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 | 17.0 |
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 10/40 (single tablet) compared with Simvastatin 40mg in stablilized 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. 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 occuring at least 30 days after randomization. Only revasculatiztion events that occur after the first 30 days of treatment will be considered as Clinical Endpoint events, in order to focus on events that can be 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. Evaluate the clinical benefit of Ezetimibe/Simvastatin Combination compared to Simvastatin on the occurance of the composite endpoint of death due to all causes, major coronary events and non-fatal stroke.
b. Evaluate the clinical benefit of Ezetimibe/Simvastatin Combination compared to Simvastatin on the occurance of the composite endpoint of death due to coronary heart disease, non fatal MI, and urgent coronary revascularization with either PCI or CABG occurring at least 30 days after randomization.
c. Evaluate the clinical benefit of Ezetimibe/Simvastatin Combination compared to Simvastatin on the occurance of the composite endpoint of CV death, non fatal MI, Unstable angna requiring hospitalization, all and revascularization 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 |
High-risk ACS NSTE-ACS & STEMI subjects meeting the following conditions: 1. NSTE-ACS subjects meeting the following definition: a. Clinically stable NSTE-ACS subjects participating in EARLY ACS Study (P03684) that do not go on to have CABG will be eligible if enrolled within 10 days of their hospitalization. b. Clinically stable NSTE-ACS subjects not participating in EARLY ACS study who meet the following criteria will be eligible to enroll within 10 days of their hospitalization: Experience symptoms of cardiac ischemia at rest lasting at least 10 min within 24 hrs of hospitalization, at least 50yrs of age, and have 1 of the following: ECG changes in at least 2 contiguous leads characterized by either ST depression or transient ST elevation, elevation in cardiac enzymes, DM, History of MI, History of PAD, History of CVD, History of CABG at least 3 yrs prior,or multivessel documented CAD. 2. LDL-C criteria: Statin naive subjects LDL-C must be at least 50 and less than or equal to 125 mg/dl, Subjects on statin LDL-C must be at least 50 and less than or equal to 100 mg/dl. 3. Fasting Plasma Triglyceride must be less than or equal to 350 mg/dl. |
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E.4 | Principal exclusion criteria |
1. Subject who is clinically unstable. A subject is considered clinically unstable if he/she displays any of the following spontaneous events for 24 hours prior to Screening-Randomization: a. Hemodynamic events: Hypotension, Pulmonary edema/CHF, Acute mitral regurgitation, Acute ventricular septal defect. b. Ischemic events: stroke, recurrent sx of cardiac ischemica. c Arrhythmic events: Ventricular fibrillation, Sustained ventricular tachycardia, complete heart block, High grade second degree heart block 2. Subject requires the following concomitant medications: cyclosporine, diltiazem, danazol, amiodarone, verapamil, niacin, fibrates as concomitant medication or any of the potent CYP3A4 inhibitors, itraconazole, ketoconazole, erythromycin, clarithromycin and Telithromycin, HIV protease inhibitors, nedazodone 3. Pregnant or lactating woman, or intenting to become pregnant 4. Active liver disease or persistent unexplained serum transaminase elevation 5. History of alcohol or drug abuse, 6. History of intolerance or hypersensitivity to statin or ezetimibe 7. Discontinuation of existing lipid lowering regimen poses a risk to the subject 8. Subject is receiving statin therapy with an LDL-C lowering potency greater than simvastatin 40mg 9. Prior enrollment in this current study under Protocol P04103 10. Subject who plans or undergoes CABG in response to the initial episode of ACS. 11. Subject has calculated creatinine clearance (CrCl) <30mL/min or dialysis within 30 days. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the time from randomization until the first occurrence of one of the following: CV death, major coronary event (non-fatal MI, documented unstable angina that requires admission into a hospital, all coronary revascularization with either PCI or CABG occuring 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 |
The planned termination of the study will occur after all subjects have
been followed for a minimum of 2.5 years and a primary endpoint event
has been documented in at least 5250 subjects. If at least 5250 subjects
have not met at least one documented primary endpoint event within 2.5
years of the completion of enrollment, the study will continue until this
number of events has accumulated.
Intrim analysis planned to occur at 50% and at 75% of 5250 subjects
with endpoint. |
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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, nonfatal
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, nonfatal
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 |
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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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 1159 |
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 | No |
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 |
Puerto Rico |
Singapore |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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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 planned termination of the study will occur after all 10,000 subjects have been followed for a minimum of 2.5 years and a primary endpoint event has been documented in at least 2955 subjects. if at least 2955 subjects do not have at least one documented primary endpoint event with 2.5 years of the completion of enrollment, the study will continue until this number of events has accumulated. It is anticipated that the whole study duration will be approximately 4 years. |
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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 | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |