A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Additional LDL-Cholesterol Reduction on Major Cardiovascular Events When Evolocumab (AMG 145) is Used in Combination With Statin Therapy In Patients with Clinically Evident Cardiovascular Disease.

INTERVENTION:

Product Name: Evolocumab Product Code: AMG 145 Pharmaceutical Form: Solution for injection in pre‐filled pen INN or Proposed

INN:

Evolocumab Current Sponsor code: AMG 145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 140‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled pen Route of administration of the placebo: Subcutaneous use Product Name: Evolocumab Product Code: AMG 145 Pharmaceutical Form: Solution for injection in cartridge INN or Proposed

INN:

Evolocumab Current Sponsor code: AMG 145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 120‐ Pharmaceutical form of the placebo: Solution for injection in cartridge Route of administration of the placebo: Subcutaneous use

CONDITION:

Dyslipidemia ; MedDRA version: 18.1 Level: LLT Classification code 10020604 Term: Hypercholesterolemia System Organ Class: 100000004861 ; MedDRA version: 18.1 Level: LLT Classification code 10058110 Term: Dyslipidemia System Organ Class: 100000004861 Therapeutic area: Diseases [C] ‐ Nutritional and Metabolic Diseases [C18]

PRIMARY OUTCOME:

Main Objective: To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first, in subjects with clinically evident cardiovascular disease. Primary end point(s): The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first. (Note: The primary endpoint includes all adjudicated strokes, ischemic and hemorrhagic.) Secondary Objective: Secondary objectives are to evaluate the effect of treatment with evolocumab, compared with placebo, in subjects with clinically evident cardiovascular disease on the risk for:; • cardiovascular death, myocardial infarction, or stroke; • cardiovascular death; • death by any cause; • myocardial infarction; • stroke; • Coronary revascularization; • cardiovascular death or hospital admissions for worsening heart failure; • fatal or non‐fatal ischemic stroke or transient ischemic attack (TIA); Timepoint(s) of evaluation of this end point: The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first. (Note: The primary endpoint includes all adjudicated strokes, ischemic and hemorrhagic.)

SECONDARY OUTCOME:

Secondary end point(s): Secondary endpoints are: ; • time to cardiovascular death, myocardial infarction, or stroke, whichever occurs first ; • time to cardiovascular death ; • time to death by any cause ; • time to first myocardial infarction ; • time to first stroke ; • time to first coronary revascularization ; • time to cardiovascular death or first hospitalization for worsening heart failure, whichever occurs first ; • time to ischemic fatal or non‐fatal stroke or TIA, whichever occurs first Timepoint(s) of evaluation of this end point: •time to cardiovascular death, myocardial infarction, or stroke, whichever occurs first ; • time to cardiovascular death ; • time to death by any cause ; • time to first myocardial infarction ; • time to first stroke ; • time to first coronary revascularization ; • time to cardiovascular death or first hospitalization for worsening heart failure, whichever occurs first ; • time to ischemic fatal or non‐fatal stroke or TIA, whichever occurs first

INCLUSION CRITERIA:

4.1.1 Signed informed consent 4.1.2 Male or female = 40 to = 85 years of age at signing of informed consent 4.1.3 History of clinically evident cardiovascular disease as evidenced by ANY of the following: o diagnosis of myocardial infarction o diagnosis of non‐hemorrhagic stroke (TIA does not qualify as stroke for inclusion) o symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle‐brachial index (ABI) < 0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Note: the proportion of subjects with history of MI or nonhemorrhagic stroke > 5 years prior to screening will be determined by the sponsor 4.1.4 At least 1 major risk factor or at least 2 minor risk factors below: Major Risk Factors (1 Required): o diabetes (type 1 or type 2) o age = 65 years at randomization (and = 85 years at time of informed consent) o MI or non‐hem