomía osteoplásica es la evacuación de un hematoma
    11. Pacientes politraumatizados con puntuación de la intensidad de las lesiones en puntos distintos de la cabeza > 18
    12. Rabdomiólisis con CK > 5000 UI/l
    13. Lesiones de la aorta ascendente o de las arterias carótidas y vertebrales
    14. Valores de creatinina sérica > 1,2 mg/dl (106 µmol/l) (mujeres), o > 1,5 mg/dl (133 µmol/l) (varones)
    15. Velocidad de filtración glomerular estimada (VFGe) < 60 ml/min, calculada con la fórmula CKD-ED (Chronic Kidney Disease-Epidemiology Collaboration)
    16. IMC < 18,5 kg/m2 y > 40 kg/m2, peso corporal > 110 kg
    17. Todo trastorno concomitante intenso (cáncer; enfermedades hematológicas, renales, hepáticas y coronarias; trastorno psiquiátrico mayor; abuso de alcohol o de drogas) que se pueda determinar en el ingreso
    18. Haber recibido un fármaco en investigación en las 4 semanas previas al TCE
    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
    El resultado clínico eGOS-I 6 meses después del TCE se evaluará cara a cara con el paciente o con un representante, mediante un cuestionario normalizado en un impreso de entrevista
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 meses
    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.
    - 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.
    - 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.
    - 24-hours value of TIL on a daily base over 14 days after start of treatment
    - Number of decompressive craniectomies (one or both hemispheres)
    Evaluaciones de la eficacia secundaria
    - La QOLIBRI 6 meses después del TCE se evaluará cara a cara con el paciente o con un representante, mediante un cuestionario normalizado en un impreso de entrevista.
    - La QOLIBRI OS 6 meses después del TCE se evaluará cara a cara con el paciente o con un representante, mediante un cuestionario normalizado en un impreso de entrevista.
    - La eGOS-I 3 meses después del TCE se evaluará cara a cara con el paciente o con un representante, mediante un cuestionario normalizado en un impreso de entrevista.
    - La QOLIBRI OS 3 meses después del TCE se evaluará cara a cara con el paciente o con un representante, mediante un cuestionario normalizado en un impreso de entrevista.
    - Valor de 24 horas del TIL a diario en los 14 días siguientes al inicio del tratamiento.
    - Número de cranectomías descompresoras (en un hemisferio o en los dos).
    E.5.2.1Timepoint(s) of evaluation of this end point
    14 days, 3 months and 6 months
    14 dias, 3 meses y 6 meses
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    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
    La última visita del último paciente
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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 2016-04-18. 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.
    Pacientes con traumatismo craneoencefálico de moderado a intenso.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    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.
    Continuar con la práctica clínica habitual en el centro de tratamiento.
    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 Decision2016-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-17
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