Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amgen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

24 May 2019 → 25 Jul 2025

Decision date (initial)

2024-04-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Amgen Inc.

External identifiers

EU CT number

2023-503673-38-00

EudraCT number

2018-004565-14

WHO UTN

U1111-1302-4393

ClinicalTrials.gov

NCT03872401

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

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 ischemiadriven
arterial revascularization,
whichever occurs first, in subjects at
high cardiovascular risk without prior
MI or stroke and receiving optimized
lipid-lowering therapy

Secondary objectives 10

1. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for MI, ischemic stroke, or any ischemia-driven arterial revascularization in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy
2. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for CHD death, MI, or any ischemia-driven arterial revascularization in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy
3. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, MI, or ischemic stroke in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy
4. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for CHD death or MI in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid lowering therapy.
5. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for MI in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy
6. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for any ischemiadriven arterial revascularization in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy
7. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for CHD death, in subjects at high cardiovasular risk without prio MI or stroke and receiving optimized lipid-lowering therapy.
8. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy.
9. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for all cause of death, in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy.
10. To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk of ischemic stroke in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid lowering therapy.

Conditions and MedDRA coding

Adults at high risk of cardiovascular events without prior MI or stroke.

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-001268-PIP01-12

Plan to share IPD

Yes

IPD plan description

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request. Information on IPD sharing Access Criteria, Time Frame and Supporting Information Type is available on ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT03872401) and on the Amgen Clinical Trials portal (http://www.amgen.com/datasharing).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Subjects must be ≥ 50 years (men) or ≥ 55 years (women) to < 80 years of age (either sex) and meeting lipid criteria
2. 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)
3. 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
4. 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 8

1. MI or stroke prior to randomization
2. CABG < 3 months prior to screening
3. eGFR < 15 mL/min/1.73 m2
4. Uncontrolled or recurrent ventricular tachycardia in the absence of an implantable-cardioverter defibrillator.
5. 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)
6. Triglycerides ≥ 500mg/dL (5.7 mmol/L) measured up to 3 months prior to screening. The most recent results must be used.
7. Last measured left-ventricular ejection fraction < 30% or New York Heart Association (NYHA) Functional Class III/IV
8. Planned arterial revascularization

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Time to CHD death, MI, or ischemic stroke, whichever occurs first
2. Time to CHD death, MI, ischemic stroke, or any ischemia-driven arterial revascularization, whichever occurs first

Secondary endpoints 10

1. Time to MI, ischemic stroke, or any ischemia-driven arterial revascularization
2. Time to CHD death, MI, or any ischemia-driven arterial revascularization
3. Time to cardiovascular death, MI, or ischemic stroke
4. Time to CHD death or MI
5. Time to MI
6. Time to any ischemia-driven arterial revascularization
7. Time to CHD death
8. Time to cardiovasular death
9. Time to all cause of death
10. Time to ischemic stroke

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amgen Inc.

Sponsor organisation

Amgen Inc.

Address

1 Amgen Center Drive

City

Thousand Oaks

Postcode

91320-1799

Country

United States

Scientific contact point

Organisation

Amgen Inc.

Contact name

Medical Information

Public contact point

Organisation

Amgen Inc.

Contact name

Medical Information

Third parties 9

Locations

22 EU/EEA countries · 403 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 160 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications