E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with a recent acute coronary syndrome (ACS) and at least 2 additional risk factors for recurrent ischemic events. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051592 |
E.1.2 | Term | Acute coronary syndrome |
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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 |
To determine if apixaban is superior to placebo for preventing the composite of cardiovascular death, myocardial infarction, or ischemic stroke in subjects with recent ACS. |
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E.2.2 | Secondary objectives of the trial |
- To determine, in subjects with recent ACS, if apixaban is superior to placebo for preventing •the composite of cardiovascular death, myocardial infarction, UA, or ischemic stroke •the composite of cardiovascular death, fatal bleeding, myocardial infarction or stroke (ischemic or hemorrhagic) •the composite of all-cause death, myocardial infarction or stroke (ischemic or hemorrhagic) - To determine, in subjects with recent ACS, if apixaban is superior to placebo for preventing the composite of cardiovascular death, myocardial infarction or ischemic stroke within each of the following baseline subpopulations: •subjects with diabetes mellitus •subjects receiving single antiplatelet therapy •subjects receiving dual antiplatelet therapy •subjects undergoing percutaneous coronary intervention (PCI) •subjects not undergoing PCI - To compare apixaban 5 mg BID and placebo with respect to major bleeding, as defined by TIMI Bleeding criteria (see Section 5.2.3.1). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Age ≥ 18 years 2) Written informed consent. 3) An acute coronary syndrome (ST-elevation or non-ST-elevation MI or UA) within 7 days characterized by: a) symptoms of myocardial ischemia at rest lasting at least 10 minutes and either b) elevation in cardiac biomarkers (troponin T or I or creatine kinase MB) above the local upper limit of normal) or c) dynamic ST-segment deviation (depression or elevation ≥ 0.1 mV (1.0 mm) 4) Completion of parenteral anticoagulation therapy for the index ACS event. 5) Clinically stable, receiving standard of care for ACS, including single (aspirin or a P2Y12 antagonist such as clopidogrel) or dual (aspirin plus a P2Y12 antagonist such as clopidogrel) antiplatelet therapy, at the discretion of the treating physician. 6) Two or more of the following risk factors a) Age ≥ 65 years b) Diabetes mellitus c) Prior myocardial infarction (other than the qualifying event) within 5 years d) Ischemic cerebrovascular disease (ischemic stroke or carotid endarterectomy) e) Peripheral vascular disease (symptoms of claudication and/or peripheral revascularization, and/or ankle-brachial index (ABI) < 0.9) f) Heart failure or left ventricular ejection fraction <40% associated with the index ACS event g) Impaired renal function (calculated CrCl < 60 mL/min) h) No revascularization for index ACS event |
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E.4 | Principal exclusion criteria |
1) Persistent severe hypertension (SBP ≥ 180 mmHg or DBP ≥ 110 mmHg) 2) Calculated CrCl < 20 mL/min or on dialysis for end-stage renal disease 3) Active bleeding or high risk for bleeding (eg, active peptic ulcer disease, other gastrointestinal pathology with a raised risk of bleeding, liver cirrhosis, malignancies with a raised risk of bleeding) 4) Known coagulopathy 5) Acute pericarditis 6) Recent (< 7 days) ischemic stroke 7) NYHA Class IV heart failure at time of randomization 8) Any history of intracranial bleeding 9) Active and/or significant, known hepatobiliary disease 10) Hemoglobin < 9 g/dl 11) Platelet count < 100,000 mm³ 12) Required ongoing treatment with a parenteral or chronic oral anticoagulation (eg, mechanical valve, recent DVT or pulmonary embolism, known left ventricular thrombus) 13) Required ongoing treatment with aspirin > 325 mg daily 14) Required ongoing treatment with a strong inhibitor of CYP3A4 [azole antifungals (itraconazole and ketoconazole)], macrolide antibiotics (clarithromycin and telithromycin), protease inhibitors [(ritonavir, indinavir, nelfinavir, atazanavir, and saquinavir), and nefazadone)] 15) Subjects who participated previously in any other study involving apixaban 16) Severe comorbid condition with life expectancy of ≤ 6 months 17) Inability to follow the protocol 18) Use of an investigational drug or device within 30 days 19) Women who are pregnant, breastfeeding, or of childbearing potential and unwilling or unable to use an acceptable method of birth control to avoid pregnancy. 20) Prisoners or subjects who are involuntarily incarcerated 21) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Primary Efficacy Outcome: Time to first occurrence of cardiovascular death, myocardial infarction, or ischemic stroke.
- Secondary Efficacy Outcomes: Time to first occurrence of: • cardiovascular death, myocardial infarction, unstable angina, or ischemic stroke • cardiovascular death, fatal bleeding, myocardial infarction or stroke (ischemic or hemorrhagic) • death (all-cause), myocardial infarction or stroke (ischemic or hemorrhagic)
- Primary Safety Outcome: Time to first occurrence of TIMI major bleeding.
- Secondary Safety Outcomes: Time to first occurrence of ISTH major bleeding. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
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 | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 300 |
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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As this is an event driven trial, the study will continue until the estimated number of outcome events is projected to occur. The End of Treatment visit will occur after the sponsor has declared the trial end date. All randomized subjects should be contacted when this date is declared and the final in-person visit should be scheduled within the following 12 weeks. Subjects should continue to take study drug until this final visit, with the last dose taken the day of this visit. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |