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    Summary
    EudraCT Number:2013-002818-12
    Sponsor's Protocol Code Number:ICH02
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-06-12
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2013-002818-12
    A.3Full title of the trial
    A phase III, randomized, open-label, 500-subject clinical trial of minimally invasive surgery plus rt-PA in the treatment of intracerebral haemorrhage.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MISTIE III. A phase III, randomized, case-controlled, open-label, 500-subject clinical trial of minimally invasive surgery plus rt-PA in the treatment of intracerebral hemorrhage.
    A.3.2Name or abbreviated title of the trial where available
    Minimally invasive surgery for ICH (MISTIE III)
    A.4.1Sponsor's protocol code numberICH02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01827046
    A.5.4Other Identifiers
    Name:INDNumber:8523
    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 SponsorThe John Hopkins University
    B.1.3.4CountryUnited States
    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 supportUS Department of Health & Human Services; National Institutes of Health; National Inst of Neuro Disorders & Stroke
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNewcastle University
    B.5.2Functional name of contact pointDr Barbara Gregson
    B.5.3 Address:
    B.5.3.1Street Address3-4 Claremont Terrace
    B.5.3.2Town/ cityNewcastle upon Tyne
    B.5.3.3Post codeNE2 4AE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01912225793
    B.5.5Fax number01912225762
    B.5.6E-mailbarbara.gregson@ncl.ac.uk
    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 Cathflo 2 mg
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim Limited
    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.3.1Product nameActilyse Cathflo 2 mg
    D.3.2Product code N/A
    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 IMPIntracerebral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAlteplase
    D.3.9.1CAS number 0105857-23-6
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameRecombinanat tissue-type Plasminogen activator rT-PA
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 for concentrate for solution for injection/infusion
    D.8.4Route of administration of the placeboIntracerebral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Spontaneous supratentorial intracerebral haemorrhage
    E.1.1.1Medical condition in easily understood language
    Brain haemorrhage
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10062025
    E.1.2Term Intracerebral haematoma evacuation
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To show whether minimally invasive surgery (MIS) plus recombinant tissue plasminogen activator (rt-PA) for three days improves outcome at six months as compared to standard medical treatment in patients with spontaneous bleeding in the brain (with no underlying cause)(ICH). It will also show whether early use of MIS+rt-PA for three days is safe for the treatment of ICH relative to rates of mortality, rebleeding, and infection in the medically treated subject at 30 days.
    E.2.2Secondary objectives of the trial
    To show whether the reduction in the size of the blood clot in the brain acheived by using MIS+rt-PA is related to improved functional outcome, as compared to medically treated subjects.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Spontaneous supratentorial ICH ≥ 30 mL diagnosed using radiographic imaging (CT, CTA, etc.), with a GCS ≤ 14 or a NIHSS ≥ 6.
    Six-hour clot size equal to the most previous clot size (within 5 mL) as determined by additional CT scans at least 6 hours apart using the ABC/2 method.
    2) Symptoms less than 24 hours prior to diagnostic CT (dCT) scan (an unknown time of onset is exclusionary).
    3) Intention to initiate surgery between 12 and 72 hours after dCT. First dose can be given within 76 hours after dCT (delays for post surgical stabilization of catheter bleeding or because of unanticipated surgical delay are acceptable with approved waiver from the CCC).
    4) SBP < 180 mmHg sustained for six hours recorded closest to the time of randomization.
    5) Historical Rankin score of 0 or 1.
    6) Age ≥ 18 and ≤ 80.
    E.4Principal exclusion criteria
    1) Infratentorial hemorrhage.
    Intraventricular hemorrhage requiring treatment with extraventricular drainage (obstruction of third and fourth ventricles).
    Thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and non-reactive pupils. Other (supranuclear) gaze abnormalities are not exclusions. Note: Patients with a posterior fossa ICH or cerebellar hematomas are ineligible.
    Irreversible impaired brain stem function (bilateral fixed, dilated pupils and extensor motor posturing), GCS ≤ 4.
    Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, Moyamoya disease diagnosed with radiographic imaging.
    Patients with unstable mass or evolving intracranial compartment syndrome.
    2) Platelet count < 100,000, INR > 1.4, or an elevated prothrombin time (PT) or activated partial thromboplastin time (aPTT).
    Any irreversible coagulopathy or known clotting disorder.
    Inability to sustain INR ≤ 1.4 using short- and long-active procoagulants (such as but not limited to NovoSeven, FFP, and/or vitamin K).
    Subjects requiring long-term anti-coagulation are excluded. Reversal of anticoagulation is permitted for medically stable patients who can realistically tolerate the short term risk of reversal. Patient must not require Coumadin (anticoagulation) during the first 30 days, and normalized coagulation parameters must be demonstrated, monitored closely and maintained during the period of brain instrumentation.
    Use of Dabigatran prior to symptom onset.
    3) Internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.
    4) Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures, etc.) or site of recent surgical intervention.
    5) Positive urine or serum pregnancy test in pre-menopausal female subjects without a documented history of surgical sterilization.
    6) Allergy/sensitivity to rt-PA.
    Prior enrollment in the study.
    Planned or simultaneous participation (between screening and Day-30) in another interventional medical investigation or clinical trial. Patients in observational, natural history, and/or epidemiological studies not involving an intervention are eligible.
    7) Subjects who are not expected to survive to the day 365 visit due to co-morbidities and/or are DNR/DNI status prior to randomization are excluded.
    Any concurrent serious illness that would interfere with the safety assessments including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, and hematologic disease.
    Patients with a mechanical heart valve.
    Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, or subacute bacterial endocarditis.
    Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated.
    8) Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
    9) In the investigator’s opinion, the patient is unstable and would benefit from a specific intervention rather than supportive care plus or minus MIS+rt-PA removal of the ICH.
    10) Inability or unwillingness of subject or legal guardian/representative to give written informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    Overall better functional outcome at 180 days, as defined by the modified Rankin Scale (mRS) using dichotomized adjudicated mRS 0-3 vs. 4-6 at 180 days post-stroke
    E.5.1.1Timepoint(s) of evaluation of this end point
    180 days post-stroke
    E.5.2Secondary end point(s)
    Dichotomized adjudicated mRS at 365 days post-stroke 0-3 vs. 4-6 and 0-2 vs. 3-6
    Ordinal adjudicated mRS (0 – 6) at 180 days post-stroke
    Mortality and Safety Events at 30 days post-randomization including procedurerelated
    mortality, symptomatic bleeding rate, and infection rate
    Mortality at 180 days post stroke
    Functional Status: NIHSS, Barthel, GOS, GOSE, MMSE at 180 days
    Type and intensity of ICU management: ICU days, hospital days, patient disposition at 180 days and 365 days
    Quality of life: SIS, EQ-5D, PBSI,Personal Health Utility Assessment
    Cost
    E.5.2.1Timepoint(s) of evaluation of this end point
    30, 180 and 365 days.
    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 No
    E.8.1.3Single blind Yes
    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
    No surgery (the IMP is given following surgery)
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    China
    Germany
    Hungary
    Israel
    Spain
    United Kingdom
    United States
    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 years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 250
    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 No
    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 No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 180
    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)
    Not different - as the interventions are surgical in nature and the rt-PA drug administration only occurs specifically following the surgery for a maximum of 3 days (i.e. it is not required to be continued once the patient is discharged from hospital).
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-09-17
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