E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ACUTE CORONARY SYNDROMES,NOS |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate 4 doses of apixaban as compared to placebo over a 26 week treatment period in selected subjects with recent (≤7 days) Acute Coronary Syndrome (ACS) for safety (bleeding) and to determine the optimal dose and regimen of apixaban for use in Phase 3 ACS treatment. |
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E.2.2 | Secondary objectives of the trial |
The secondary safety objectives are:
• to evaluate the incidence of cardiovascular and all-cause death, non-fatal myocardial infarction, severe recurrent ischemia and non-hemorrhagic stroke during the 30 days after discontinuation of therapy • to assess the incidence of adverse events and abnormal clinical laboratory test results.
The secondary efficacy objectives are:
• to evaluate the incidence of the composite of cardiovascular death, non-fatal myocardial infarction, severe recurrent ischemia and non-hemorrhagic stroke through Week 26. • to evaluate the incidence of the composite of all-cause death, non-fatal myocardial infarction, severe recurrent ischemia and non-hemorrhagic stroke through Week 26. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed written informed consent; 2) Recent (≤7 days) Acute Coronary Syndrome with: a) symptoms of myocardial ischemia (chest pain, dyspnea, etc.) lasting a total of at least 10 minutes (see Section 7.2.1) And either b) elevation in cardiac biomarkers (troponin T or I or creatine kinase-MB) above the upper limit of normal or c) dynamic ST segment deviation [depression or elevation of ≥0.1 mV (1.0 mm)] 3) Clinically stable, receiving standard care for ACS, including antiplatelet therapy [acetylsalicylic acid (ASA) ≤ 165 mg/day, with or without clopidogrel 75 mg/day, based on the choice of the treating physician] 4) Either unknown coronary anatomy or angiographic evidence of atherosclerotic plaque in any major coronary artery, significant branch, or coronary bypass graft. 5) Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile), and men, ages 18 (or legal age of consent) to 90.
Plus 1 or more additional risk characteristics from the following: 1) Age ≥ 65 years 2) Both elevation in cardiac markers and dynamic ST deviation ≥ 1 mm 3) Diabetes mellitus 4) MI within the last 12 months (other than qualifying event) 5) Cerebrovascular disease [prior (>3 months) ischemic stroke; prior TIA or asymptomatic >70% stenosis in either internal carotid artery] 6) Peripheral vascular disease (claudication with decreased pulses, a prior peripheral revascularization procedure, or an ABI <0.9) 7) Prior symptomatic CHF or a left ventricular ejection fraction <40% 8) Non-revascularized multivessel CAD (≥2 vessels) 9) Mild or moderate renal insufficiency (calculated CrCl 30-90 mL/min)
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E.4 | Principal exclusion criteria |
1) Women of child bearing potential: a. Any female who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal. b. Women who are pregnant or breastfeeding. c. Women with a positive pregnancy test on enrollment or prior to study drug administration. 2) Scheduled/planned cardiac catheterization, PCI, CABG or other invasive procedure planned in the 26 weeks following randomization; 3) Persistent severe hypertension, defined as systolic blood pressure of ≥180 mm Hg or diastolic pressure of ≥110 mm Hg 4) Severe renal dysfunction (calculated creatinine clearance <30 mL/min) 5) Active bleeding or at high risk for bleeding (e.g., cirrhosis of the liver, any history of intracranial hemorrhage, active peptic ulcer disease) 6) Known coagulopathy 7) Acute pericarditis or pericardial effusion 8) Recent stroke (within the last 3 months) 9) Prior New York Heart Association (NYHA) Class IV; *Plus exclusion criteria 23, active hepatobiliary disease 10) Platelet count ≤100,000/mm3 11) Hemoglobin < 10 g/dL; 12) Hematocrit < 30%; 13) Inability to take aspirin due to allergy or intolerance; 14) Need for ongoing treatment with a parenteral or oral anticoagulant (see Section 6.4.1), eg, subjects with mechanical valves, warfarin eligible atrial fibrillation 15) Need for chronic (>3 months) daily NSAID or chronic high dose ASA use (>325 mg/day); *Plus exclusion criteria 24, strong CYP3A4 inhibitors 16) Below the legal lower age (country specific); 17) Participation in another investigational drug or device study within the prior 30 days; 18) Subjects who participated previously in this or any other study involving BMS-562247; 19) Any condition which, in the opinion of the Investigator, may pose a significant hazard to the subject if he or she is enrolled in the trial; 20) Subject inability to follow the protocol; 21) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
22) Netherlands Specific Exclusion Criteria 23) Active hepatobiliary disease, based on an ALT or AST > 2X ULN or a Total Bilirubin ≥ 1.5X ULN (unless an alternative causative factor [e.g., Gilbert’s syndrome] is identified). 24) Need for ongoing treatment with known strong inhibitors of CYP3A4, for example: azole antifungals (itraconazole and ketoconazole), macrolide antibiotics (clarithromycin and telithromycin), protease inhibitors (ritonavir, indinavir, nelfinavir, atazanavir, and saquinavir), and nefazadone.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Analyses The primary objective of this study is related to safety. There is no primary efficacy outcome. Secondary Efficacy outcomes are:
• the composite of cardiovascular death, non-fatal myocardial infarction, severe recurrent ischemia and non-hemorrhagic stroke occurring through Week 26 • the composite of all-cause death, non-fatal myocardial infarction, severe recurrent ischemia and non-hemorrhagic stroke occurring through Week 26. • the composite of all-cause death and myocardial infarction occurring through Week 26 • the composite of all-cause death and non-hemorrhagic stroke occurring through Week 26 • all-cause death occurring through Week 26 • cardiovascular death occurring through Week 26 • the composite of all-cause death and severe recurrent ischemia occurring through Week 26.
Safety Analysis The primary safety outcome for this trial is the composite of major bleeding and clinically relevant non-major bleeding occurring through the end of treatment.
The secondary safety outcomes for this trial are 1) all bleeding events, including major bleeding, clinically relevant non-major bleeding and minor bleeding occurring through the end of treatment and 2) the composite of all-cause death, non-fatal myocardial infarction, severe recurrent ischemia and non-hemorrhagic stroke during the 30 days after discontinuation of therapy. Other safety outcome measures will also be assessed, and will include adverse events and abnormal standard clinical laboratory test results, e.g., hemoglobin, platelet count, ALT/AST and creatinine. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 108 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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The last visit for each subject is defined as the Week 26 last treatment visit. The end of the trial is defined as the date of the last follow-up phone call for the last subject, during which adverse events and study endpoints are assessed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |