E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Abnormal amounts of lipids in the blood |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058110 |
E.1.2 | Term | Dyslipidemia |
E.1.2 | System Organ Class | 100000004861 |
|
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. |
|
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.
|
|
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)
-Subjects must have an LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L) or non-HDL-C ≥ 130 mg/dL (≥ 3.4 mmol/L) at screening, after ≥ 4 weeks of 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) multi-vessel percutaneous coronary intervention (PCI)
(b) PCI or coronary artery bypass grafting (CABG) with residual ≥50% stenosis in a separate, unrevascularized segment or vessel, or
(c) multi-vessel CABG at least 5 years 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
B. Significant atherosclerotic cerebrovascular disease meeting at least 1 of the following criteria:
1. prior transient ischemic attack with ≥ 50% carotid stenosis
2. carotid artery stenosis of ≥ 70% or 2 or more ≥ 50% stenosis
3. prior 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)
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 microalbuminuria (urinary albumin to creatinine ratio ≥ 30mg/g) and/or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2
2. chronic treatment with insulin
3. diabetes diagnosis ≥ 10 years ago
- At least 1 of the following high risk criteria at screening (most recent lab values 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. diabetes or known evidence of 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 stenosis of ≥ 50% in a patient with diabetes meeting above inclusion criterion D
4. LDL ≥ 130 mg/dL ( ≥ 3.4 mmol/L) or non-HDL ≥ 160 mg/dL (> 4.2 mmol/L)
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 ≥ 3.0 mg/dL
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 |
|
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
- Atrial fibrillation not on anticoagulation therapy
- Uncontrolled hypertension (sitting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg) at screening
- Last measured left-ventricular ejection fraction < 30% or New York Heart Association (NYHA) Functional Class III/IV
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, or in situ cancers of the cervix, prostate, or breast duct within 5 years prior to screening
- 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
4. Prior/Concomitant Therapy
- Previously received or receiving evolocumab or any other therapy to inhibit PCSK9
- 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
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 subject is pregnant, had a positive pregnancy test at screening, breastfeeding, or planning to become pregnant or breastfeed during treatment and for an additional 15 weeks after the last dose of investigational product.
- 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 personal directly involved with the study or is a family member of the investigational study staff |
|
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 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continually during treatment period and at EOS |
|
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 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continually during treatment period and at EOS |
|
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 |
|
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 | 32 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 350 |
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 |
Bulgaria |
Canada |
China |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Russian Federation |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
|
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
|
|
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 | 8 |
E.8.9.1 | In the Member State concerned days | 18 |
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 |