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    Summary
    EudraCT Number:2017-003236-37
    Sponsor's Protocol Code Number:20160184
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-09-05
    Trial results View 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 ConcernedCzechia - SUKL
    A.2EudraCT number2017-003236-37
    A.3Full title of the trial
    High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS)
    Vyšetření plátů věnčitých tepen vysoko rozlišovací metodou v rámci globálního, randomizovaného klinického hodnocení evolokumabu (HUYGENS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Assessment of Coronary Plaques in a Global Evolocumab Study
    Vyšetření plátů věnčitých tepen v rámci globálního klinického hodnocení evolokumabu
    A.3.2Name or abbreviated title of the trial where available
    HUYGENS
    A.4.1Sponsor's protocol code number20160184
    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 (EUROPE) GmbH
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6301
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@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 420 mg solution for injection in cartridge
    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 cartridge
    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 number120
    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 cartridge
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10020604
    E.1.2Term Hypercholesterolemia
    E.1.2System Organ Class 100000004861
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10058110
    E.1.2Term Dyslipidemia
    E.1.2System Organ Class 100000004861
    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 evolocumab on fibrous cap thickness (FCT) in subjects with non ST elevation acute coronary syndrome (NSTE ACS) who are taking maximally tolerated statin therapy.
    E.2.2Secondary objectives of the trial
    - To evaluate the effects of evolocumab on coronary plaque morphology in subjects with NSTE-ACS who are taking maximally tolerated statin therapy.
    -Safety: to evaluate the safety and tolerability of evolocumab treatment in subjects with NSTE-ACS who are taking maximally tolerated statin therapy.
    -Exploratory:
    •To evaluate the effects of evolocumab on lipid parameters in subjects with NSTE ACS who are taking maximally tolerated statin therapy.
    •To evaluate the effects of evolocumab on features of coronary plaques in subjects with NSTE ACS who are taking maximally tolerated statin therapy using different imaging techniques.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key Inclusion Criteria
    •Age ≥ 18 years at screening.
    •Clinical indication for coronary angiography during admission due to NSTE-ACS with interventional treatment of culprit plaque.
    •LDL-C level via local lab assessment based on statin use at screening:
    - No statin use: ≥ 130 mg/dL
    - Low- or moderate-intensity statin use: ≥ 80 mg/dL
    - High-intensity statin use: ≥ 60 mg/dL
    •On maximally tolerated statin therapy in accordance with standard of care per local guidelines prior to randomization.
    •Tolerates placebo run-in injection at screening.
    •Meet all the following criteria at the qualifying coronary angiogram:
    - Angiographic evidence of coronary artery disease (CAD) with ≥ 20% reduction of lumen diameter by angiographic visual estimation, in addition to the culprit plaque.
    - Left main coronary artery must not have a > 50% reduction in lumen diameter by visual angiographic estimation.
    - Targeted vessel:
    -may not be the culprit vessel for the current or a previous myocardial infarction (MI).
    -has not undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and may not be a bypass graft.
    -may not be a candidate for PCI or CABG currently or over the next 12 months, in the opinion of the investigator.
    -must be accessible by the OCT catheter.
    - Targeted segment:
    -must have up to 50% but not > 50% reduction in lumen diameter by visual angiographic estimation and must be at least 40 mm in length.
    -must contain at least 1 image with an FCT of ≤ 120 µm and at least 1 image with a lipid arc of > 90° as determined by the imaging core laboratory.
    -distal plaques of up to 50% stenosis by visual angiographic estimation are permitted, provided that such stenosis is not a target for PCI or CABG.
    E.4Principal exclusion criteria
    Subjects are excluded from the study if any of the following criteria apply.
    •Disease Related:
    -ST-segment elevation myocardial infarction (STEMI) or left bundle branch block (LBBB).
    -ACS likely to be caused by a non-atherosclerotic process, in the opinion of the investigator (ie, type 2 myocardial infarction, which is characterized by an imbalance between myocardial oxygen demand and supply).
    -Clinically significant heart disease which in the opinion of the investigator is likely to require coronary bypass surgery, PCI (does not apply to PCI of non STEMI (NSTEMI) during initial screening angiogram), surgical or percutaneous valve repair and/or replacement during the course of the study.
    -Any cardiac surgery within 6 weeks prior to screening.
    •Diagnostic Assessments
    -Triglycerides ≥ 400 mg/dL (4.5 mmol/L) at screening.
    -Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening.
    •Other Medical Conditions
    -Malignancy except non-melanoma skin cancers, cervical, or breast ductal carcinoma in situ within the last 5 years.
    -Intolerant to statins as determined by principal investigator.
    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.
    •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). Other investigational procedures while participating in this study are excluded.
    •Other Exclusions
    -Baseline OCT does not meet OCT imaging criteria as determined by the imagine core laboratory technical standards.
    -Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 15 weeks after the last dose of investigational product. (Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test.)
    -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. Refer to Appendix 5 for additional contraceptive information.
    -Female subject who has not used an acceptable method(s) of birth control for at least 1 month prior to screening, unless the female subject is sterilized or postmenopausal.
    -Known sensitivity to any of the products or components (eg, carboxymethylcellulose) to be administered during dosing.
    -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’s and investigator’s knowledge.
    -Unreliability based on the investigator's (or designee’s) knowledge (eg, alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, or psychosis).
    -History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
    E.5 End points
    E.5.1Primary end point(s)
    Absolute change in minimum fibrous cap thickness (FCT) in a matched segment of artery as determined by optical coherence tomography (OCT) from baseline to week 50.
    E.5.1.1Timepoint(s) of evaluation of this end point
    OCT: at screening and week 50 ± 2 week
    E.5.2Secondary end point(s)
    1. Coronary artery segment-based:
    - Percent change in minimum FCT in a matched segment of artery as
    determined by OCT from baseline to week 50.
    - Absolute change in mean minimum FCT for all images assessed in an individual subject as determined by OCT from baseline to week 50.
    - Absolute change in the maximum lipid arc in a matched segment of artery as determined by OCT from baseline to week 50.
    2. Plaque-based: Absolute change in minimum FCT, maximum lipid arc, and lipid core length in lipid rich plaques defined as minimum FCT < 120 μm and lipid arc > 90° in at least 3 consecutive images as determined by OCT from baseline to week 50.
    3. Safety: Subject incidence of treatment-emergent adverse events
    and serious adverse events.
    4. Exploratory:
    -Absolute and percent changes in lipid parameters by visit from baseline.
    -Absolute change in number of microchannels in matched segments of all lesions assessed in an individual subject as determined by OCT from baseline to week 50.
    -Absolute change in macrophage composition in matched segments of all lesions assessed in an individual subject as determined by OCT from baseline to week 50.
    -Absolute change in lipid content in matched segments of all lesions assessed in an individual subject as determined by IVUS from baseline to week 50.
    E.5.2.1Timepoint(s) of evaluation of this end point
    OCT: at screening and week 50 ± 2 week.
    IVUS: at screening and week 50 ± 2 week.
    Adverse events and serious adverse events: at screening, day 1, week 4, 12, 24, 36, 50 and 52.
    Lipid testing: at screening.
    Fasting lipid testing: at day 1, week 24 and week 50.
    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 No
    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 No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    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
    Australia
    Japan
    South Africa
    United States
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days11
    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: 102
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 48
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 95
    F.4.2.2In the whole clinical trial 150
    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)
    None
    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 The Vascular Research Network (VRN)
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-11-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-01-21
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