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    EudraCT Number:2012-003609-80
    Sponsor's Protocol Code Number:ECASS-4:ExTEND
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-07-15
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    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.
    4° Studio cooperativo europeo sull'ictus acuto: estensione della finestra terapeutica per la trombolisi nei deficit neurologici critici
    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.
    Estensione del tempo di trattamento trombolitico dopo l'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.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 Pharma GmbH & Co. KG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTFS Trial Form Support
    B.5.2Functional name of contact pointPaola Vietti
    B.5.3 Address:
    B.5.3.1Street AddressViale Parioli 12
    B.5.3.2Town/ cityROME
    B.5.3.3Post codeIT-00197
    B.5.4Telephone number+3906807 60 72
    B.5.5Fax number+3906 806 93 521
    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. name Actilyse
    D. of the Marketing Authorisation holderBoehringer Ingelheim Pharma GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.1Product nameActilyse
    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 milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 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
    Acute Ischemic Stroke
    Ictus ischemico acuto
    E.1.1.1Medical condition in easily understood language
    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.
    Valutare l'ipotesi secondo cui i pazienti affetti da ictus ischemico con penombra ischemica significativa a 4,5 - 9 ore dall'insorgenza dell'ictus o dopo il risveglio con la sintomatologia dell'ictus ("ictus al risveglio") avranno esiti clinici migliori con la somministrazione per via endovenosa di rt-PA (alteplase) rispetto ai pazienti trattati 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.
    Raccolta di dati esplorativi sull'esito funzionale, inclusi depressione e disturbi cognitivi ed effetto della trombolisi.
    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-system1) – 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
    - Pazienti che presentano ictus ischemico acuto;
    - Il paziente, o un rappresentante legalmente riconosciuto, ha fornito il consenso informato per iscritto. Un testimone indipendente potrà firmare il modulo di consenso se il paziente è in grado di dare consenso orale, ma non è in grado di firmare;
    - Età ≥ 18 anni;
    - Inizio del trattamento entro ≥ 4,5 - 9 ore dall'insorgenza dell'ictus
    -I pazienti con ictus "al risveglio" potranno essere inclusi. Sono definiti ictus "al risveglio" quelli la cui sintomatologia non è presente all'inizio del sonno, ma al risveglio. Il tempo di insorgenza dell'ictus deve essere preso come punto intermedio tra l'inizio del sonno (o l'ultimo riconosciuto normale) e il tempo di risveglio.
    - Punteggio NIHSS da 4 a 26 con segni clinici di infarto emisferico;
    - Immagini di penombra ischemica ottenute mediante valutazione locale utilizzando un sistema di analisi computerizzato (ad es. RAPID) - con un Tmax ≥ 6 secondi di ritardo, un rapporto volume di perfusione (PWI) rispetto a core dell'infarto (DWI) ≥ 1,2 e un volume minimo di perfusione della lesione di 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
    - Emorragia intracranica (ICH) rilevata da TAC o RM;
    - Rapido miglioramento dei sintomi, in particolare se, a giudizio dello sperimentatore, il miglioramento può portare il paziente a raggiungere un punteggio NIHSS < 4 alla randomizzazione;
    - Punteggio mRS pre-ictus >1 (indicativo di precedente disabilità);
    - Controindicazione all'esame di neuroimmagini con RM (risonanza magnetica);
    - Core dell'infarto >1/3 del territorio dell'arteria cerebrale media (ACM) qualitativamente o >100 ml quantitativamente (determinato da lesione DWI con RM);
    - Partecipazione a qualunque sperimentazione nei 30 giorni precedenti;
    - Aspettativa di vita < 3 mesi;
    - Qualsiasi condizione che, a giudizio dello sperimentatore, possa comportare rischi per il paziente iniziando la terapia in studio o pregiudicarNe la partecipazione del paziente (questo vale per i pazienti con microangiopatia grave come la sindrome uremica-emolitica o la porpora trombotica trombocitopenica);
    - Gravidanza (clinicamente evidente) o allattamento;
    - Precedente ictus tre mesi prima della randomizzazione;
    - Anamnesi recente (a giudizio dello sperimentatore) o presentazione clinica di emorragia intracranica (ICH), emorragia subaracnoidea (ESA), malformazione arterio-venosa (MAV), aneurisma o neoplasia cerebrale;
    - Attuale uso di anticoagulanti orali e un prolungato tempo di protrombina (INR > 1,6 ) o qualsiasi tempo di tromboplastina parziale attivata (aPTT) superiore di 1,5 volte il range normale o tempo di trombina (TT) prolungato, che indica l'uso potenziale di dabigatran etexilato;
    - Uso di eparina, salvo per l'eparina a bassa dose per via sottocutanea, nelle 48 ore precedenti la randomizzazione
    - Uso di inibitori della glicoproteina IIb-IIIa nelle 72 ore precedenti la randomizzazione;
    - Ipoglicemia clinicamente significativa;
    - Ipertensione non controllata definita come pressione arteriosa > 185 mmHg sistolica o > 110 mmHg diastolica in almeno 2 diverse occasioni con almeno 10 minuti di distanza, o che richiede un trattamento aggressivo per ridurre la pressione sanguigna entro tali limiti. La definizione di "trattamento aggressivo" viene lasciata a discrezione dello sperimentatore;
    - Diatesi emorragica ereditaria o acquisita;
    - Emorragia gastrointestinale o urinaria nei 21 giorni precedenti la randomizzazione;
    - Intervento di chirurgia maggiore nei 14 giorni precedenti la randomizzazione che comporta un rischio a giudizio dello sperimentatore;
    - Esposizione ad un agente trombolitico nelle 72 ore precedenti la randomizzazione.
    E.5 End points
    E.5.1Primary end point(s)
    Categorical shift in the modified Rankin Scale (mRS) at Day 90
    Cambio di categoria nella scala Rankin modificata (mRS) al giorno 90.
    E.5.1.1Timepoint(s) of evaluation of this end point
    90 days after administration of IMP
    90 giorni dopo la somministrazione dell'IMP
    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
    - Disabilità al giorno 90, dicotomizzata come un esito favorevole (mRS) 0-1 vs. 2-6A;
    - Variazione di ≥ 11 punti della scala NIHSS (National Institute of Health Stroke Scale) o raggiungimento di punteggio ≤ 1 su questa scala il giorno 1 e il giorno 90;
     - Riperfusione a 12-24 ore dopo il trattamento;
     -Ricanalizzazione a 12-24 ore dopo il trattamento;
     - Crescita dell'infarto su immagini pesate in diffusione (DWI) entro 12-24 ore dopo il trattamento;
     - Punteggio NIHSS al giorno 7;
     - Indice di Barthel (BI) al giorno 90;
     - Punteggio MoCA (Montreal Cognitive Assessment) al giorno 90.
    E.5.2.1Timepoint(s) of evaluation of this end point
    90 days after administration of IMP
    90 giorni dopo la somministrazione dell'IMP
    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. 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 No
    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.
    La fine dello studio sarà definito come l'ultima visita dell'ultimo paziente rimasto nello studio.
    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 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 2013-07-15. 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. of subjects incapable of giving consent
    The patiens might be incapable of personally giving informed consent because of their medical condition.
    I pazienti potrebbero essere incapaci di dare il proprio consenso a causa delle loro condizioni mediche.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state38
    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.
    Cure standard
    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 Decision2013-07-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-17
    P. End of Trial
    P.End of Trial StatusOngoing
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