E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate and severe traumatic brain injury |
Traumatismo craneoencefálico de moderado a intenso |
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E.1.1.1 | Medical condition in easily understood language |
Moderate and severe traumatic brain injury |
Traumatismo craneoencefálico de moderado a intenso |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060690 |
E.1.2 | Term | Traumatic brain injury |
E.1.2 | System Organ Class | 100000004863 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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 |
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E.2.2 | Secondary 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) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
14 days, 3 months and 6 months |
14 dias, 3 meses y 6 meses |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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Last visit of last subject |
La última visita del último paciente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |