| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004861 |
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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 assess the percent change from baseline in LDL-C levels after 12 weeks of treatment at the usual start dose comparisons of ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 mg, and ezetimibe/simvastatin 10/20 mg versus atorvastatin 20 mg, and at the alternative start dose comparison of ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg. |
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| E.2.2 | Secondary objectives of the trial |
1) To assess the percentage of patients who achieve an LDL-C of < 70 mg/dL after 12 weeks of treatment at the usual start dose comparisons of ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 mg, and ezetimibe/simvastatin 10/20 mg versus atorvastatin 20 mg, and at the alternative start dose comparison of ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg.
2)To assess the percentage of patients achieving an LDL-C level <100 mg/dL for both patients at high risk for CHD without atherosclerotic vascular disease and moderately high risk for CHD, and <70 mg/dL for patients at high risk for CHD with atherosclerotic vascular disease after 12 weeks of treatment at the usual start dose comparisons of ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 mg, and ezetimibe/simvastatin 10/20 mg versus atorvastatin 20 mg, and at the alternative start dose comparison of ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patient is a male or post menopausal female and ≥65 years of age on the day of signing informed consent.
• Patient meets one of the following criteria:
o Therapy naïve patients who are at high risk for CHD with established coronary and other atherosclerotic vascular disease or,
Note: Established atherosclerotic vascular disease includes history of myocardial infarction, stable angina, coronary artery procedures (angioplasty or bypass surgery) or evidence of clinically significant myocardial ischemia. Other atherosclerotic vascular disease includes clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease [transient ischemic attacks or stroke of carotid origin or >50% obstruction of a carotid artery]).
Therapy naïve is defined as not being treated with a lipid lowering agent within 6 weeks (8 weeks if a fibrate) prior to Visit 2 (Week -1).
o Therapy naïve patients who are at high risk for CHD without atherosclerotic vascular disease who have diabetes or,
o Therapy naïve patients who are at high risk for CHD without atherosclerotic vascular disease or diabetes with ≥2 risk factors and a 10-year risk for CHD >20% (as determined by the Framingham calculation) or,
o Therapy naïve patients, or patients rendered naïve by the appropriate prior washout, who are at moderately high risk for CHD with ≥2 risk factors and a 10-year risk for CHD 10-20% (as determined by the Framingham calculation).
Note: Patients rendered naïve is defined as washed out of a lipid lowering agent for 6 weeks (8 weeks if a fibrate) prior to Visit 2 (Week -1).
• Patient has a baseline LDL-C level of ≥130 mg/dL at Visit 2 (Week -1).
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| E.4 | Principal exclusion criteria |
• Patient has a hypersensitivity or intolerance to ezetimibe, simvastatin or atorvastatin or any component of these medications.
• Patient has exclusionary laboratory values at Visit 1 (Week -3) for either test listed in the table below:
Laboratory Test Exclusionary Value
liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) > 1.5 X ULN with no active liver disease
Creatine kinase (CK) > 2 X ULN
• Patient’s triglycerides (TG) are > 350 mg/dL (3.96 mmol/L) at Visit 2.
• Patient has uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins (i.e., secondary causes of hyperlipidemia, such as hypothyroidism or hyperthyroidism).
Note: A patient with hyper or hypothyroidism is defined by a TSH below the central laboratory's lower limit of the normal reference range or > 20% above the upper limit of the normal reference range. For patients receiving thyroid hormone, there is no lower TSH threshold for entry and the patient must be on a stable dose for > or equal to 6 weeks before the randomization visit. For patients whose TSH is above the entry criteria, thyroid hormone therapy may be adjusted or initiated provided there is time to stabilize the patient and still meet the enrollment timelines. One redraw will be allowed if the original TSH value is less than 40% above or below the reference range, but the patient must meet the criterion upon redraw.
• Patient has congestive heart failure defined by NYHA (New York Heart Association) Class III or IV.
• Patient has unstable angina pectoris.
• Patient has had a myocardial infarction, coronary artery bypass surgery, angioplasty or uncontrolled or severe peripheral artery disease within 3 months of Visit 1 (Week -3).
• Patient has had a partial ileal bypass, gastric bypass, or other significant intestinal malabsorption.
• Patient has uncontrolled hypertension (treated or untreated) with systolic blood pressure >160 mm Hg or diastolic >100 mm Hg at Visit 1 (Week -3). Investigators are encouraged to maximize blood pressure control according to current guidelines prior to randomization.
• Patient has impaired renal function (creatinine ≥2.0 mg/d [176.8 mmol/L]) or a history of nephrotic range proteinuria at Visit 1 (Week -3).
• Patient has uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins (i.e., secondary causes of hyperlipidemia), such as Cushing syndrome at Visit 1 (Week -3).
• Patient has type 2 diabetes mellitus that is poorly controlled (HbA1c ≥8.5% at Visit 1 (Week -3) or newly diagnosed (within 3 months of Visit 1) and/or patient has recent history of repeated hypoglycemia or unstable glycemic control.
• Patient has disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation.
• Patient is known to be HIV positive.
• Patient has a history of malignancy ≤ 5 years prior to signing informed consent, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer.
• Patient is currently taking cyclosporine, erythromycin, azole antifungals (i.e., itraconazole, ketoconazole, fluconazole) or fusidic acid.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the mean percent change from baseline (Visit 3) in LDL-C after 12 weeks of treatment with the usual and alternative start dosages of ezetimibe/simvastatin (i.e., 10/20 mg and 10/40 mg, respectively) and atorvastatin (i.e., 10 and 20 mg, and 40 mg, respectively). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| 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 | 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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| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 4 |
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