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    Summary
    EudraCT Number:2012-003190-26
    Sponsor's Protocol Code Number:RESTART13
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-11-26
    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 number2012-003190-26
    A.3Full title of the trial
    REstart or STop Antithrombotics Randomised Trial (RESTART)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    RESTART
    A.3.2Name or abbreviated title of the trial where available
    REstart or STop Antithrombotics Randomised Trial (RESTART)
    A.4.1Sponsor's protocol code numberRESTART13
    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 SponsorACCORD (Academic and Clinical Central Office for Research & Development)
    B.1.3.4CountryUnited Kingdom
    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 supportUniversity of Edinburgh
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Edinburgh
    B.5.2Functional name of contact pointDr Rustam Al-Shahi Salman
    B.5.3 Address:
    B.5.3.1Street AddressBramwell Dott Building, DCN, Western General Hospital
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH4 2XU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0131 537 2082
    B.5.5Fax number0131 537 2944
    B.5.6E-mailrustam.al-shahi@ed.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorACCORD (Academic and Clinical Central Office for Research & Development)
    B.1.3.4CountryUnited Kingdom
    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 supportNHS Lothian
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Edinburgh
    B.5.2Functional name of contact pointDr Rustam Al-Shahi Salman
    B.5.3 Address:
    B.5.3.1Street AddressBramwell Dott Building, DCN, Western General Hospital
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH4 2XU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0131 537 2082
    B.5.5Fax number0131 537 2944
    B.5.6E-mailrustam.al-shahi@ed.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 No
    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 nameAspirin
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    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) No
    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 No
    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.IMP: 2
    D.1.2 and D.1.3IMP Role
    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 No
    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 nameDipyridamole
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    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) No
    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 No
    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.IMP: 3
    D.1.2 and D.1.3IMP Role
    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 No
    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 nameClopidogrel
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    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) No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Spontaneous Intracerebral Haemorrhage (ICH)
    E.1.1.1Medical condition in easily understood language
    Brain Haemorrhage
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10022753
    E.1.2Term Intracerebral haemorrhage
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    For adults surviving spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, does a policy of starting antiplatelet therapy result in a beneficial net reduction of all serious vascular events over two years compared with a policy of avoiding antiplatelet therapy?

    The primary objective of the pilot phase is to estimate, when all participants have completed at least two years of follow-up, the relative and absolute effects of antiplatelet drugs on the risk of brain haemorrhage happening again associated with a policy of starting antiplatelet drugs after the acute phase of brain haemorrhage. Ultimately, we want to determine whether antiplatelet drugs are beneficial for patients after brain haemorrhage because the gains from prevention of clotting problems outweigh the risks of bleeding at any site. This pilot phase of the trial may roll seamlessly i
    E.2.2Secondary objectives of the trial
    To determine whether patients with tiny deposits of blood in the brain called 'microbleeds' on brain magnetic resonance imaging (MRI) have an increased risk of having a recurrent brain haemorrhage if prescribed antiplatelet drugs following a brain haemorrhage.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The brain MRI sub-study is incorporated into the current protocol.

    Brain microbleeds on MRI appear to be a biomarker of bleeding-prone microangiopathies (such as arteriolosclerosis and cerebral amyloid angiopathy), they predict recurrent ICH, and lobar microbleeds also appeared to modify the effect of aspirin on recurrent ICH risk in one observational study. Furthermore, a collaborative meta-analysis of case-case comparisons has found a preponderance of brain microbleeds amongst patients who had an ICH whilst taking antiplatelet drugs compared to those who were not on any antithrombotics when they had an ICH. So we intend to perform a brain MRI sub-study in ~550 of the 720 participants to better understand these micro-angiopathies by exploring whether there is a statistical interaction between the presence, number, or location of brain microbleeds and the effect of antiplatelet drugs on the primary outcome.
    E.3Principal inclusion criteria
    1. Patient age ≥18 years.

    2. Spontaneous ICH
    o not attributable to preceding traumatic brain injury, on the basis of:
     a history from the patient/witness of spontaneous symptom onset without preceding head trauma (head trauma occurring subsequent to ICH symptom onset is permissible)
     brain imaging appearances consistent with spontaneous ICH (which may be accompanied by the brain/bone/soft tissue appearances of trauma occurring subsequently)
    o either ‘secondary’ to an underlying structural cause (e.g. aneurysm, tumour, arteriovenous malformation, or intracranial venous thrombosis), or ‘primary’ (if the investigator either does not suspect an underlying structural cause, or it is not detected by further radiographic investigation).1,44

    3. Patient had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease for any length of time before the onset of the qualifying ICH.

    4. Patient is approaching the end of their hospital admission/assessment for the qualifying ICH.

    5. Patient and their doctor are both uncertain about whether to start or avoid antiplatelet drugs.

    6. Patient is registered with a general practitioner (GP).

    7. Brain imaging study that first diagnosed the qualifying ICH is available.

    8. Consent to randomisation from the patient (or personal / legal / professional representative if the patient does not have mental capacity).

    9. If eligible for the brain MRI sub-study, the MRI must be performed after the ICH but before randomisation.
    E.4Principal exclusion criteria
    1. ICH due to traumatic brain injury, in the opinion of the investigator.

    2. ICH due to haemorrhagic transformation of an ischaemic stroke, in the opinion of the investigator.

    3. Patient is pregnant, breastfeeding, or of childbearing age and not taking contraception.

    4. Patient is being treated or followed up in another CTIMP.

    5. Patient and carer unable to understand spoken or written English (and local translator is not available).

    6. Patients are ineligible for the brain MRI sub-study if they are claustrophobic or they have a contraindication to MRI.
    E.5 End points
    E.5.1Primary end point(s)
    Fatal or non-fatal radiographically- or pathologically-proven recurrent symptomatic intracerebral haemorrhage (ICH).

    We define ICH as the abrupt onset of headache, altered level of consciousness, or focal neurological deficit, anatomically referable to a focal collection of blood predominantly located within the brain parenchyma (diagnosed on brain imaging or at autopsy), which was not attributable to prior trauma or haemorrhagic transformation of an ischaemic stroke. This also applies when neurological deterioration occurs with radiographic or pathological evidence of ICH volume growth early after the qualifying ICH (due to either haematoma expansion or re-bleeding).
    E.5.1.1Timepoint(s) of evaluation of this end point
    This outcome will be evaluated using survival analysis techniques for its occurrence over at least two years.
    E.5.2Secondary end point(s)
    A. Fatal events (i.e. followed by death within 30 days):

    1. Complication of qualifying ICH
    (a) Neurological deterioration (e.g. hydrocephalus or perihaematomal oedema)
    (b) Non-neurological complications (e.g. pneumonia)
    2. Symptomatic extradural haemorrhage, subdural haemorrhage, subarachnoid haemorrhage, or intraventricular haemorrhage (not accompanying spontaneous ICH)
    3. Symptomatic major extracranial haemorrhage, sub-divided by site (requiring transfusion or endoscopic treatment or surgery, or resulting in death within 30 days)
    4. Symptomatic vaso-occlusive events: transient ischaemic attack, ischaemic stroke, unstable angina (www.outcomes-umassmed.org/grace/Files/Standard_Definitions.pdf), acute spontaneous myocardial infarction (type 1),40 peripheral arterial occlusion, mesenteric ischaemia, retinal arterial occlusion, deep vein thrombosis or pulmonary embolism.
    5. Cardiac death with symptoms suggestive of myocardial ischaemia (type 3),40 or evidence of arrhythmia
    6. Deaths from any other known cause
    7. Rapidly fatal stroke, consistent with the clinical manifestations of ICH, but without radiographic or pathological confirmation
    8. Unwitnessed deaths without a clear cause and without further investigation

    B. Non-fatal events (i.e. not followed by death within 30 days):

    1. Symptomatic extradural haemorrhage, subdural haemorrhage, subarachnoid haemorrhage, or intraventricular haemorrhage (not accompanying spontaneous ICH)
    2. Symptomatic major extracranial haemorrhage, sub-divided by site (requiring transfusion or endoscopic treatment or surgery)
    3. Symptomatic vaso-occlusive events: transient ischaemic attack, ischaemic stroke, unstable angina, myocardial infarction, peripheral arterial occlusion, mesenteric ischaemia, retinal arterial occlusion, deep vein thrombosis or pulmonary embolism.
    4. Non-fatal stroke, with brain imaging performed too late to distinguish ICH from cerebral infarction
    5. Annual ratings of participant function completed by participant or their carer:
    (a) Simplified modified Rankin Scale postal questionnaire
    (b) Structured telephone interview with non-responders to the postal questionnaire
    E.5.2.1Timepoint(s) of evaluation of this end point
    These outcomes will be evaluated using survival analysis techniques for their occurrence over at least two years.

    Further analyses, such as the effect on the composite endpoint of all serious vascular events (which would be likely to be the primary outcome in the main phase of the trial), will be specified in our statistical analysis plan.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis Yes
    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 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
    A policy of avoid antiplatelet agents (ATC B01AC Platelet aggregation inhibitors excluding heparin)
    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 concerned99
    E.8.5The trial involves multiple Member States No
    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 Information not present in EudraCT
    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 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.1.1Number 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: 470
    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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Following ICH some patients may suffer temporary or permanent cognitive and physical difficulties, rendering them mentally incapacitated according to the statutory definitions; the methods of their recruitment will follow statutory recommendations.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state720
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 720
    F.4.2.2In the whole clinical trial 720
    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)
    All patients randomised to antiplatelet drugs will have the opportunity to continue with this treatment after the study ends if both the patient and their hospital doctor or General Practitioner feel this is beneficial.
    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 Decision2013-01-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-06
    P. End of Trial
    P.End of Trial StatusOngoing
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