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    Summary
    EudraCT Number:2017-001355-31
    Sponsor's Protocol Code Number:PROOF
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2019-05-27
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-001355-31
    A.3Full title of the trial
    Penumbral Rescue by Normobaric O=O Administration in Patients with Ischemic Stroke and Target Mismatch ProFile:
    A Phase II Proof-of-Concept Trial
    Rescate de la zona de penumbra mediante la administración de O=O normobárico en pacientes con accidente cerebrovascular isquémico y perfil desajustado: Una Prueba de concepto fase II
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Inhalation of oxygen at a normal pressure for penumbral rescue (rescue of not yet destroyed brain tissue) in patients with stroke due to a large vessel occlusion ("ischemic stroke")
    Inhalación de oxígeno a una presión normal para rescate de la zona de penumbra (rescate de tejido cerebral aún no destruido) en pacientes con accidente cerebrovascular debido a una oclusión de un vaso grande ("accidente cerebrovascular isquémico")
    A.3.2Name or abbreviated title of the trial where available
    PROOF
    PROOF
    A.4.1Sponsor's protocol code numberPROOF
    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 SponsorEberhard-Karls University Tübingen represented by University Hospital Tübingen and its Commercial Director
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEU Commission
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVall d'Hebron Institut de Recerca
    B.5.2Functional name of contact pointUnidad de Ictus
    B.5.3 Address:
    B.5.3.1Street AddressPasseig Vall d'Hebron 119-129
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08035
    B.5.3.4CountrySpain
    B.5.4Telephone number+349348930002701
    B.5.5Fax number+34934894180
    B.5.6E-mailaro@vhir.org
    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 Yes
    D.2.1.1.1Trade name Medical oxygen
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Medicinal gas, compressed
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOXYGEN
    D.3.9.1CAS number 7782-44-7
    D.3.9.4EV Substance CodeSUB14733MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % (V/V) percent volume/volume
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    Acute ischemic stroke
    accidente cerebrovascular isquémico
    E.1.1.1Medical condition in easily understood language
    Acute ischemic stroke
    accidente cerebrovascular isquémico
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10061256
    E.1.2Term Ischaemic stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10055221
    E.1.2Term Ischemic stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of the PROOF trial is to investigate efficacy and safety of normobaric hyperoxygenation (NBHO) as a neuroprotective treatment in patients with acute ischemic stroke due to large vessel occlusion likely to receive endovascular mechanical thrombectomy (TBY) in a randomized controlled clinical phase IIb trial.

    To demonstrate an effect of NBHO on penumbral salvage in ischemic stroke.
    El objetivo principal del ensayo PROOF es investigar la eficacia y seguridad de la hiperoxigenación normobárica (NBHO) como un tratamiento neuroprotector en pacientes con accidente cerebrovascular isquémico agudo debido a la oclusión de vasos grandes que probablemente reciban trombectomía mecánica endovascular (TBY) en un ensayo clinico de fase IIb aleatorizado y controlado.
    E.2.2Secondary objectives of the trial
    To show clinical efficacy and safety of NBHO adjunct to standard treatment.
    Para mostrar la eficacia clínica y la seguridad de NBHO junto al tratamiento estándar.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    • Exploratory analyses of imaging
    • Exploratory analyses of biochemical biomarkers to develop a blood-based test to monitor efficacy and safety of NBHO treatment
    Análisis exploratorios de imágenes
    Análisis exploratorios de biomarcadores bioquímicos para desarrollar una prueba de sangre para controlar la eficacia y la seguridad del tratamiento con NBHO
    E.3Principal inclusion criteria
    • Age: 18 to 80 years
    • Clinical signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke
    • LVO on CT angiography or MR angiography consistent with clinical signs and symptoms, i.e. either the terminal ICA with involvement of the M1-segment of the MCA/carotid-T, the proximal M1-segment, or the distal M1-segments (distal to perforating branches)
    • Neither TBY nor IVT are a prerequisite for inclusion; patients not receiving TBY or IVT or both can be enrolled. Clinical treatment decisions should not delay study enrollment.
    • NIHSS score of ≥ 6 at screening
    • NIHSS item 1a (level of consciousness) of 0 or 1
    • Alberta Stroke Program Early CT score (ASPECTS) of 7-10 on non-contrast CT or 6-10 on diffusion-weighted MRI (DWI-MRI)
    • CT perfusion (preferably whole-brain, minimal coverage ≥ 75 mm) or MR perfusion imaging performed prior to NBHO
    • NBHO can be initiated within 3 hours of certain stroke symptom onset (witnessed or last seen well) and within 20 minutes after end of baseline brain imaging (i.e. within 20 minutes after last image)
    • Pre-stroke mRS of 0 or 1
    • Breastfeeding women can participate, but must be instructed to stop breastfeeding after randomization
    • Due to the emergency situation in which patients are enrolled and the presumed safety of the IMP as applied in the PROOF trial, their own written informed consent is not obtained prior to study inclusion but has to be gained as soon as possible. Patients who are able to give consent will be informed about trial participation orally and may consent to or decline participation. Patients unable to give consent will be enrolled through a deferred consent procedure
    • Edad: 18 a 80 años
    • Signos y síntomas clínicos de diagnóstico de un accidente isquémico agudo anterior.
    • Oclusión de gran vaso determinada en angiografía por TAC o angiografía por resonancia magnética consistente con los signos y síntomas clínicos, es decir, la arteria carótida interna terminal con afectación del segmento M1 de la arteria cerebral media / carótida-T, el segmento proximal M1 o los segmentos M1 distales (distales a las ramas perforantes)
    • Ni TBY ni IVT son un requisito previo para la inclusión; Los pacientes que no reciben TBY o IVT o ambos pueden inscribirse. Las decisiones de tratamiento clínico no deben retrasar la inscripción en el estudio.
    • En la selección una puntuación NIHSS ≥ 6
    • Nivel de consciencia según el ítem 1a del NIHSS de 0 o 1
    • Puntuación Alberta Stroke Program Early CT (ASPECTS) de 7-10 en TAC sin contraste o de 6-10 en resonancia de difusión (DWI-MRI)
    • Antes del inicio de NBHO, TAC - perfusión (preferiblemente de todo el cerebro, cobertura mínima ≥ 75 mm) o perfusión por resonancia magnética.
    • NBHO puede iniciarse dentro de las 3 horas tras el inicio de ciertos síntomas del accidente cerebrovascular y dentro de los 20 minutos después de finalizar la imagen de cerebro basal.
    • Puntuación mRS anterior al accidente cerebrovascular de 0 o 1
    • Las mujeres en período de lactancia pueden participar, pero deberán ser informadas de que deben para la lactancia después de la aleatorización.
    • Debido a la situación de urgencia en la que se incluyen a los pacientes y a la seguridad del fármaco en investigación, el consentimiento informado del paciente no se obtendrá antes de la inclusión del estudio, pero tiene que obtenerse tan pronto como sea posible. Los pacientes que pueden dar su consentimiento serán informados oralmente sobre la participación en el ensayo y pueden consentir o rechazar su participación. Para los pacientes que no puedan dar su consentimiento, este se obtendrá por un procedimiento diferido (consulte la Sección 14.5 Información del sujeto y consentimiento informado).
    E.4Principal exclusion criteria
    Neurological:
    • Rapid improvement in neurological status to an NIHSS < 6 or evidence of vessel recanalization prior to randomization
    • Seizures at stroke onset if it makes the diagnosis of stroke doubtful and precludes obtaining an accurate baseline NIHSS assessment
    • Acute neurological symptoms related to other pathology than ischemic stroke
    • Evidence of intracranial hemorrhage (except of cerebral microbleeds), intracranial tumor (except small meningioma), and/or intracranial arteriovenous malformation as confirmed by baseline brain imaging
    • Intracranial aneurysm or prior stent implantation in the vascular territory (upstream and downstream) affected by qualifying LVO
    • TBY procedure initiated (groin puncture) prior to randomization
    • Previously known or CT angiographic / MR angiographic visualization of ipsilateral high-grade stenosis, complete cervical carotid occlusion, or flow-limiting carotid dissection
    • Suspected aortic dissection or cerebral vasculitis based on medical history or CT angiography / MR angiography
    • Clinical or imaging evidence of acute bilateral stroke or stroke in other vascular territories than qualifying LVO (except of clinically silent micro-lesions on DWI-MRI in patients who received MR-based acute brain imaging)
    • Significant mass effect with midline shift as confirmed by brain imaging
    • Any co-existing neurological (especially neuromuscular) disorder
    Respiratory:
    • Known history of chronic pulmonary disease (e.g. COPD, pulmonary fibrosis, alveolitis or pneumonitis)
    • Any condition leading to hypoxic respiratory drive (e.g. neuromuscular disease)
    • Prior to enrolment, > 2 L/min oxygen required to maintain peripheral oxygen saturation ≥ 95%
    • Acute respiratory distress that may, in the clinical judgment of the investigator, interfere with the study intervention
    • Acute pneumonia, alveolitis or pneumonitis of viral, bacterial, fungal or any other etiology.
    • Endotracheal intubation at time of screening or anticipated intubation for other reasons than TBY procedure
    Other:
    • Clinical suspicion of acute myocardial infarction (e.g. pressure or tightness in the chest, pain in the chest, back, jaw, and other areas of the upper body that lasts more than a few minutes or that goes away and comes back, shortness of breath)
    • Baseline blood glucose of < 50 mg/dL (2.78 mmol) or > 400 mg/dL (22.20 mmol)
    • Body temperature ≥ 38.0°C at screening
    • Presumed septic embolus, or suspicion of bacterial endocarditis
    • History of severe allergy (more than rash) to contrast medium
    • Current treatment with nitrofurantoin or amiodaron, paraquat poisoning, or history of treatment with bleomycin
    • Pregnancy at screening, to be excluded (β-HCG in serum or urine) in all women ≤ 55 years except if surgically sterile; in women >55 years pregnancy must be excluded only in case of increased probability e.g. due to in-vitro fertilization
    • Any co-existing or terminal disease (except qualifying stroke) with anticipated life expectancy of less than 6 months
    • Any pre-existing condition that may, in the clinical judgment of the investigator, not allow safe participation in the study (e.g. alcohol or substance abuse, co-existing disease) or would complicate assessment of outcomes (e.g. dementia, psychiatric disease) or would confound the neurological or functional evaluations (e.g. dementia)
    • Participation in another interventional (drug or device) study within the last four weeks
    • Prior participation in the PROOF trial (no subject will be allowed to enroll in this trial more than once).
    Neurológicos:
    • Rápida mejora de la condición neurológica a una puntuación NIHSS < 6 o evidencia de recanalización de los vasos previa a la aleatorización.
    • Convulsiones al inicio del accidente cerebrovascular si hace que el diagnóstico de accidente cerebrovascular sea dudoso y no permite obtener una evaluación NIHSS basal precisa
    • Síntomas neurológicos agudos relacionados con otras patologías diferentes del accidente isquémico
    • En la selección, evidencias radiológicas confirmadas de hemorragia intracraneal (excepto microhemorragias cerebrales), tumores intracraneales (excepto meningiomas pequeños), y/o malformaciones arteriovenosas intracraneales.
    • Aneurisma intracraneal o implantación previa de un stent en el área vascular afectado por la oclusión de vasos grandes.
    • Inicio del procedimiento de TBY previo a la aleatorización.
    • Historia o confirmación por Angiografía por TAC o Angiografía por Resonancia Magnética de estenosis ipsilateral de grado alto, oclusión completa de la carótida cervical o disección del flujo de la carótida
    • Sospecha de disección aórtica o vasculitis cerebral basada en la historia médica o en angiografía de TAC / Angiografía de resonancia magnética.
    • Evidencia clínica o por imagen de accidente cerebrovascular agudo bilateral o en otras áreas diferentes de la zona de oclusión de grandes vasos (excepto microlesiones silenciosas clínicamente en DWI-MRI)
    • Efecto de masa significativo con cambio en la línea media confirmado por imágenes cerebrales
    • Cualquier trastorno neurológico previo (especialmente neuromuscular)

    Respiratorios:

    • Historia conocida de enfermedad pulmonar crónica (EPOC; fibrosis pulmonar, alveolitis o pneumonitis)
    • Cualquier condición que conlleve hipoxia respiratoria (p.ej. enfermedad neuromuscular)
    • Antes de la inclusión, es necesario un nivel de oxígeno > 2 L/min para mantener la saturación periférica de oxígeno ≥ 95%
    • Dificultad respiratoria aguda, que a criterio médico, pueda interferir durante la intervención del estudio.
    • Neumonía aguda, alveolitis o neumonitis viral, bacteriana, micótica o de cualquier otra etiología
    • En la selección, intubación endotraqueal o previsión de intubación por otras causas diferentes del procedimiento de TBY
    Otras:

    • Sospecha clínica de infarto agudo de miocardio (p.ej. presión o opresión en el pecho,dolor en pecho, espalda, mandíbula o otras áreas superiors del cuerpo durante más de unos minutos, intermientes o dificultad para respirar,

    • Glucosa en sangre de < 50 mg/dL (2.78 mmol) o > 400 mg/dL
    (22.20 mmol) en la visita basal
    • Temperatura corporal ≥ 38.0°C en la visita basal
    • Sospecha de émbolo séptico o de endocarditis bacteriana
    • Historia de alergia severa (más que una irritación) al contraste.
    • Tratamiento actual con nitrofurantoina o amiodarone, intoxicación por paraquat, o historia de tratamiento con bleomicina
    • Mujeres embarazas (β-HCG en sangre o orina) en mujeres menores o iguales a 55 años, excepto si han sido sometidas a esterilización quirúrgica. Para mujeres mayores de 55 años solo deben ser excluidas en caso probabilidad de embarazo, por ejemplo mediante técnicas in-vitro.
    • Presentar una enfermedad terminal con una esperanza de vida inferior a los 6 meses (exceptuando el ICTUS que genera la inclusión en el estudio)
    • Cualquier condición previa que a criterio del investigador, no permita participar de forma segura en el estudio (p.ej. alcoholismo, abuso de drogas, una enfermedad) o que pueda complicar el resultado clínico del paciente (p.ej. demencia o problemas psiquiátricos) o que pueda provocar confusión neurológica o funcional (p.ej. demencia)
    • Participación en otro ensayo clínico (con medicamento o producto sanitario) las 4 semanas previas al inicio.
    • Participación previa en el estudio PROOF (no se permitirá que ningún paciente se incluya más de una vez)
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the ischemic core growth defined as the difference in ischemic core volume (in mL) from baseline to 24 hours; intention-to-treat analysis
    La variable principal es la diferencia entre el volumen basal del núcleo isquémico (en ml) y el volumen a las 24 horas, analisis por intención de tratar
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 24 hours
    despues de 24h
    E.5.2Secondary end point(s)
    Key secondary efficacy endpoint is the change in National Institutes of Health Stroke Scale (NIHSS) scores from baseline to 24 hours.
    Secondary clinical efficacy endpoints: Survival at visit 6 (V6), and V7; NIHSS score (neurological status) at V2, V4, V5, V6, and V7; modified Rankin Scale (mRS) score, and Barthel Index score at V6 and V7; MoCA at V7 (controlled for Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) at V5), Stroke Impact Scale 16 (SIS-16), EuroQoL Questionnaire (EQ-5D-5L), and Montgomery–Åsberg Depression Rating Scale (MADRS) scores at V7; PaO2 at V3, and V5
    Clinical safety endpoints:all-cause death at V6, and V7; stroke related death at V6, and V7; symptomatic intracranial hemorrhage until V6; vital signs (systolic and diastolic blood pressure, heart and respiratory rate, peripheral capillary oxygen saturation (SpO2)) at V1-V7, with body temperature at V1, V5, and V6; 12-lead electrocardiogram (ECG) at V1, and V5; laboratory (blood count, clinical chemistry, coagulation) at V5, and V6; length of ICU stay, hospital stay, and duration of ventilation at V6, and V7; concomitant invasive procedures (e.g. intravenous/intra-arterial thrombolysis, thrombectomy, stenting, carotid surgery, decompressive hemicraniectomy, cardioversion, patent foramen ovale (PFO) closure) until V7.
    Secondary imaging efficacy endpoints: relative changes in ischemic core volume (in %) from baseline to 24 hours; absolute and relative ischemic core change from baseline to 24 hours using cerebral blood flow (CBF)
    < 30% for ischemic core estimation at baseline in all patients, independent of imaging modality; penumbral salvage from baseline to 24 hours; TICI (Thrombolysis in Cerebral Infarction perfusion scale grade) in patients who underwent TBY; revascularization on 24-hour follow-up imaging.
    Imaging safety endpoints: new microbleeds on 24-hour follow-up imaging; any intracranial hemorrhage on 24-hour follow-up imaging; peri-interventional occurrence of vasospasms; ischemic lesions in new territories on 24-hour follow-up imaging.
    Objetivo secundario y variable

    Para demostrar la eficacia y la seguridad del producto en investigación junto al tratamiento habitual, se compararán las siguientes variables entre grupos:

    La principal variable secundaria de eficacia es el cambio en la puntuación de las escalas NIHSS (National Institutes of Health Stroke Scale) en la basal y a las 24 horas.

    Variables secundarias de eficacia: supervivencia en las visitas 6 (V6) y 7 (V7); puntuación NIHSS (status neurológico) en V2, V4, V5, V6, y V7; Puntuación de la escala mRS y puntuación del Índice Barthel en V6 y V7; Evaluación MoCA en V7; Puntuación escala IQCODE en V5; Escalas SIS-16,EQ-5D-5L, y MADRS en V7; PaO2 en V3 y V5.

    Variables secundarias de seguridad: toda causa de muerte en V6 y V7; muerte relacionada por el accidente cerebrovascular en V6 y V7; hemorragia intracraneal sintomática hasta V6; signos vitales (presión sistólica y diastólica, frecuencia cardiaca y respiratoria; saturación de oxígeno periférica capilar V1 a V7; temperatura V1, V5 y V6; electrocardiograma de 12 derivaciones V1 y V; parámetros de laboratorio en V5 y V6; estancia en la UCI, estancia en el hospital, y duración de la ventilación en V6 y V7; procedimientos invasivos concomitantes.

    Variables secundarias de eficacia en imagen: diferencias en el volumen del volumen isquémico (en %) entre la visita basal y las 24 horas; cambios, absoluto y relativo, del núcleo isquémico entre la visita basal y las 24 horas, utilizando el flujo sanguíneo cerebral; <30% de estimación del núcleo isquémico basal en todos los pacientes independientemente del tipo de imagen; recuperación del área de penumbra desde la basal hasta las 24 horas; seguimiento de la revascularización durante 24 horas; Grado de la escala TICI en pacientes sometidos a TBY

    Variables de seguridad en imagen: presencia de nuevas microhemorragias en las siguientes 24 horas; hemorragias intracraneales en las siguientes 24 horas; aparición de vasoespamos en la zona peri intervencional; lesiones isquémicas en nuevas áreas en las siguientes 24 horas
    E.5.2.1Timepoint(s) of evaluation of this end point
    please see timepoints in the description above
    por favor vea los objetivos descritos en apartados anteriores.
    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 No
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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
    evaluación cegada del punto final (diseño de prueba)
    blinded endpoint assessment (PROBE design)
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    tratamiento estandard
    standard treatment
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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
    Belgium
    Czech Republic
    Finland
    France
    Spain
    Sweden
    Switzerland
    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 last subject
    ultima visita ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months60
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months60
    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: 228
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 228
    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
    Due to the underlying disease (ischemic stroke), patients will in most cases not be able to give consent personally. However, in case they are able to, they must be informed prior to trial enrolment.
    Debido a la enfermedad subyacente (ACI), los pacientes en la mayoría de los casos no podrán dar su consentimiento personalmente. Sin embargo, en caso de que puedan, deben ser informados antes de la inclusión del estudio
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state422
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 422
    F.4.2.2In the whole clinical trial 456
    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)
    Patients are treated according to the local routine. There is only one additional follow-up visit at day 90 after randomization.
    Los pacientes son tratados según la clinica habitual. Solo hay una visita de seguimiento adicional a los 90 dias después de la aleatorización.
    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 Decision2019-11-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-29
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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