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    Summary
    EudraCT Number:2012-003609-80
    Sponsor's Protocol Code Number:ECASS-4:ExTEND
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-07-12
    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 number2012-003609-80
    A.3Full title of the trial
    European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits.
    Estudio cooperativo europeo sobre el ictus agudo - 4.
    Ampliación de la ventana terapéutica para la trombólisis en los déficits neurológicos críticos.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Extending the time for thrombolytic treatment after stroke.
    Ampliación de la ventana terapéutica para la trombólisis tras un ictus.
    A.4.1Sponsor's protocol code numberECASS-4:ExTEND
    A.5.4Other Identifiers
    Name:ECASS-4: ExTENDNumber:None
    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 SponsorRuprecht-Karls-University Heidelberg, Medical Faculty
    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 supportBoehringer Ingelheim GmbH & Co. KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTFS Trial Form Support AB
    B.5.2Functional name of contact pointPär Thored
    B.5.3 Address:
    B.5.3.1Street AddressRuben Rausings gata 11A
    B.5.3.2Town/ cityLUND
    B.5.3.3Post codeSE-22100
    B.5.3.4CountrySweden
    B.5.4Telephone number+4646280 19 33
    B.5.5Fax number+4646280 18 01
    B.5.6E-mailpar.thored@tfscro.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 Yes
    D.2.1.1.1Trade name Actilyse
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim Pharma GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Powder and solvent for solution for injection/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 INNALTEPLASE
    D.3.9.1CAS number 105857-23-6
    D.3.9.4EV Substance CodeSUB05378MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.9
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 placeboPowder and solvent 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
    Acute Ischemic Stroke
    Ictus isquémico agudo
    E.1.1.1Medical condition in easily understood language
    Stroke
    Ictus
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To test the hypothesis that ischemic stroke patients selected with significant penumbral mismatch at 4.5-9 hours post onset of stroke or wake up with stroke symptoms will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo.
    Analizar la hipótesis de que los pacientes con ictus isquémico con discordancia (mismatch) significativa de la penumbra a las 4,5-9 horas después de la aparición del ictus o después de despertar con síntomas de ictus ("ictus del despertar") mejorarán los resultados clínicos cuando se administra rt-PA (alteplasa) por vía intravenosa en comparación con los tratados con placebo.
    E.2.2Secondary objectives of the trial
    Collection of explorative data of functional outcome, including depression and cognitive impairment and the effect of thrombolysis.
    Recogida de datos exploratorios de los desenlaces funcionales, incluyendo depresión y trastornos cognitivos y el efecto de la trombólisis
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients presenting with acute ischemic stroke
    - Patient, family member or legally responsible person depending on local ethics requirements has given informed consent
    - Patient?s age is ?18 years
    - Treatment onset within ? 4.5 ? 9 hours after stroke onset
    - Patients who wake with stroke may be included if neurological and other exclusion criteria are satisfied. These ?wake up? strokes are defined as having no symptoms at sleep onset, but stroke symptoms on waking
    - NIHSS score of 4 to 26 with clinical signs of hemispheric infarction
    - Penumbral imaging via centralized software system (e.g. RAPID-system) ? Using a Tmax ? 6 second delay, a
    perfusion volume (PWI) to infarct core ratio (DWI) of 1.2, and a perfusion lesion minimum volume of 20 ml
    -Pacientes que presentan ictus isquémico agudo
    -Paciente, o su representante legal, que haya otorgado el consentimiento informado por escrito. Un testigo independiente puede firmar el formulario de consentimiento si el paciente es capaz de dar su consentimiento verbalmente, pero es incapaz de firmar
    -Edad del paciente ? 18 años
    -Inicio del tratamiento ? 4,5-9 horas después de la aparición del ictus
    -Se pueden incluir pacientes con "ictus al despertar". Los ictus "al despertar" se definen como aquellos no presentan síntomas de ictus en la conciliación del sueño, pero sí al despertarse. La hora de inicio del ictus debe tomarse como el punto medio entre el inicio del sueño (o el último conocido como normal) y la hora de despertar.
    ? Puntuación en la NIHSS de 4 a 26 con signos clínicos de infarto hemisférico
    ? Imagen de la discordancia de la penumbra mediante evaluación local a través de un sistema informático de análisis (p. ej., RAPID) - Uso de una retraso de Tmáx ? 6 segundos, una relación entre el volumen de perfusión (PWI) y el core (tejido lesionado) del infarto (DWI) de ? 1,2, y un volumen de lesión por perfusión mínimo de 20 ml.
    E.4Principal exclusion criteria
    - Intracranial hemorrhage (ICH) identified by CT or MRI
    - Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient having an NIHSS score of <4 at randomization
    - Pre-stroke mRS score of more than 1 (indicating previous disability)
    - Contra indication to imaging with MR
    - Infarct core >1/3 MCA territory qualitatively or >100 ml quantitatively (determined by DWI lesion on MR)
    - Participation in any investigational study in the previous 30 days
    - Any terminal illness such that patient would not be expected to survive more than 3 months
    - Any condition that could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study (this applies to patients with severe microangiopathy such as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura). The judgment is left to the discretion of the investigator
    - Pregnant women (clinically evident)
    - Previous stroke within last three months
    - Recent past history or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arterio-venous (AV)
    malformation, aneurysm, or cerebral neoplasm. At the discretion of each Investigator
    - Current use of oral anticoagulants and a prolonged prothrombin time (INR > 1.6) or any aPTT elevation above 1.5 controls or prolonged Thrombin-Time (TT) indicating the potential use of Dabigatran-Etexilate
    - Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours
    - Use of glycoprotein IIb-IIIa inhibitors within the past 72 hours
    - Clinically significant hypoglycemia
    - Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or >110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure to within these limits. The definition of ?aggressive treatment? is left to the discretion of the responsible Investigator.
    - Hereditary or acquired hemorrhagic diathesis
    - Gastrointestinal or urinary bleeding within the preceding 21 days
    - Major surgery within the preceding 14 days which poses risk in the opinion of the investigator
    - Exposure to a thrombolytic agent within the previous 72 hours
    -Hemorragia intracraneal (HIC) identificada por TC o RM
    -Síntomas de mejoría rápida, particularmente, si a juicio del investigador, es probable que la mejoría tenga como resultado que el paciente obtenga una puntuación en la NIHSS de < 4 en la aleatorización
    -Puntuación de EmR antes del ictus de > 1 (indicativa de una discapacidad previa)
    -Contraindicación de exploración por RM
    -Core de infarto > 1/3 de territorio ACM o > 100 ml cuantitativamente (determinado por la lesión DWI en la RM).
    -Participación en algún estudio de investigación en los últimos 30 días
    -Esperanza de vida de < 3 meses
    -Cualquier afección que, en opinión del investigador, pudiera conllevar riesgos para el paciente si se inicia el tratamiento del estudio o afecta a la participación del paciente en el estudio (se aplica a pacientes con microangiopatía grave como un síndrome urémico hemolítico o púrpura trombocitopénica trombótica).
    -Mujeres embarazadas (confirmado clínicamente) o en periodo de lactancia.
    -Ictus en los tres meses anteriores a la aleatorización
    -Antecedentes recientes (a juicio del investigador) o signos clínicos de HIC, hemorragia subaracnoidea (HSA), malformación arteriovenosa (AV), aneurisma o neoplasia cerebral.
    -Uso actual de anticoagulantes orales y un tiempo de protombina prolongado (INR > 1,6) o cualquier tiempo de tromboplastina parcial activada (TTPa) superior a 1,5 veces los límites de normalidad del tiempo de protrombina (TT), indicativo del posible uso de dabigatrán etexilato.
    -Uso de heparina, excepto heparina subcutánea a dosis bajas, en el plazo de 48 horas antes de la aleatorización
    -Uso de inhibidores de la glucoproteína IIb-IIIa en las 72 horas anteriores a la aleatorización.
    -Hipoglucemia clínicamente significativa.
    -Hipertensión no controlada definida por una presión arterial > 185 mmHg sistólica o > 110 mmHg diastólica en al menos 2 ocasiones independientes con al menos 10 minutos de diferencia, o que requiere un tratamiento agresivo para reducir la presión arterial dentro de estos límites. La definición de "tratamiento agresivo" se deja a discreción del investigador.
    -Diátesis hemorrágica hereditaria o adquirida
    -Hemorragia gastrointestinal o urinaria en los 21 días previos a la aleatorización
    -Cirugía mayor en los 14 días previos a la aleatorización que suponga un riesgo a juicio del investigador.
    -Exposición a un fármaco trombolítico en el plazo de 72 horas antes de la aleatorización
    E.5 End points
    E.5.1Primary end point(s)
    Categorical shift in the modified Rankin Scale (mRS) at Day 90
    Cambio categórico en la Escala modificada de Rankin (EmR) en el día 90
    E.5.1.1Timepoint(s) of evaluation of this end point
    90 days after administration of IMP
    90 días tras la administración del tratamiento.
    E.5.2Secondary end point(s)
    - Disability at Day 90, dichotomized as a favorable outcome
    (mRS) 0?1 vs. 2 - 6A
    - Change in ? 11 NIHSS points or reaching ? 1 on this scale
    - Reperfusion at 24 hrs post stroke
    - Recanalization at 24 hrs post stroke
    - Infarct growth on DWI within 24 hrs
    - NIHSS at day 7±1
    - Depression (Montgomery-Asberg Depression Rating Scale [MADRS])
    - Montreal Cognitive Assessment (MoCA) at day 90
    - Quality of life (Stroke Impact Scale) at day 90
    -Incapacidad en el día 90, dicotomizada como un desenlace favorable (EmR) 0-1 frente a 2-6
    -Cambio en ? 11 puntos en la Escala del ictus del National Institute of Health (NIHSS) o alcanzar ? 1 en esta escala en el día 1 y el día 90
    -Reperfusión a las 12-24 horas después del tratamiento
    -Recanalización a las 12-24 horas después del tratamiento
    -Crecimiento del infarto en imágenes ponderadas por difusión (DWI) en las 12-24 horas posteriores al tratamiento
    -Puntuación en la NIHSS en el día 7
    -Índice de Barthel (IB) en el día 90
    -Puntuación de la Evaluación cognitiva de Montreal (ECMo) en el día 90
    E.5.2.1Timepoint(s) of evaluation of this end point
    90 days after administration of IMP
    90 días tras la administración del tratamiento.
    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) 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 Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA27
    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
    The end of the study will be defined as the last visit of the last patient remaining in the study.
    El final del estudio se definirá como la última visita del último paciente en estudio.
    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 months0
    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 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: 132
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 132
    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 No
    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
    The patiens might be incapable of personally giving informed consent because of their medical condition.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 264
    F.4.2.2In the whole clinical trial 264
    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)
    Standard care.
    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 Decision2013-09-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-11-07
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