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    Summary
    EudraCT Number:2011-005906-32
    Sponsor's Protocol Code Number:WAKE-UP
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-11-19
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2011-005906-32
    A.3Full title of the trial
    Efficacy and safety of MRI-based thrombolysis in wake-up
    stroke: a randomised, double-blind, placebo-controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of MRI-based thrombolysis in wake-up stroke.
    A.4.1Sponsor's protocol code numberWAKE-UP
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01525290
    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 SponsorUniversity Medical Center Hamburg-Eppendorf
    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 supporteuropean union
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitiy Medical Center Hamburg-Eppendorf
    B.5.2Functional name of contact pointG¨tz Thomalla
    B.5.3 Address:
    B.5.3.1Street AddressMartinistr. 52
    B.5.3.2Town/ cityHamburg
    B.5.3.3Post code20246
    B.5.3.4CountryGermany
    B.5.4Telephone number004940741050137
    B.5.5Fax number004940741056721
    B.5.6E-mailthomalla@uke.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
    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 infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Intrauterine use
    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 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
    Patients with acute ischaemic stroke proven by MRI and unknown time from symptom onset which otherwise fulfil the approval criteria for intravenous thrombolysis in acute stroke.
    E.1.1.1Medical condition in easily understood language
    Patients with acute ischaemic stroke
    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 18.1
    E.1.2Level PT
    E.1.2Classification code 10061256
    E.1.2Term Ischaemic stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objective is to test the efficacy and safety of MRI-based intravenous thrombolysis with Alteplase in patients waking-up with stoke symptoms or patients with unknown sumptom onset.
    E.2.2Secondary objectives of the trial
    not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Clinical Inclusion Criteria
    - Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g., stroke symptoms recognized on
    awakening)
    - Last known well (without neurological symptoms) &gt;4.5 hours of treatment initiation
    - Measurable disabling neurological deficit (defined as an impairment of one or more of the following: language, motor
    function, cognition, gaze, vision, neglect)
    - Age 18-80 years
    -Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening)
    - Written informed consent by patient or proxy

    Imaging Inclusion Criteria:
    - Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR)
    completed and showing a pattern of “DWI-FLAIR-mismatch”, i.e. acute ischemic lesion visibly on DWI (“positive
    DWI”) but no marked parenchymal hyperintensity visible on FLAIR (“negative FLAIR”) indicative of an acute ischemic
    lesion ≤4.5 hours of age
    E.4Principal exclusion criteria
    Clinical Exclusion Criteria
    - Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra-arterial thrombolysis,
    mechanical recanalization techniques)
    - Pre-stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability
    corresponding to an MRS score &gt;1)
    - Participation in any investigational study in the previous 30 days
    - Severe stroke by clinical assessment (e.g. NIHSS &gt;25)
    - Hypersensitivity to Alteplase or any of the excipients
    - Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed
    in women up to 55 years of age)
    - Significant bleeding disorder at present or within past 6 months
    - Known haemorrhagic diathesis
    - Manifest or recent severe or dangerous bleeding
    - Known history of or suspected intracranial haemorrhage
    - Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from
    aneurysm
    - History of CNS damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery)
    - Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a
    non-compressible blood-vessel
    - Current use of anticoagulants (e.g. Phenprocoumon, Warfarin, new anticoagulants such as Dabigatran) or current
    use of heparin and elevated thromboplastin time (low-dose subcutaneous heparin is allowed)
    - Platelet count &lt;100.000/mm3 (&lt;100G/l)
    - Blood glucose &lt;50 or &gt;400 mg/dl (&lt;2.8 or 22.2 mmol/l)
    - Severe uncontrolled hypertension, i.e. systolic blood pressure &gt;185 mmHg or diastolic blood pressure &gt;110 mmHg
    or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits)
    - Manifest or recent bacterial endocarditis, pericarditis
    - Manifest or recent acute pancreatitis
    - Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations
    - Neoplasm with increased bleeding risk
    - Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis
    - Major surgery or significant trauma in past 3 months
    - Stroke within 30 days
    - Life expectancy 6 months or less by judgement of the investigator
    - Any condition associated with a significantly increased risk of severe bleeding not mentioned above
    - Any contraindication to MRI (e.g. cardiac pacemaker)

    Imaging Exclusion Criteria:
    - Poor MRI quality precluding interpretation according to the study protocol
    - Any sign of intracranial haemorrhage on baseline MRI
    - FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion inidicative of
    an acute ischemic lesion with a high likelihood of being &gt; 4.5 hours old
    - Large DWI lesion volume &gt; 1/3 of the MCA or &gt;50% of the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory (visual inspection) or &gt;100 ml
    - Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV-tPA treatment in the judgement of the investigator
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy endpoint :

    - "Favourable Outcome" defined by a score of 0-1 on the Modified Ranking Scale (MRS) 90 (+/-10) days after stroke

    Primary Safety Endpoints :

    - Mortality 90 (+/-10) days after stroke

    - Death or dependency 90 (+/-10) days after stroke (MRS 4-6)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary Efficacy endpoint :
    - 90 (+/-10) days after stroke
    Primary Safety Endpoints :
    - 90 (+/-10) days after stroke
    - 90 (+/-10) days after stroke
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints :

    - Global Outcome Score (combination of MRS0-1, NIHSS 0-1, Barthel Index 95-100, Glasgow Coma Scale 1) 90 (+/-10) days after stroke

    - Categorical shift in MRS 90 (+/-10) days after stroke

    - Responder analysis relating MRS 90 (+/-10) days after stroke to baseline NIHSS score : "response" defined by NIHSS<7 = MRS 0; NIHSS 8-14 = MRS 0-1 ; NIHSS>14 = MRS 0-2

    - Infarct volume after 22-36 hours

    - Depressive symptoms 90 (+/-10) dyays after stroke (Beck Depression Inventory)

    - Functional Health Status and Quality of Life 90 (+/-10) days after stroke (EQ-5D)

    - Use of health care system resources 90 (+/-10) days after stroke)

    Secondary Safety endpoints :

    - Symptomatic intracranial haemorrhage (SICH) as defined in SITS-MOST

    - SICH as defined in ECASS II

    - SICH as defined in NINDS

    - Parenchymal haemorrhage type 2 (PH-2)

    - 22-36 hours after treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    90 (+/-10) days after stroke
    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 EEA50
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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
    We expect that 20-40% of the patients will be unable to give informed consent. Excluding this group from teh trial would entail severe scientific and clinical drawbacks.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 800
    F.4.2.2In the whole clinical trial 800
    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)
    Post medical treatment at the study sites according to standard of 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 Decision2015-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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