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    Summary
    EudraCT Number:2018-004565-14
    Sponsor's Protocol Code Number:20170625
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-05-15
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-004565-14
    A.3Full title of the trial
    A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate the Impact of Evolocumab on Major Cardiovascular Events in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke
    A.4.1Sponsor's protocol code number20170625
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03872401
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmgen Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAmgen Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen Biotechnologia Sp. z o.o.
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street Addressul. Pulawska 145
    B.5.3.2Town/ cityWarszawa
    B.5.3.3Post code02-715
    B.5.3.4CountryPoland
    B.5.4Telephone number+4822581 30 00
    B.5.5Fax number+4822581 30 01
    B.5.6E-mailMedinfo-pol@amgen.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Repatha 140 mg solution for injection in pre-filled pen
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEvolocumab
    D.3.2Product code AMG145
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEVOLOCUMAB
    D.3.9.2Current sponsor codeAMG 145
    D.3.9.4EV Substance CodeSUB128552
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection in pre-filled pen
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Dyslipidemia
    E.1.1.1Medical condition in easily understood language
    Abnormal amounts of lipids in the blood
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10058110
    E.1.2Term Dyslipidemia
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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 ischemic stroke;
    4. CHD death or MI
    5. MI;
    6. any ischemia-driven arterial revascularization;
    7. CHD death;
    8. cardiovascular death;
    9. all cause of death;
    10. ischemic stroke;

    in subjects at high cardiovascular risk without prior MI or stroke and receiving optimized lipid-lowering therapy.
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    3. The most recent results (historical or screening) must be used


    -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
    E.4Principal 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 or atrial flutter 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
    - Triglycerides ≥ 500 mg/dL (5.7 mmol/L) measured up to 3 months
    prior to screening. The most recent results must be used.
    - End stage renal disease (ESRD), defined as an eGFR < 15 mL/min/1.73 m2 or receiving dialysis measured up to 6 months prior to screening. The most recent results must be used.

    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.
    E.5 End points
    E.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    Continually during treatment period and at EOS
    E.5.2Secondary 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 ischemic stroke
    - Time to CHD death or MI
    - 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.5.2.1Timepoint(s) of evaluation of this end point
    Continually during treatment period and at EOS
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    cardiovascular outcomes study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned57
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA428
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    Italy
    Latvia
    Lithuania
    Netherlands
    Poland
    Portugal
    Romania
    Slovakia
    Spain
    Sweden
    E.8.7Trial 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
    The end of the study visit, for subjects that have not terminated the
    study early, occurs once the specified number of events to support the
    primary endpoints has been reached.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6660
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5340
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state850
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 7101
    F.4.2.2In the whole clinical trial 12000
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects may be eligible for continued treatment with Amgen investigational product(s) by an extension protocol or as provided for by the local country’s regulatory mechanism. However, Amgen reserves the unilateral right, at its sole discretion, to determine whether to supply Amgen investigational product(s) and by what mechanism, after termination of the study and before the product(s) is/are available commercially.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Synexus Limited
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Bioclinica
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-07-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-12
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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