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 | 19.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058110 |
E.1.2 | Term | Dyslipidemia |
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 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. |
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E.2.2 | Secondary objectives of the trial |
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)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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-hemorrhagic stroke within 6 months of screening
o additional diagnosis of myocardial infarction or non-hemorrhagic
stroke excluding qualifying MI or non-hemorrhagic stroke (a)
o current daily cigarette smoking
o history of symptomatic PAD (intermittent claudication with ABI
< 0.85, or peripheral arterial revascularization procedure, or
amputation due to atherosclerotic disease) if eligible by MI or
stroke history
Minor Risk Factors (2 Required):
o history of non-MI related coronary revascularization (a)
o residual coronary artery disease with ≥ 40% stenosis in ≥ 2 large vessels
o 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
o Most recent hsCRP > 2.0 mg/L by central laboratory before
randomization
o 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
o metabolic syndrome (b)
4.1.5 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
4.1.6 Most recent fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory before randomization
(a)Note: there is no time limit on additional qualifying medical history.
(b)Definition: metabolic syndrome for this protocol is defined as ≥ 3 of the following (Alberti et al, 2009):
• waist circumference > 102 cm (> 40 in.) for men and > 88 cm (> 35 in.) for women (Asian men, including Japanese > 90 cm; Asian women, except Japanese > 80 cm; Japanese women > 90 cm)
• triglycerides ≥ 150 mg/dL (1.7 mmol/L) by central laboratory at final screening
• HDL-C < 40 mg/dL (1.0 mmol/L) for men and < 50 mg/dL (1.3 mmol/L) for women by central laboratory at screening (Note: if the HDL-C level is one of criterion used to make the diagnosis of metabolic syndrome, it cannot be used as a separate risk factor)
• systolic blood pressure (SBP) ≥ 130 mmHg or diastolic BP (DBP) ≥ 85 mmHg or hypertension treated with medication
• fasting glucose ≥ 100 mg/dL (≥ 5.6 mmol/L) by central laboratory at final screening |
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E.4 | Principal exclusion criteria |
4.2.1 Subject must not be randomized within 4 weeks of their most recent MI or stroke
4.2.2 NYHA class III or IV, or last known left ventricular ejection fraction < 30%
4.2.3 Known hemorrhagic stroke at any time
4.2.4 Uncontrolled or recurrent ventricular tachycardia
4.2.5 Planned or expected cardiac surgery or revascularization within 3 months after randomization
4.2.6 Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg
4.2.7 Use of cholesteryl ester transfer protein (CETP) inhibition treatment, mipomersen, or lomitapide within 12 months prior to randomization. Fenofibrate therapy must be stable for at least 6 weeks prior to final screening at a dose that is appropriate for the duration of the study in the judgment of the investigator. Other fibrate therapy (and derivatives) are prohibited
4.2.8 Prior use of PCSK9 inhibition treatment other than evolocumab or use of evolocumab < 12 weeks prior to final lipid screening
4.2.9 Untreated or inadequately treated hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, and free thyroxine (T4) levels that are outside normal range at final screening
4.2.10 Severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 at final screening
4.2.11 Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as determined by central laboratory analysis at final screening
4.2.12 Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal)
4.2.13 Personal or family history of hereditary muscular disorders
4.2.14 LDL or plasma apheresis within 12 months prior to randomization
4.2.15 Severe, concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 3 years
4.2.16 CK > 5 times the ULN at final screening
4.2.17 Known major active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
4.2.18 Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 10 years
4.2.19 Subject has received drugs via a systemic route that have known major interactions with background statin therapy (see Appendix F) within 1 month prior to randomization or is likely to require such treatment during the study period
4.2.20 Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
4.2.21 Female subject who has either (1) not used acceptable method(s) of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment with IP and for an additional 15 weeks after the end of treatment with IP, unless the subject is sterilized or postmenopausal;
menopause is defined as 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years old or 12 months
of spontaneous and continuous amenorrhea with a follicle-stimulating hormone (FSH) level > 40 IU/L (or according to the definition of "postmenopausal range" for the laboratory involved) in a female < 55 years old unless the subject has undergone bilateral oophorectomy
• acceptable methods of preventing pregnancy include not having intercourse, birth control pills, injections, implants, or patches, intrauterine devices (IUDs), tubal ligation/occlusion, sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used
with spermicide
4.2.22 Subject is pregnant or breast feeding, or planning to become pregnant or to breastfeed during treatment with IP and/ or within 15 weeks after the end of treatment with IP
4.2.23 Known sensitivity to any of the active substances or their excipients to be administered during dosing
4.2.24 Subject likely to not be available to complete all protocol-required study visits or procedures, to the best of the subject’s and investigator’s knowledge
4.2.25 History or evidence of any other clinically significant disorder, condition or disease other than those outlined above that, in the opinion of the Investigator or Amgen physician, if consulted, may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion. |
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E.5 End points |
E.5.1 | 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.) |
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E.5.1.1 | 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.) |
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E.5.2 | 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 hospitalization for worsening heart failure, whichever occurs first
• time to ischemic fatal or non-fatal stroke or TIA, whichever occurs first |
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E.5.2.1 | 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 hospitalization for worsening heart failure, whichever occurs first
•time to ischemic fatal or non-fatal stroke or TIA, whichever occurs first |
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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 | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 550 |
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 |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
Denmark |
Estonia |
Finland |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Iceland |
India |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lithuania |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Norway |
Philippines |
Poland |
Portugal |
Romania |
Russian Federation |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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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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Study is event driven based on 1630 MACE secondary endpoint events and will conclude when all subjects have attended an end of study visit and had appropriate safety follow-up (ie LSLV) |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 56 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 56 |
E.8.9.2 | In all countries concerned by the trial days | 0 |