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    Summary
    EudraCT Number:2014-000096-80
    Sponsor's Protocol Code Number:01
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2016-07-05
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-000096-80
    A.3Full title of the trial
    Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of clot dissolving treatment for stroke that occurs during sleep
    A.3.2Name or abbreviated title of the trial where available
    TWIST
    A.4.1Sponsor's protocol code number01
    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 or Tromsø
    B.1.3.4CountryNorway
    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 supportNational Association for Public Health
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOslo University Hospital
    B.5.2Functional name of contact pointEivind Berge
    B.5.3 Address:
    B.5.3.1Street AddressKirkeveien 166
    B.5.3.2Town/ cityOslo
    B.5.3.3Post codeNO-0407
    B.5.3.4CountryNorway
    B.5.4Telephone number+4722119100
    B.5.5Fax number+4722118280
    B.5.6E-maileivind.berge@medisin.uio.no
    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 Metalyse
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    D.2.1.2Country which granted the Marketing AuthorisationNorway
    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 in pre-filled syringe
    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 INNTENECTEPLASE
    D.3.9.1CAS number 191588-94-0
    D.3.9.4EV Substance CodeSUB04718MIG
    D.3.10 Strength
    D.3.10.1Concentration unit U/g unit(s)/gram
    D.3.10.2Concentration typeequal
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute ischaemic stroke upon awakening ("wake-up stroke")
    E.1.1.1Medical condition in easily understood language
    Stroke that occurs during sleep
    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 answer the following question:
    - Can thrombolytic treatment with tenecteplase given within 4.5 hours of wake-up reduce the risk of poor functional outcome at 3 months?
    E.2.2Secondary objectives of the trial
    To answer the following question:
    - Can findings on plain CT and CT angiography (and CT perfusion at selected centres) identify patients who benefit from such treatment, compared to patients without such findings?
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Value of multi-modal CT for selection of patients with wake-up stroke for thrombolytic treatment (Protocol version/date 160204).

    This sub-study covers the second objective (paragraph E.2.2, above).
    E.3Principal inclusion criteria
    • Stroke symptoms on awakening that were not present before sleep
    • Clinical diagnosis of stroke with limb weakness with NIHSS score >5, or dysphasia.
    • Treatment with tenecteplase is possible within 4.5 hours of awakening
    • Written consent from the patient, non-written consent from the patient (witnessed by non-participating health care personnel), or written consent from the nearest family member.
    E.4Principal exclusion criteria
    • Age < 18 years
    • Findings on plain CT that indicate that the patient is unlikely to benifit from treatment:
    - Infarction comprising more than >1/3 of the middle cerebral artery territory on plain CT
    - Intracranial haemorrhage, structural brain lesions which can mimic stroke (e.g cerebral tumour)
    • Patient will be treated with intra-arterial interventions for proximal cerebral artery occlusion
    • High risk of bleeding, e.g.:
    - Major surgery, trauma or gastrointestinal or urinary tract haemorrhage within the previous 21 days, or arterial puncture at a non-compressible site within the previous 7 days.
    - Any known defect in coagulation, e.g. current use of vitamin K antagonist with an INR > 1.7, or other oral anticoagulant, or heparins
    - Known defect of clotting or platelet function (but patients on antiplatelet agents can be included)
    - Ischaemic stroke in previous 2 weeks, previous intracranial haemorrhage, or known arteriovenous malformation or aneurysm
    • Persistent blood pressure elevation (systolic ≥185 mmHg or diastolic ≥110 mmHg), despite blood pressure lowering treatment
    • Blood glucose < 3.0 or > 20.0 mmol/L
    • Childbearing potential, pregnancy, positive pregnancy test, breastfeeding
    • Other serious or life-threatening disease before the stroke: severe mental or physical disability (e.g. Mini Mental Status score < 20, or modified Rankin Scale score ≥ 3), or life expectancy less than 12 months
    • Patient unavailability for follow-up (e.g. no fixed address)
    E.5 End points
    E.5.1Primary end point(s)
    Functional outcome (defined by the modified Rankin Scale)
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 months
    E.5.2Secondary end point(s)
    Clinical events:
    • Intracranial haemorrhage during the first 7 days
    • Stroke progression during the first 7 days
    • Recurrent ischaemic stroke during the first 7 days
    • Death from all cause during the first 7 days and during 3 months’ follow-up

    Clinical outcomes:
    Barthel Index score, EuroQol score, and MMSE scores at 3 months.

    Health-economic variables:
    Costs related to length of hospital stay, care in nursing home etc., re-hospitalisations during first 3 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    3 months
    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 No
    E.6.5Efficacy No
    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 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 No
    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
    Best standard care alone (without tenecteplase)
    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 concerned14
    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 years2
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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
    Many patients with acute stroke will have reduced capacity to give consent.
    F.3.3.7Others Information not present in EudraCT
    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 500
    F.4.2.2In the whole clinical trial 500
    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 will recieve best 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 Decision2016-07-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-13
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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