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    Summary
    EudraCT Number:2012-003609-80
    Sponsor's Protocol Code Number:ECASS-4:ExTEND
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-06-18
    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 ConcernedAustria - BASG
    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.
    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.
    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 Pharma GmbH & Co. KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversität Heidelberg
    B.5.2Functional name of contact pointProfessor Dr. med Werner Hacke
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 400
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number+49 6221 568211
    B.5.5Fax number+49 6221 565348
    B.5.6E-mailwerner.hacke@med.uni-heidelberg.de
    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 AuthorisationAustria
    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 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.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 injection/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
    E.1.1.1Medical condition in easily understood language
    Stroke
    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.
    E.2.2Secondary objectives of the trial
    Collection of explorative data of functional outcome, including depression and cognitive impairment and the effect of thrombolysis.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients presenting with acute ischemic Middle Cerebral Artery (MCA) stroke
    - Patient, or legally acceptable representative has given written informed consent. An independent witness may sign the consent form if the patient is able to give verbal consent, but unable to sign
    - Patient’s age is ≥18 years
    - Treatment onset within ≥ 4.5 – 9 hours after stroke onset*
    *Patients with 'wake up' strokes may be included. 'Wake up’ strokes are defined as having no stroke symptoms at sleep onset, but on waking. The time of stroke onset is to be taken as the mid-point between sleep onset (or last known to be normal) and time of waking.
    - NIHSS score of 4 to 26 with clinical signs of hemispheric infarction
    - Penumbral mismatch imaging via local assessment using a computer based analysis system (e.g. RAPID) if available, using a perfusion volume (PWI) to infarct core (DWI) ratio of ≥ 1.2, and a minimum perfusion lesion volume of 20 ml.
    E.4Principal exclusion criteria
    - Intracranial hemorrhage (ICH) identified by CT or MRI
    - Rapidly improving symptoms, particularly if, in the opinion of the investigator, the improvement is likely to result in the patient having an NIHSS score of <4 at randomization
    - Pre-stroke mRS score of >1 (indicating previous disability)
    - Contra indication to imaging with MRI
    - Infarct core >1/3 MCA territory qualitatively or >100 ml quantitatively (determined by DWI lesion on MRI)
    - Any MRI findings indicative of a high risk of ICH related to potential iv-rtPA treatment in the judgment of the investigator
    - Participation in any investigational study in the previous 30 days
    - A life expectancy of <3 months
    - Any condition that, in the opinion of the investigator, 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).
    - Pregnant (clinically evident) or breastfeeding women
    - Previous stroke within the three months prior to randomization
    - Recent history (in the opinion of the investigator) or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm.
    - Use of oral anticoagulants within 48 hours prior to randomization (including, but not limited to Rivaroxaban, Apixaban, or Edoxaban) and a prolonged prothrombin time (INR > 1.6) or any activated partial thromboplastin (aPTT) time exceeding 1.5 times the normal range or prolonged Thrombin-Time (TT), indicating the potential use of Dabigatran-Etexilate.
    - Use of heparin, except for low dose subcutaneous heparin, within 48 hours prior to randomization
    - Use of glycoprotein IIb-IIIa inhibitors within 72 hours prior to randomization.
    - Platelet count <100.000/μl (<100G/l)
    - Blood glucose <50mg/dl (2.8 mmol/l) or >400mg/dl (22.2mmol/l)
    - 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 investigator.
    - Hereditary or acquired hemorrhagic diathesis
    - Gastrointestinal or urinary bleeding within 21 days prior to randomization
    - Manifest or recent acute pancreatitis
    - Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis
    - Major surgery within 14 days prior to randomization which poses a risk in the opinion of the investigator.
    - Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel
    - Exposure to a thrombolytic agent within 72 hours prior to randomization
    - Hypersensitivity to alteplase or any of the excipients
    E.5 End points
    E.5.1Primary end point(s)
    Categorical shift in the modified Rankin Scale (mRS) at Day 90
    E.5.1.1Timepoint(s) of evaluation of this end point
    90 days after administration of IMP
    E.5.2Secondary end point(s)
    - Disability at Day 90, dichotomized as a favorable outcome
    (mRS) 0–1 vs. 2 - 6*
    *This is the key secondary endpoint to ensure the combined analysis with the EXTEND trial
    - Change in ≥ 11 National Institute of Health Stroke Scale (NIHSS) points or reaching ≤ 1 on this scale at day 1 and day 90
    - Reperfusion at 12-24 hours after treatment
    - Recanalization at 12-24 hours after treatment
    - Infarct growth on diffusion weighted imaging (DWI) within 12-24 hours after treatment
    - NIHSS at day 7
    - Barthel Index (BI) at day 90
    - Montreal Cognitive Assessment (MoCA) score at day 90

    Tertiary endpoints (in some centers)
    - Montgomery-Asberg Depression Rating Scale (MADRS) score at day 90

    Safety endpoints
    - Death due to any cause
    - Neurological death
    - Symptomatic intracranial hemorrhage (ICH) as defined by ECASS-3 definition
    E.5.2.1Timepoint(s) of evaluation of this end point
    90 days after administration of 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.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 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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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 2013-06-18. 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
    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 state15
    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 Decision2013-07-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-26
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-12-18
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