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    Summary
    EudraCT Number:2015-005555-27
    Sponsor's Protocol Code Number:ESR-14-14073
    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:2018-05-03
    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 number2015-005555-27
    A.3Full title of the trial
    Prevention of Cerebral Ischaemia in Stent Treatment of Carotid Artery Stenosis - A randomised multi-centre Phase II Trial comparing Ticagrelor versus Clopidogrel with outcome assessment on MRI (PRECISE-MRI)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prevention of Cerebral Ischaemia in Stent Treatment for Carotid Artery Stenosis
    A.3.2Name or abbreviated title of the trial where available
    PRECISE-MRI
    A.4.1Sponsor's protocol code numberESR-14-14073
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02677545
    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 Hospital Basel
    B.1.3.4CountrySwitzerland
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Ticagrelor (Brilique) AZD 6140
    D.2.1.1.2Name of the Marketing Authorisation holderAstra Zeneca Sweden
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTicagrelor (Brilique) AZD 6140
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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 RoleComparator
    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 Clopidogrel
    D.2.1.1.2Name of the Marketing Authorisation holderZentiva
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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
    Carotid artery stenting (CAS) is a treatment for atherosclerotic carotid stenosis. The main adverse events are thromboembolic brain infarcts during the procedure. This Ticagrelor, a novel reversible inhibitor of the platelet adenosine diphosphate receptor P2Y12, was superior to clopidogrel as add-on to aspirin in preventing stent thrombosis and clinical adverse events during stenting of the coronary artery. Therefore,ticagrelor may be superior to clopidogrel in preventing brain infarcts during
    E.1.1.1Medical condition in easily understood language
    Stent treatment reopens carotid arteries narrowed down by
    atherosclerosis. This study tests medication against blood clots to
    prevent strokes during carotid artery stenting.
    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
    Treatment with a stent is given to certain patients with atherosclerosis causing narrowing of the carotid artery, in order to reduce the risk of brain stroke. The carotid artery is the main artery of the neck that supplies blood to the brain. Atherosclerosis is caused by a deposition of fats in the arterial wall. A possible adverse effect of carotid artery stenting is that it may cause a stroke during the procedure. Strokes that cause symptoms are rare but magnetic resonance imaging (MRI) may frequently pick up silent strokes occurring during the procedure. This study aims to determine the optimal drug therapy to prevent brain strokes during stent treatment of the carotid artery. The principle research question is whether ticagrelor, a novel inhibitor of blood platelets, is superior to the standard drug clopidogrel, given in combination with aspirin, to prevent brain strokes visible on MRI in patients undergoing carotid artery stenting.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to compare the number and volume of brain strokes visible on MRI, the occurrence of brain bleeds visible on MRI, and clinical adverse events such as stroke or myocardial infarction between the two treatments.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Written informed consent as documented by signature from the patient;
    - Men or women ≥40 years of age;
    - Moderate (50-69% narrowing of the artery according to the measuring method used in the NASCET trial) or severe (70-99%) stenosis of the extracranial internal carotid artery caused by atherosclerosis;
    - Symptomatic carotid stenosis (any transient or permanent symptoms caused by focal
    ischaemia in the vascular territory supplied by the carotid artery in the past 180 days, including ischaemic stroke, transient ischaemic attack (TIA), amaurosis fugax or ischaemic retinal infarct), as long as the patient is clinically stable and independent (score on the modified Rankin Scale ≤2) at the time of randomisation; or asymptomatic carotid stenosis (no ischaemic symptoms in the past 180 days);
    - Stenosis amenable for treatment by carotid artery stenting (CAS) according to routine clinical work-up (degree of stenosis and suitability of vascular anatomy for CAS must be demonstrated either by consistent findings on two of the following non-invasive imaging modalities: duplex ultrasound, magnetic resonance angiography, or computer tomography angiography; or by intra-arterial digital subtraction angiography;
    - CAS scheduled to take place within 1-3 days of randomisation.
    E.4Principal exclusion criteria
    - Inability or unwillingness of the patient to understand and/or comply with study procedures and/or follow-up, e.g. due to language problems, psychological disorders, dementia, etc.;
    - Women who are pregnant or breast feeding, or who intend to become pregnant during the course of the study. Women of childbearing age must take a pregnancy test to be eligible for the study;
    - Lack of safe contraception, defined as: Female Participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the Investigator in individual cases. Female Participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential;
    - Acute ischaemic stroke with symptom onset in the previous 24 hours before randomisation;
    - Fresh thrombus in the relevant carotid artery;
    - Patient clinically unstable at the time of randomisation (includes worsening in NIH Stroke Scale of >2 points over the previous 24 hours);
    - Patient dependent on others in functions of daily living at the time of randomisation (score on the modified Rankin Scale >2);
    - Patients with known bleeding diathesis or coagulation disorder (e.g., thromboticthrombocytopenic purpura);
    - Any active pathological bleed;
    - Severe thrombocytopenia (platelet count <50’000/uL);
    - History of previous symptomatic intracranial haemorrhage at any time (asymptomatic
    microbleeds do not qualify)
    - History of gastrointestinal bleed within the past 6 months;
    - Any contraindication to non-contrast MRI, including but not limited to:
    -- cardiac pacemaker incompatible with MRI;
    -- metal implants incompatible with MRI;
    -- claustrophobia);
    - Contraindications to ticagrelor, clopidogrel, or ASA, or to any of their excipients, including known hypersensitivity or allergy;
    - Increased risk of bradycardic events (e.g., patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree atrioventricular (AV) block, or history of bradycardia-related syncope;
    - Need for medication not permitted during treatment period:
    -- Antithrombotic therapy other than Study Medication or permitted concomitant
    medication including:
    --- Antiplatelet therapy (other than ASA 75-100 mg daily), e.g.: open-label clopidogrel or ticagrelor; GPIIb/IIIa inhibitors, ticlopidine, prasugrel,
    dipyridamole, ozagrel, cilostazol;
    --- Therapeutic-dose anticoagulation (other than unfractioned heparin at the start
    of the CAS procedure), e.g.: phenprocoumon, warfarin, oral thrombin and factor Xa inhibitors, bivalirudin, hirudin, argatroban, unfractionated and low molecular weight heparins;
    -- Receipt of any intravenous or intra-arterial thrombolysis or mechanical thrombectomy within 24 hours prior to randomisation. If a patient requires intravenous or intra-arterial thrombolytic therapy during the treatment period, the Study Medication must be discontinued for at least 24 hours;
    -- Strong cytochrome P450 3A (CYP3A) inhibitors leading to substantial increases in
    ticagrelor plasma levels: ketoconazole, itraconazole, voriconazole, telithromycin,
    clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir,
    saquinavir, nelfinavir, indinavir, atanazavir; or consumption of more than 1 litre of
    grapefruit juice daily;
    -- Strong CYP3A inducers leading to substantial decreases in ticagrelor plasma levels: rifampicin, rifabutin, phenytoin, carbamazepine, and phenobarbital;
    -- CYP3A substrates with narrow therapeutic indices which may be substantially
    increased by co-administration of ticagrelor: cyclosporine, quinidine, simvastatin at
    doses >40 mg daily or lovastatin at doses >40 mg daily. (Co-administration of
    ticagrelor with simvastatin increases simvastatin Cmax by 81% and AUC by 56% and
    increases simvastatin acid Cmax by 64% and AUC by 52% with some individual
    increases equal to 2- to 3-fold. Ticagrelor may have similar effect on lovastatin, but is not expected to have a clinically meaningful effect on other statins including atorvastatin and rosuvastatin);
    -- Anticipated requirement for long-term (>7 days) non-steroidal anti-inflammatory drugs (NSAIDs; short-term treatment with NSAIDs up to 7 days is allowed during the
    treatment period at the investigator’s discretion);
    - Need for invasive procedure (surgery or intervention) other than the index CAS procedure for which the patient was randomised, which requires halting of Study Medication within the next 30 days after randomisation;
    - History of major surgery within the past 30 days;
    - Moderate or severe hepatic impairment;
    - Renal impairment requiring dialysis;
    - Known or suspected non-compliance, drug or alcohol abuse.
    E.5 End points
    E.5.1Primary end point(s)
    The Primary efficacy outcome is the presence of at least one new ischaemic brain lesion on the second magnetic resonance imaging (MRI) scan done 1-3 days after the carotid artery stent (CAS) procedure or on the third MRI scan done 28-32 days after CAS, which had not been present on the first MRI scan done 1-3 days before CAS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. 1-3 days after the carotid artery stent procedure
    2. 28-32 days after the carotid artery stent procedure
    E.5.2Secondary end point(s)
    1. Total number of new ischaemic brain lesions
    2. Total volume of new ischaemic brain lesions
    3. New haemorrhagic brain lesions
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. 1-3 days after the carotid artery stent procedure
    2. 28-32 days after the carotid artery stent procedure
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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) Yes
    E.8.2.2Placebo No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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
    Germany
    Italy
    Netherlands
    Switzerland
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 270
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 370
    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)
    At the last study visit taking place one month after stent treatment, the physician in charge will determine the antiplatelet medication which the participant should receive as part of his/her ongoing routine clinical care. This may include clopidogrel or aspirin monotherapy, or combined treatment with clopidogrel and aspirin for up to 6 months after the stent procedure, followed by monotherapy.
    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 Decision2017-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-06
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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