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    Summary
    EudraCT Number:2005-001059-39
    Sponsor's Protocol Code Number:P04103
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-05-26
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2005-001059-39
    A.3Full title of the trial
    A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial - IMPROVE IT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (P04103 AM5)
    A.3.2Name or abbreviated title of the trial where available
    IMPROVE IT
    A.4.1Sponsor's protocol code numberP04103
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00202878
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc
    B.5.2Functional name of contact pointGlobal Clinical Trial Operations
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive, PO Box 100
    B.5.3.2Town/ cityWhitehouse Station, New Jersey
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number001908-740-5524
    B.5.5Fax number001908-740-3007
    B.5.6E-mailpeter_margaret.burroughs@merck.com
    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 Inegy
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp and Dhome - Schering Plough Ltd.
    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 nameInegy
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEzetimibe
    D.3.9.1CAS number 163222-33-1
    D.3.9.2Current sponsor codeMK0653
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSimvastatin
    D.3.9.1CAS number 79902-63-9
    D.3.9.2Current sponsor codeMK0733
    D.3.9.3Other descriptive nameSimvastatin
    D.3.9.4EV Substance CodeSUB10529MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Zocor
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp and Dhome, S.A.
    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 nameZocor
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSimvastatin
    D.3.9.1CAS number 79902-63-9
    D.3.9.2Current sponsor codeMK0733
    D.3.9.3Other descriptive nameSimvastatin
    D.3.9.4EV Substance CodeSUB10529MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    D.8 Placebo: 2
    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
    Primary Hyperlipidemia
    E.1.1.1Medical condition in easily understood language
    Primary Hyperlipidemia
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10016205
    E.1.2Term Familial hyperlipidaemia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical benefit of Ezetimibe/Simvastatin Combination (single tablet) compared with simvastatin 40 mg in stabilized acute coronary syndrome (ACS) subjects. Clinical benefit will be defined as the reduction in the risk of the occurrence of the composite endpoint of CV death, major coronary events, and non-fatal stroke. CV death, major coronary events, and non-fatal stroke are designated primary endpoint events. Major coronary events include non-fatal MI, documented unstable angina that requires admission into a hospital, and all coronary revascularization with either PCI or CABG occurring at least 30 days after randomized treatment assignment. Only revascularization events that occur after the first 30 days of treatment will be considered as clinical endpoint events, in order to focus on revascularization events that can be reasonably expected to be affected by treatment and are unrelated to the initial ACS event.
    E.2.2Secondary objectives of the trial
    a. To evaluate the clinical benefit of Ezetimibe/Simvastatin Combination compared with simvastatin in stabilized ACS subjects on the occurrence of the composite endpoint of death due to all causes, major coronary events, and non-fatal stroke. b. To evaluate the clinical benefit of Ezetimibe/Simvastatin Combination compared with simvastatin in stabilized ACS subjects on the occurrence of the composite endpoint of death due to coronary heart disease (CHD) (CHD death), non-fatal MI, and urgent coronary revascularization with either PCI or CABG occurring at least 30 days after randomization. c. To evaluate the clinical benefit of Ezetimibe/Simvastatin Combination compared with simvastatin in stabilized ACS subjects on the composite endpoint of CV death, non-fatal MI, documented unstable angina that requires admission into a hospital, all revascularization (including both coronary and non-coronary) occurring at least 30 days after randomization, and non-fatal stroke.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The high-risk ACS population will comprise both subjects with NSTE-ACS with or without MI and subjects with STEMI according to the following conditions: 1. A subject with NSTE-ACS according to the following criteria may be enrolled: a. A NSTE-ACS subject participating in the EARLY-ACS Study (Protocol No. P03684) who has been clinically stabilized will be eligible for entry in the current study under Protocol No. P04103 ≤10 days (≤240 hours) of presenting to the hospital. The subject must complete the acute segment of EARLY-ACS treatment (the acute segment of EARLY-ACS treatment is the initial phase of administration of randomized treatment with eptifibatide or matching placebo through catheterization) and be clinically stable before enrolling in the current study. b. A subject not participating in the EARLY-ACS Study, but who is defined as NSTE-ACS by meeting all of the following criteria, and has been clinically stable for at least 24 hours prior to screening/randomization will be eligible to enter directly into the current study ≤10 days (≤240 hours) of acute admittance into a hospital: The subject has experienced symptoms of cardiac ischemia at rest prompting acute care hospitalization with at least one episode lasting at least 10 minutes, no less than 50 years of age; and have ANY 1 of the following criteria: Electrocardiogram changes (new ST-segment depression ≥0.1 mV or transient (<30 minutes) ST-segment elevation ≥0.1 mV), Any of the following cardiovascular biomarkers elevated > ULN: Troponina I, Troponina T, Creatine kinase-MB fraction (CK-MB); Diabetes mellitus; History of prior MI; History of peripheral arterial disease;History of cerebrovascular disease; History of CABG ≥3 years prior to entry; Multivessel coronary artery disease previously documented by catheterization (2 or 3 vessels with ≥50% stenosis) including the catheterization performed during the index admission for the qualifying event. a. Subject must meet the following criteria for LDL-C concentrations at the time of admittance into a hospital: A lipid-therapy naïve subject which LDL-C concentration is ≥50 mg/dL (≥1.3 mmol/L) and ≤125 mg/dL (≤3.2 mmol/L); A subject receiving chronic prescription lipid-lowering therapy which his/her LDL-C concentration is ≥50 mg/dL (≥1.3 mmol/L) and ≤100 mg/dL (≤2.6 mmol/L). 3. Subject must have a plasma triglyceride (TG) level ≤350 mg/dL (≤4.0 mmol/L). 4. A subject in whom a PCI is planned as management for the qualifying ACS event should undergo PCI prior to Randomization and within the 10-day period after initial hospitalization for the qualifying ACS event.
    E.4Principal exclusion criteria
    A subject will be excluded from entry if any of the criteria listed below are met: 1. Subject who is clinically unstable. A subject is considered clinically unstable if he/she displays any of the following events within 24 hours prior to Screening/Randomization: Hemodynamic events (Hypotension, defined as sustained systolic blood pressure of <90 mmHg due to cardiac failure with associated symptoms; Unstable or severe Pulmonary edema/decompensated CHF; Acute mitral regurgitation; Acute ventricular septal defect), Recurrent symptoms of cardiac ischemia, Stroke or transient ischemic attack (TIA), Arrhythmic events (Ventricular fibrillation; Sustained ventricular tachycardia lasting >30 seconds; Complete heart block; High grade second degree heart block). 2. Subject who plans or undergoes CABG in response to the initial episode of ACS. 3. Subject requires the following concomitant medications: cyclosporine, diltiazem, danazol, amiodarone, verapamil, niacin, fibrates as concomitant medications or any of the potent CYP3A4 inhibitors, itraconazole, ketoconazole, erythromycin, clarithromycin, and telithromycin, HIV protease inhibitors, nefazodone, probucol, resins, grapefruit juice >1 quart/day, torceptrapib, and any investigational drugs. Routes of administration other than oral or parenteral (eg, topical, intraocular, otic) of antifungal or antibiotics are acceptable. Short-term therapy of any prohibited medication is acceptable, provided study medication is interrupted during the administration and restarted after short-term therapy is completed. 4. Subject is a pregnant or lactating woman, or woman intending to become pregnant. 5. Subject has active liver disease or persistent unexplained serum transaminase elevations (≥2 x ULN). Subject with a transient increases in serum transaminases due to the index MI may be enrolled. 6. Subject has calculated creatinine clearance (CrCl) <30 mL/min or dialysis within 30 days. Creatinine clearance is to be calculated according to the Cockcroft-Gault equation. 7. Subject has a history of alcohol and/or drug abuse. 8. Subject has an allergy/sensitivity to any statin, ezetimibe, and/or their excipients 9. The investigator feels that discontinuation of existing lipid-lowering regimen poses a risk to the subject. 10. Subject is receiving chronic prescription lipid-lowering therapy with LDL-C lowering potency greater than simvastatin 40 mg. 11. Subject with prior enrollment in this current study under Protocol No. P04103.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint measure will be the time from randomization until the first occurrence of one of the following: CV death, major coronary events (non-fatal MI, documented unstable angina that requires admission into a hospital, all coronary revascularization with either PCI or CABG occurring at least 30 days after randomization), or non-fatal stroke.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Two interim efficacy analyses will be performed when approximately 50% and 75% of the expected total primary events are available.
    The study will continue until each subject has been followed for a minimum of 2.5 years and at least one primary endpoint event has been documented in a minimum of 5250 subjects. If at least 5250 subjects do not have at least one documented primary endpoint event within 2.5 years of the completion of
    enrollment, the study will continue until this number of primary endpoint events has accumulated.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoint measures will be as follows:
    1. Time from randomization until the first occurrence of death due to any cause, major coronary events, or non-fatal stroke.
    2. Time from randomization until the first occurrence of CHD death, non-fatal MI, or urgent coronary revascularization with either PCI or CABG occurring at least 30 days after randomization.
    3. Time from randomization until the first occurrence of CV death, non-fatal MI, documented unstable angina that requires admission into a hospital, all revascularization (“All revascularization” includes coronary revascularization and non-coronary revascularization) occurring at least 30 days after randomization, and non-fatal stroke.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Two interim efficacy analyses will be performed when approximately 50% and 75% of the expected total primary events are available.
    The study will continue until each subject has been followed for a minimum of 2.5 years and at least one primary endpoint event has been documented in a minimum of 5250 subjects. If at least 5250 subjects do not have at least one documented primary endpoint event within 2.5 years of the completion of
    enrollment, the study will continue until this number of primary endpoint events has accumulated.
    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) 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 No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3.1Comparator description
    simvastatina
    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 EEA478
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    Chile
    Colombia
    Czech Republic
    Denmark
    Ecuador
    Estonia
    Finland
    France
    Germany
    Hong Kong
    Hungary
    India
    Israel
    Italy
    Korea, Republic of
    Malaysia
    Netherlands
    New Zealand
    Norway
    Peru
    Poland
    Portugal
    Singapore
    Slovakia
    South Africa
    Spain
    Sweden
    Switzerland
    Turkey
    Ukraine
    United Kingdom
    United States
    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
    The study will continue until each subject has been followed for a minimum of 2.5 years and at least one primary endpoint event has been documented in a minimum of 5250 subjects. If at least 5250 subjects do not have at least one documented primary endpoint event within 2.5 years of the completion of enrollment, the study will continue until this number of primary endpoint events has accumulated.
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 18000
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18000
    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 Yes
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 4400
    F.4.2.2In the whole clinical trial 18000
    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)
    Standard of 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 Decision2006-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-04-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-09-18
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