Evaluation of Evolocumab on Cardiovascular Outcomes in High-Risk Patients Without Prior Myocardial Infarction or Stroke
- Trial ID
- 2023-503673-38-00
- Protocol
- 20170625
- Sponsor
- Amgen Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is 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. This objective is clinically relevant as it aims to determine the potential of evolocumab to reduce major cardiovascular events, which are significant causes of morbidity and mortality in high-risk populations.
Secondary objectives include:
- Evaluating the effect of evolocumab on the risk for MI, ischemic stroke, or any ischemia-driven arterial revascularization.
- Assessing the risk for CHD death, MI, or any ischemia-driven arterial revascularization.
- Determining the risk for cardiovascular death, MI, or ischemic stroke.
- Evaluating the risk for CHD death or MI.
- Assessing the risk for MI.
- Evaluating the risk for any ischemia-driven arterial revascularization.
- Determining the risk for CHD death.
- Assessing the risk for cardiovascular death.
- Evaluating the risk for all-cause death.
- Determining the risk of ischemic stroke.
These secondary objectives aim to provide a comprehensive understanding of the cardiovascular benefits of evolocumab in reducing various cardiovascular events and mortality in a high-risk population, thereby informing clinical decision-making and therapeutic strategies.
Participants
The clinical trial involves a total of **4899 participants** who are adults at high risk of cardiovascular events without a prior history of myocardial infarction (MI) or stroke. The study population includes both **male and female** subjects, with men aged **50 years and older** and women aged **55 years and older**, up to a maximum age of **79 years**. Participants were selected based on specific lipid criteria, including LDL-C levels of at least 90 mg/dL, non-HDL-C levels of at least 120 mg/dL, or apolipoprotein B levels of at least 80 mg/dL. The trial does not include a vulnerable population. Lifestyle considerations such as current tobacco use and a family history of premature coronary artery disease are relevant factors for inclusion. The trial population was carefully selected to ensure that participants meet the necessary high-risk criteria for cardiovascular events, including significant coronary artery disease, atherosclerotic cerebrovascular disease, or peripheral arterial disease, as well as diabetes mellitus with associated microvascular disease. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the impact of **evolocumab** on major cardiovascular events in adults at high cardiovascular risk without prior myocardial infarction or stroke. The trial aims to assess the effect of evolocumab compared to placebo on the risk of coronary heart disease death, myocardial infarction, or ischemic stroke, whichever occurs first, in subjects receiving optimized lipid-lowering therapy. The study is expected to run from June 2019 to June 2025, with a maximum treatment period of 72 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, lipid levels, and diagnostic evidence of cardiovascular conditions. Following randomization, participants will receive either evolocumab or placebo administered subcutaneously. Regular follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted.
The expected length of participant involvement is approximately 72 weeks, contingent upon adherence to the study protocol. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or non-compliance with study procedures. The primary endpoints of the trial include the time to coronary heart disease death, myocardial infarction, or ischemic stroke, while secondary endpoints encompass various combinations of these events and ischemia-driven arterial revascularization.
Treatment
The clinical trial involves the administration of **Evolocumab**, a monoclonal antibody used to reduce cardiovascular risk. Evolocumab is provided as a **solution for injection** and is administered via the **subcutaneous** route. Each pre-filled pen contains 140 mg of evolocumab in 1 mL of solution. The maximum daily dose is 140 mg, with a total maximum dose of 21.84 mg over the treatment period. The treatment duration is set for a maximum of 72 weeks. Participants will receive the medication at a frequency determined by the study protocol, ensuring adherence to the dosing schedule. Compliance with the administration schedule will be monitored throughout the trial to ensure accurate assessment of the drug's efficacy and safety.
The study also includes a **placebo** group, which will receive a placebo designed to match the experimental treatment, **AMG 145**. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in a manner identical to the active treatment, following the same subcutaneous route and dosing schedule. This allows for a direct comparison of outcomes between the evolocumab and placebo groups, providing a robust assessment of the drug's impact on major cardiovascular events in patients at high cardiovascular risk.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the impact of **evolocumab** on major cardiovascular events in patients at high cardiovascular risk without prior myocardial infarction or stroke. The primary endpoints for efficacy assessment include the time to coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke, whichever occurs first. Additionally, the time to CHD death, MI, ischemic stroke, or any ischemia-driven arterial revascularization, whichever occurs first, will also be evaluated.
Secondary endpoints will further assess efficacy by measuring the time to various cardiovascular events, including MI, ischemic stroke, any ischemia-driven arterial revascularization, CHD death, cardiovascular death, and all-cause mortality. These endpoints will be measured using time-to-event analysis, which is a common method in cardiovascular outcome trials.
The trial is designed as a double-blind, randomized, placebo-controlled, multicenter study. Patients will receive either evolocumab or a placebo, with the treatment period extending up to 72 weeks. The study will ensure that all efficacy parameters are collected and analyzed systematically to determine the effect of evolocumab compared to placebo in reducing the risk of major cardiovascular events.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects must be ≥ 50 years (men) or ≥ 55 years (women) to < 80 years of age (either sex) and meeting lipid criteria
- Lipid Criteria (see Section 11.8 for permissible concomitant lipid-lowering therapy): 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 umol/L)
- 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: - 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 - 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. - 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: -prior transient ischemic attack with ≥ 50% carotid stenosis -internal or external carotid artery stenosis of ≥ 70% or 2 or more ≥ 50% stenoses -prior internal or external carotid artery revascularization C. Significant peripheral arterial disease meeting at least 1 of the following criteria: - ≥ 50% stenosis in a limb artery -history of abdominal aorta treatment (percutaneous and surgical) due to atherosclerotic disease -ankle brachial index (ABI) < 0.85 D. Diabetes mellitus with at least 1 of the following: -known microvascular disease, defined by diabetic nephropathy or treated retinopathy. Diabetic nephropathy defined as persistent microalbuminuria (urinary albumin to creatinine ratio ≥ 30mg/g) and/or persistent estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 that is not reversible due to an acute illness -chronic daily treatment with an intermediate or long-acting insulin -diabetes diagnosis ≥ 10 years ago
- At least 1 of the following high-risk criteria (most recent lab values within 6 months prior to screening, as applicable): - polyvascular disease, defined as coronary, carotid, or periperal artery stenosis > 50% in a seocnd distinct vasuclar location in a patient with coronary, cerebral of peripheral arterial diseasse (A, B or C above). - present of either diabetes mellitus or metabolic syndrome (Section 11.9) in a subject with coronary, cerebral, or peripheral artery disease (A, B or C above) -at least 1 coronary, carotid or periperal artery residual stenosis of > 50% in a patient with daibetes meeting inclusion criterion D above) - LDL-C > 130mg/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 -lipoprotein (a) > 125 nmol/L (50 mg/dL) - known familial hypercholesterolemia -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 CABD in the subject's monther or sister at age < 60 years -high sensitive c-reactive protein (hsCRP) > 3.0 mg/L in the absence of an acute illness - current tobacco use - > 65 years of age - menopause before 40 years of age - eGFR 15 to 45 mL/min/1.73 m2 - coronary artery calcification score > 300 in a patient without a coronary revascularization prior to randomization
Exclusion Criteria
- MI or stroke prior to randomization
- CABG < 3 months prior to screening
- eGFR < 15 mL/min/1.73 m2
- Uncontrolled or recurrent ventricular tachycardia in the absence of an implantable-cardioverter defibrillator.
- Atrial fibrillation or atrial flutter not on anticoagulation therapy (vitamin K antagonist, heparin, low-molecular weight heparin, fondaparinux, or non-Vitamin K antagonist oral anticoagulant)
- Triglycerides ≥ 500mg/dL (5.7 mmol/L) measured up to 3 months prior to screening. The most recent results must be used.
- Last measured left-ventricular ejection fraction < 30% or New York Heart Association (NYHA) Functional Class III/IV
- Planned arterial revascularization
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 18 Jun 2019 | 165 |
 Belgium | Not Recruiting | 18 Jun 2019 | 62 |
 Bulgaria | Not Recruiting | 18 Jun 2019 | 442 |
 Czechia | Not Recruiting | 18 Jun 2019 | 987 |
 Denmark | Not Recruiting | 18 Jun 2019 | 209 |
 Estonia | Not Recruiting | 18 Jun 2019 | 63 |
 Finland | Not Recruiting | 18 Jun 2019 | 122 |
 France | Not Recruiting | 18 Jun 2019 | 142 |
 Germany | Not Recruiting | 18 Jun 2019 | 209 |
 Greece | Not Recruiting | 18 Jun 2019 | 116 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo for AMG 145 | Placebo | N/A | — | — | — | N/A |
EVOLOCUMAB | Test | — | SUBCUTANEOUS | 140 | 72 | SUB128552 |