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    Summary
    EudraCT Number:2016-000686-23
    Sponsor's Protocol Code Number:RAVE_v1
    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:2016-06-01
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-000686-23
    A.3Full title of the trial
    The Rotterdam Antiplatelet Therapy in Vascular Patients Study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Research on treatment strategies for adequate anitplatelet therapy for the prevention of major cardiac events after vascular surgery
    A.3.2Name or abbreviated title of the trial where available
    RAVE
    A.4.1Sponsor's protocol code numberRAVE_v1
    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 SponsorErasmus MC
    B.1.3.4CountryNetherlands
    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 supportErasmus MC
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointK.H.J.M. Mol
    B.5.3 Address:
    B.5.3.1Street AddressPO BOX 2040
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3000CA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031107035109
    B.5.5Fax number0031107033722
    B.5.6E-mailk.mol@erasmusmc.nl
    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 nameClopdiogrel Mylan 75 mg coated tablets
    D.3.2Product code RVG 106706
    D.3.4Pharmaceutical form 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
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    myocardial injury in patients undergoing major vascular surgery, leading to (spontaneous) acute coronary syndrome and death through intracoronary plaque damage and subsequent thrombosis after major vascular surgery.
    E.1.1.1Medical condition in easily understood language
    Patients undergoing major vascular surgery are at risk for long term complications such as myocardial damage, infarction or even death because of the extensive risk of thrombosis.
    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
    In patients with asymptomatic hsTnT release before and after major vascular surgery the following objectives will be investigated:

    Primary objective:
    To asses the efficacy of clopidogrel, as compared to placebo, on top of standard treatment with aspirin on
    A: the composite endpoint of MACE, defined as;
    -cardiovascular death,
    -nonfatal myocardial infarction,
    -stroke,
    -severe ischemia of the peripheral arterial circulation leading to intervention
    In patients with myocardial injury (defined as asymptomatic troponin release) after major vascular surgery
    E.2.2Secondary objectives of the trial
    B: individual components of MACE
    C: To assess the safety of clopidogrel, in terms of bleeding complications, defined as life-threatening bleeding, moderate and minor bleeding, postoperatively and during long-term follow-up.

    In patients with asymptomatic preoperative hsTnT release scheduled for major vascular surgery the following objective will be investigated
    D: Presence of significant coronary artery disease and the impact of presence of vulnerable plaques according to PROSPECT criteria
    In the specific subgroup of patients undergoing major vascular surgery.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Preoperative myocardial injury (baseline value), defined as hsTnT release > 14 ng/L.
    2.Absence of significant occlusive coronary artery disease as diagnosed through angiography (and confirmed by FFR).
    3.Postoperative myocardial injury, defined as hsTnT release > 14 ng/L, which exceed the baseline value.
    E.4Principal exclusion criteria
    1. if troponin elevation is diagnosed as myocardial infarction by cardiologist.
    2. Presence of significant occlusive coronary artery disease, as diagnosed through preoperative angiography, requiring treatment.
    3. No postoperative hsTnT values above the clinical reference of 14 ng/L and no rise with respect to baseline value.
    4. Active bleeding.
    5. Active cardiac conditions at the time of randomisation such as unstable angina pectoris, active congestive heart failure (CHF), serious cardiac arrhythmias, symptomatic valvular disease.
    6. Clear indication for long-term P2Y12 inhibitor use.
    7. Preoperative use of P2Y12 inhibitors.
    8. Previous allergy or intolerance to clopidogrel.
    9. Use of oral anticoagulants after surgery.
    10. Use of intravenous glycoprotein IIB/IIA receptor inhibitors in the previous three days.
    11. Coronary revascularization therapy in the previous six months.
    12. Renal failure requiring dialysis.
    13. Significant liver disease (i.e. ALAT, ASAT > 3x ULN).
    14. Cancer with an expected life expectancy less than 6 months.
    15. Excessive alcohol use.
    16. No informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    1. Efficacy outcomes:
    MACE:
    Defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke and arterial thrombotic events.

    Death:
    Subdivided as cardiovascular and non-cardiovascular. All deaths with a clear cardiovascular cause including haemorrhagic or unknown cause will be classified as cardiovascular. Only deaths due to a documented non-cardiovascular cause will be classified as non-cardiovascular.

    Myocardial infarction (2 of 3 criteria):
    1. Typical ischemic chest pain,
    2. Elevation of troponin (TnT) values,
    3. New ECG changes which include new persistent ST/T changes, new BBB or new Q-waves in at least 2 consecutive leads

    Severe coronary ischemia leading to an intervention:
    Unstable angina with ECG changes requiring hospitalization, which leads to coronary revascularization (PTCA, CABG) (or transfer for revascularization) during hospitalization.

    Revascularization of coronary arteries:
    PTCA
    CABG

    Arterial thrombotic events complicating vascular surgery, leading to severe limb ischemia and consequently to intervention:
    Severe limb ischemia of the lower extremity which is deemed to threaten the viability of the limb, and is associated with continuing ischemic pain, and neurological deficit, or inadequate skin capillary circulation, or inaudible arterial flow signals by Doppler of the pedal arteries AND which leads to hospitalization for an intervention such as thrombolytic therapy, angioplasty, bypass surgery or amputation.

    Reperfusion of peripheral arteries:
    1. Catheter directed thrombolytic therapy of a peripheral artery
    2. Percutaneous transluminal angioplasty of the iliac or femoral arteries
    3. Surgical revascularization of the aortic or infrainguinal arteries

    Stroke:
    New focal neurological deficit thought to be vascular in origin lasting greater than 24 hours. Confirmation with CT scan/MRI is recommended but not mandatory. Strokes will be further classified as ischemic, haemorrhagic, or uncertain.

    TIA :
    Transient ischemic attack; new onset focal neurological deficit that resolves within 24 hours.

    Unstable angina with ECG changes:
    An episode of angina lasting greater than 15 minutes which is refractory to the patient’s usual medications, which leads to hospital admission and is associated with ECG changes consistent with coronary ischemia.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients will be seen on outpatient clinic visit monthly for a total follow-up time of 1 year.
    E.5.2Secondary end point(s)
    Safety outcomes

    Life-threatening bleeding
    Fatal or intra-cranial bleeding or bleeding requiring surgical intervention or transfusion of at least 4 units of blood or plasma expanders, or a drop in hemoglobin of ≥ 5 g/dL hemoglobin or a ≥ 15% absolute decrease in hematocrit.

    Moderate and minor bleeding
    Bleeding which requires ≤3 units of blood or blood products. Minor bleedings will be classified as all other bleedings not requiring transfusion, however will lead to temporary or permanent cessation of study medication and/or aspirin.

    (Bleeding definitions are in concordance with TIMI bleeding criteria)


    Other endpoints:

    Presence of significant obstructive coronary artery disease:
    Significant obstructive coronary artery disease will be assed by consulting cardiologist and measurements and cut-off values are according to current guidelines used in the Erasmus Medical Center.

    Quality of life during follow-up period

    Novel biomarker identification:
    Identification of biomarkers that predict the recurrence of an acute vascular event during 1-year follow-up. Blood sample collection will be done as described elsewhere. Blood samples will be analysed after all study participants have completed one-year follow-up.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be seen on outpatient clinic visits postoperatively on 30-days and every 3 months for a total follow-up time of 1 year.
    Quality of life will be assessed twice, at 6 months and at end of study.
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 No
    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.8.5The 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 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 years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state100
    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)
    After this trail, patients will continue their original treatment.
    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 Decision2017-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-31
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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