| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10016205 |
| E.1.2 | Term | Familial hyperlipidaemia |
| E.1.2 | System Organ Class | 100000004850 |
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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 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. |
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| E.2.2 | Secondary 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. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
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| E.4 | Principal 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. |
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| E.5 End points |
| E.5.1 | Primary 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. |
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| E.5.1.1 | Timepoint(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. |
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| E.5.2 | Secondary 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. |
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| E.5.2.1 | Timepoint(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. |
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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 | Yes |
| 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 | 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) | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 478 |
| 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 |
| 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 |
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| E.8.7 | Trial 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
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| 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. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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