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 |
Abnormal amounts of lipids in the blood |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058110 |
E.1.2 | Term | Dyslipidemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 effect of treatment with evolocumab, compared with placebo, on the risk for coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke, whichever occurs first, in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy. -To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for CHD death, MI, ischemic stroke, or any ischemia-driven arterial revascularization, whichever occurs first, in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for: 1. MI, ischemic stroke, or any ischemia driven arterial revascularization; 2. CHD death, MI, or any ischemia-driven arterial revascularization; 3. cardiovascular death, MI, or stroke; 4. MI; 5. any ischemia-driven arterial revascularization; 6. CHD death; 7. cardiovascular death; 8. all cause of death; 9. ischemic stroke;
in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria: -Subject has provided informed consent prior to initiation of any study specific activities/procedures
-Adult subjects ≥ 50 years (men) or ≥ 55 years (women) to < 80 years of age (either sex) and meeting lipid criteria
-Subjects must have an LDL-C ≥ 90 mg/dL (≥ 2.3 mmol/L) OR non-high density lipoprotein (HDL)-C ≥ 120 mg/dL (≥ 3.1 mmol/L) OR apolipoprotein B ≥ 80 mg/dL (≥ 1.56 µmol/L) 1. Lipid entry criteria can be measured up to 3 months prior to screening in the absence of changes to background therapy 2. Lipid criteria should be assessed after ≥ 2 weeks of stable, optimized lipid-lowering therapy
-Diagnostic evidence of at least 1 of the following (A – D) at screening:
A. Significant coronary artery disease meeting at least 1 of the following criteria: 1. History of coronary revascularization with multi-vessel coronary disease as evidenced by any of the following: (a) percutaneous coronary intervention (PCI) of 2 or more vessels, including branch arteries (b) PCI or coronary artery bypass grafting (CABG) with residual ≥ 50% stenosis in a separate, unrevascularized vessel, or (c) multi-vessel CABG 5 years or more prior to screening 2. Significant coronary disease without prior revascularization as evidenced by either a ≥ 70% stenosis of at least 1 coronary artery, ≥ 50% stenosis of 2 or more coronary arteries, or ≥ 50% stenosis of the left main coronary artery 3. known coronary artery calcium score ≥ 100 in subjects without a coronary artery revascularization prior to randomization
B. Significant atherosclerotic cerebrovascular disease meeting at least 1 of the following criteria: 1. prior transient ischemic attack with ≥ 50% carotid stenosis 2. internal or external carotid artery stenosis of ≥ 70% or 2 or more ≥ 50% stenoses 3. prior internal or external carotid artery revascularization
C. Significant peripheral arterial disease meeting at least 1 of the following criteria: 1. ≥ 50% stenosis in a limb artery 2. history of abdominal aorta treatment (percutaneous and surgical) due to atherosclerosic disease 3. ankle brachial index (ABI) < 0.85
D. Diabetes mellitus with at least 1 of the following: 1. known microvascular disease, defined by diabetic nephropathy or treated retinopathy. Diabetic nephropathy defined as persistent microalbuminuria (urinary albumin to creatinine ratio ≥ 30 mg/g) and/or persistent estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 that is not reversible due to an acute illness 2. chronic daily treatment with an intermediate or long-acting insulin 3. diabetes diagnosis ≥ 10 years ago
- At least 1 of the following high risk criteria at screening (most recent lab values within 6 months prior to screening, as applicable):
1. polyvascular disease, defined as coronary, carotid, or peripheral artery stenosis ≥ 50% in a second distinct vascular location in a patient with coronary, cerebral or peripheral arterial disease (above inclusion criterion A-C) 2. presence of either diabetes mellitus diabetes or metabolic syndrome in a subject with coronary, cerebral, or peripheral artery disease (above inclusion criterion A-C) 3. at least 1 coronary, carotid, or peripheral artery residual stenosis of ≥ 50% in a patient with diabetes meeting above inclusion criterion D 4. LDL-C ≥ 130 mg/dL (≥ 3.36 mmol/L), OR non-HDL-C ≥ 160 mg/dL (≥ 4.14 mmol/L), OR apolipoprotein B ≥ 120 mg/dL (2.3 µmol/L) if available 5. lipoprotein (a) > 125 nmol/L (50 mg/dL) 6. known familial hypercholesterolemia 7. family history of premature coronary artery disease defined as an MI or CABG in the subject's father or brother at age < 55 years or an MI or CABG in the subject's mother or sister at age < 60 years 8. high sensitive c-reactive protein (hsCRP) ≥ 3.0 mg/dL in the absence of an acute illness 9. current tobacco use 10. ≥ 65 years of age 11. menopause before 40 years of age 12. eGFR 15 to < 45 mL/min/1.73 m2 13. coronary artery calcification score ≥ 300 in a patient without a coronary revascularization prior to randomization |
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E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria apply: 1. Disease Related - MI or stroke prior to randomization - CABG < 3 months prior to screening - Uncontrolled or recurrent ventricular tachycardia in the absence of an implantable-cardioverter defibrillator. - Atrial fibrillation not on anticoagulation therapy (vitamin K antagonist, heparin, low-molecular weight heparin, fondaparinux, or non-Vitamin K antagonist oral anticoagulant) - Last measured left-ventricular ejection fraction < 30% or New York Heart Association (NYHA) Functional Class III/IV - Planned arterial revascularization
2. Diagnostic Assessments - Fasting triglycerides ≥ 500 mg/dL (5.7 mmol/L) at screening - End stage renal disease (ESRD), defined as an eGFR < 15 mL/min/1.73 m2 or receiving dialysis at screening
3. Other Medical Conditions - Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years prior to day 1 - History or evidence of clinically significant disease (eg, malignancy, respiratory, gastrointestinal, renal or psychiatric disease) or unstable disorder that, in the opinion of the investigator(s), Amgen physician or designee would pose a risk to the patient’s safety or interfere with the study assessments, procedures, completion, or result in a life expectancy of less than 1 year - Persistent acute liver disease or hepatic dysfunction, defined as Child Pugh score of C
4. Prior/Concomitant Therapy - Previously received a cholesterol ester transfer protein (CETP) inhibitor (ie, anacetrapib, dalcetrapib, evacetrapib), mipomersen, lomitapide, or has undergone LDL-apheresis in the last 12 months prior to LDL-C screening - Previously received or receiving any other therapy to inhibit PCSK9 in the following timeframe prior to screening: (a) bococizumab at any time (b) evolocumab, alirocumab, or any other monoclonal antibody against PCSK9 within 3 months (c) inclisiran within 12 months
5. Prior/Concurrent Clinical Study Experience - Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies).
6. Other Exclusions - Female subjects of childbearing potential unwilling to use 1 acceptable method of effective contraception during treatment and for an additional 15 weeks after the last dose of investigational product. - Subject has known sensitivity to any of the products or components to be administered during dosing. - Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge. - Subject is staff personnel directly involved with the study or is a family member of the investigational study staff - Female subject is pregnant, had a positive pregnancy test at screening (by a serum pregnancy test and/or urine pregnancy test), breastfeeding, or planning to become pregnant or breastfeed during treatment and for an additional 15 weeks after the last dose of investigational product.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Time to CHD death, MI, or ischemic stroke, whichever occurs first - Time to CHD death, MI, ischemic stroke, or any ischemia-driven arterial revascularization, whichever occurs first |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continually during treatment period and at EOS |
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E.5.2 | Secondary end point(s) |
- Time to MI, ischemic stroke, or any ischemia-driven arterial revascularization - Time to CHD death, MI, or any ischemia-driven arterial revascularization - Time to cardiovascular death, MI, or stroke - Time to MI - Time to any ischemia-driven arterial revascularization - Time to CHD death - Time to cardiovascular death - Time to all cause of death - Time to ischemic stroke |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continually during treatment period and at EOS |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
cardiovascular outcomes study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 428 |
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 |
Ukraine |
Taiwan |
Australia |
Brazil |
Canada |
China |
Korea, Republic of |
Mexico |
Russian Federation |
United Kingdom |
United States |
Austria |
Belgium |
Bulgaria |
Czechia |
Denmark |
Estonia |
Finland |
France |
Germany |
Hungary |
Iceland |
Italy |
Latvia |
Lithuania |
Netherlands |
Poland |
Portugal |
Romania |
Slovakia |
Spain |
Sweden |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |