A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Additional LDL-Cholesterol Reduction on Major Cardiovascular Events When AMG 145 is Used in Combination With Statin Therapy In Patients with Clinically Evident Cardiovascular Disease AMG 145 FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk)
This is a phase 3, multicenter, double-blind, randomized, placebo controlled, parallel group, cardiovascular outcomes study for aMG 145 in subjects with clinically evident cardiovascular disease as evidenced by a history of myocardial infarction or stroke. after signing informed consent, subjects will enter a lipid stabilization period of up to 15 weeks where they will receive lipid lowering therapy with a maximally tolerated dose of atorvastatin between 20 mg to 80 mg Po QD with a recommended dose of 80 mg if tolerated. a dose of 20 mg QD is acceptable if it is documented that there is achievement of LDL-C goal or non-HDL goal or intolerance to higher dose. if a subject is receiving atorvastatin therapy at the maximal dose per local regulatory approval and the investigator recommends additional lipid lowering therapy beyond statin use, ezetimibe may be added during the lipid stabilization period. after at least 4 weeks of stable lipid lowering therapy with a maximal tolerated dose of study provided
atorvastatin (and ezetimibe if applicable), fasting LDL-C and non-HDL-C will be evaluated for eligibility determination. if plasma LDL-C is [GreaterThanorequalTo] 70 mg/dL (1.8 mmol/L) or non-HDL-C is [GreaterThanorequalTo] 100 mg/dL (2.6 mmol/L) and other assessed eligibility criteria continue to be met, subjects will be randomized with an allocation ratio of 1:1 to either receive aMG 145 or placebo.
Randomization will be stratified by the most recent screening LDL-C level ([Less Than] 85 mg/dL [2.2 mmol/L] vs [GreaterThanorequalTo] 85 mg/dL) and by geographical region. aMG 145 and placebo will be blinded. Central laboratory results of the lipid panel, apoa1, apoB, lipoprotein(a), and high sensitivity Creactive
protein (hsCRP) will be blinded post-treatment until unblinding of the clinical database and will not be reported to the investigator post-screening. The study includes collection of biomarker samples, where approved by the independent ethics committee and/or institutional review board (ieC/iRB) and applicable regulatory and other authorities, all subjects will be invited to consent to pharmacogenetic analyses.
The study will end when at least 1630 subjects have experienced a secondary endpoint event of cardiovascular death, myocardial infarction, or stroke. Subjects will be encouraged to complete all planned visits regardless of their adherence to investigational product (iP) administration. at the end of the study, vital status should be obtained for all subjects unless prohibited by local law.
all deaths and components of primary and secondary endpoints will be adjudicated by an independent external Clinical events Committee (CeC), using standardized definitions. instructions regarding submission of potential endpoints (PePs) will be provided. an external independent Data Monitoring Committee (DMC) will formally review the accumulating data from this and other ongoing studies with aMG 145 to ensure there is no avoidable increased risk for harm to subjects. The independent DMC will be chaired by an external academic cardiologist who is an expert in lipids and clinical trials. analyses for the DMC will be provided by an independent biostatistical group (iBG), which is external to amgen. an executive Committee (eC) has been formed to advise amgen on trial design and implementation, to conduct independent data analysis, and for assistance in the communication of trial results. an external independent Lipid Monitoring Committee (LMC) will be formed to review lipid results to ensure study design parameters are met. The LMC will be advisory to amgen and the eC. Details for each committee will be provided in a committee charter.
1. Signed informed consent
2. Male or female >= 40 to <= 85 years of age at signing of informed consent
3. History of clinically evident cardiovascular disease within 5 years of screening as evidenced by ANY of the following:
(i) diagnosis of myocardial infarction
(II) diagnosis of non-hemorrhagic stroke
(III) symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index
(ABI) < 0.85, or peripheral arterial re vascularization procedure, or amputation due to atherosclerotic disease
Note: the proportion of subjects with history of MI or non-hemorrhagic stroke > 5 years prior to screening will be determined by the sponsor.
4. At least 1 major risk factor or at least 2 minor risk factors below:
Major Risk Factors (1 Required):
(i) diabetes (type 1 or type 2)
(ii) age >= 65 years at randomization (and <= 85 years at time of informed consent)
(iii) MI or non-hemorrhagic stroke within 6 months of screening
(iv) additional diagnosis of myocardial infarction or non-hemorrhagic stroke excluding qualifying MI or non-hemorrhagic stroke.
(v) history of symptomatic PAD (intermittent claudication with ankle-brachial index [ABI] < 0.85,or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease) if eligible by MI or stroke history.
(vi) current daily cigarette smoking
Minor Risk Factors (2 Required):
(i) history of non-MI related coronary revascularizationa
(ii) residual coronary artery disease with >= 40% stenosis in >= 2 large vessels
(iii) Most recent HDL-C < 40 mg/dL (1.0 mmol/L) for men and < 50 mg/dL (1.3 mmol/L) for women by central laboratory before randomization
(iv) Most recent hsCRP > 2.0 mg/L by central laboratory at screening before randomization
(v) Most recent LDL-C > 130 mg/dL (3.4 mmol/L) or non-HDL-C >= 160 mg/dL (4.1 mmol/L) by central laboratory before randomization
(vi) metabolic syndrome
5. Most recent fasting LDL-C >= 70 mg/dL (>= 1.8 mmol/L) ) or non-HDL-C >= 100 mg/dL (> 2.6 mmol/L) by central laboratory during screening after >= 2 weeks of stable lipid lowering therapy per Appendix E
6. Most recent fasting triglycerides <= 400 mg/dL (4.5 mmol/L) by central laboratory before randomization.