Imaging of Coronary Plaques in Participants Treated With Evolocumab

High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS)

To evaluate the effect of evolocumab on fibrous cap thickness (FCT) in participants with non-ST-elevation acute coronary syndrome (NSTE-ACS) who are taking maximally tolerated statin therapy.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease (CAD)
• Intervention / Treatment: Drug: Evolocumab; Drug: Statin therapy; Drug: Placebo

Detailed Description

This study seeks to identify morphologic changes, such as increase in FCT in atherosclerotic plaques associated with treatment with evolocumab and maximally tolerated statin therapy with or without additional lipid-modifying medication in patients presenting with NSTE-ACS using optical coherence tomography (OCT; primary, secondary, and exploratory endpoints).

• Study Type: Interventional
• Enrollment (Actual): 164
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Epping, Victoria, Australia, 3076
      • The Northern Hospital
• Czechia
  • Brno, Czechia, 625 00
    • Fakultni Nemocnice Brno
  • Hradec Kralove, Czechia, 500 05
    • Fakultni Nemocnice Hradec Kralove
• Germany
  • Berlin, Germany, 12203
    • Charite Universitätsmedizin Berlin Campus Benjamin Franklin
  • Hamburg, Germany, 20246
    • Universitäres Herzzentrum Hamburg GmbH
  • München, Germany, 80636
    • Deutsches Herzzentrum München des Freistaates Bayern
• Hungary
  • Balatonfured, Hungary, 8230
    • Allami Szivkorhaz Balatonfured
  • Budapest, Hungary, 1122
    • Semmelweis Egyetem
  • Budapest, Hungary, 1134
    • Magyar Honvédség Egészségügyi Központ
  • Pecs, Hungary, 7624
    • Pécsi Tudományegyetem Klinikai Központ
• Italy
  • Bergamo, Italy, 24127
    • Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII
  • Cuneo, Italy, 12100
    • Azienda Ospedaliera Santa Croce e Carle
  • Firenze, Italy, 50134
    • Azienda Ospedaliera Universitaria Careggi
  • Milano, Italy, 20138
    • IRCCS Centro Cardiologico Monzino
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria Federico II
  • Roma, Italy, 00184
    • Azienda Ospedaliera San Giovanni Addolorata
  • Rozzano MI, Italy, 20089
    • Irccs Istituto Clinico Humanitas
• Netherlands
  • Alkmaar, Netherlands, 1815 JD
    • Noordwest Ziekenhuisgroep
  • Amsterdam, Netherlands, 1091 AC
    • Onze Lieve Vrouwe Gasthuis
  • Amsterdam, Netherlands, 1081 HV
    • Vrjie Universiteit Medisch Centrum
  • Nijmegen, Netherlands, 6525 GA
    • Radboud Universitair Medisch Centrum
  • Nijmegen, Netherlands, 6532 SZ
    • Canisius-Wilhelmina Ziekenhuis
  • Tilburg, Netherlands, 5042 AD
    • Elisabeth-TweeSteden Ziekenhuis
  • Zwolle, Netherlands, 8025 AB
    • Isala Klinieken
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Heart and Vascular Institute
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Midwest Cardiovascular Research and Education Foundation
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provided informed consent prior to initiation of any study-specific activities/procedures.
• Age greater than or equal to 18 years at screening
• Clinical indication for coronary angiography during admission due to NSTE-ACS with interventional treatment of culprit plaque
• An eligible low-density lipoprotein cholesterol (LDL-C) level via local lab assessment based on statin use at screening

No statin use: greater than or equal to 130 mg/dL Low- or moderate-intensity statin use greater than or equal to 80 mg/dL High-intensity statin use greater than or equal to 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
• Meets all the following criteria at the qualifying coronary angiogram:

Angiographic evidence of coronary artery disease (CAD) with greater than or equal to 20% reduction of lumen diameter by angiographic visual estimation, in addition to the culprit plaque.

Left main coronary artery must not have a greater than 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 optical coherence tomography (OCT) catheter.

Targeted segment:

Must have up to 50% but not greater than 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 a fibrous cap thickness (FCT) of less than or equal to 120 μm and at least 1 image with a lipid arc of greater than 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.

Exclusion Criteria:

• ST-segment elevation myocardial infarction (STEMI) or left bundle branch block (LBBB).
• Acute coronary syndromes (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.
• Triglycerides greater than or equal to 400 mg/dL (4.5 mmol/L) at screening.
• Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m^2 at screening.
• 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.
• Previously received or receiving evolocumab or any other therapy to inhibit proprotein convertase subtilisin/kexin type 9 (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.
• 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.
• 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.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evolocumab; Participants receive evolocumab subcutaneous injection once every month (QM) for 48 weeks. As prescribed and provided by the investigator, participants will be treated with maximally tolerated statin therapy, not expected to change for the duration of the study participation.	Drug: Evolocumab; Participants will receive evolocumab (AMG 145) subcutaneous monthly.; Other Names: Repatha, AMG 145, EvoMab; Drug: Statin therapy; high-intensity statin treatment with atorvastatin ≥ 40 mg daily or equivalent as background therapy Investigators will up-titrate statin therapy to the maximally tolerated dose, in accordance with local guidelines, prior to randomization.
Placebo Comparator: Placebo; Participants receive placebo subcutaneous injection QM for 48 weeks. As prescribed and provided by the Investigator, participants will be treated with maximally tolerated statin therapy, not expected to change for the duration of the study participation.	Drug: Statin therapy; high-intensity statin treatment with atorvastatin ≥ 40 mg daily or equivalent as background therapy Investigators will up-titrate statin therapy to the maximally tolerated dose, in accordance with local guidelines, prior to randomization.; Drug: Placebo; Participants will receive matching placebo subcutaneous monthly.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Minimum FCT	Absolute change from baseline in minimum FCT in a matched segment of artery as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.	Baseline, week 50

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Minimum FCT	Percent change from baseline in minimum FCT in a matched segment of artery as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.	Baseline, week 50
Absolute Change From Baseline in Mean Minimum FCT	Absolute change from baseline in mean minimum FCT for all images assessed in an individual participant as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.	Baseline, week 50
Absolute Change From Baseline in the Maximum Lipid Arc	Absolute change from baseline in the maximum lipid arc in a matched segment of artery as determined by OCT. Lower value of lipid arc indicates a better situation.	Baseline, week 50
Absolute Change From Baseline in Minimum FCT in Lipid Rich Plaques	Absolute change from baseline in minimum FCT in lipid rich plaques as determined by OCT. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Higher value of FCT indicates a better situation	Baseline, week 50
Absolute Change From Baseline in Maximum Lipid Arc in Lipid Rich Plaques	Absolute change from baseline in maximum lipid arc in lipid rich plaques. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Lower value of lipid arc indicates a better situation.	Baseline, week 50
Absolute Change From Baseline in Lipid Core Length in Lipid Rich Plaques	Absolute change from baseline in lipid core length in lipid rich plaques. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Lower value of lipid core length indicates a better situation.	Baseline, week 50

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Nicholls SJ, Nissen SE, Prati F, Windecker S, Kataoka Y, Puri R, Hucko T, Kassahun H, Liao J, Somaratne R, Butters J, Di Giovanni G, Jones S, Psaltis PJ. Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study. Cardiovasc Diagn Ther. 2021 Feb;11(1):120-129. doi: 10.21037/cdt-20-684.
• Pharmacoeconomic Review Report: Icosapent Ethyl (Vascepa): (HLS Therapeutics Inc.): Indication: Prevention of cardiovascular events in statin-treated patients [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Aug. Available from http://www.ncbi.nlm.nih.gov/books/NBK566010/
• Nicholls SJ, Kataoka Y, Nissen SE, Prati F, Windecker S, Puri R, Hucko T, Aradi D, Herrman JR, Hermanides RS, Wang B, Wang H, Butters J, Di Giovanni G, Jones S, Pompili G, Psaltis PJ. Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction. JACC Cardiovasc Imaging. 2022 Jul;15(7):1308-1321. doi: 10.1016/j.jcmg.2022.03.002. Epub 2022 Mar 16.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2018
• Primary Completion (Actual): December 18, 2020
• Study Completion (Actual): January 21, 2021

Study Registration Dates

• First Submitted: June 18, 2018
• First Submitted That Met QC Criteria: June 18, 2018
• First Posted (Actual): June 27, 2018

Study Record Updates

• Last Update Posted (Actual): May 3, 2022
• Last Update Submitted That Met QC Criteria: April 7, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Coronary angiography; Coronary artery disease; Lipid-lowering therapy; Optical coherence tomography (OCT); Statin; Cardiovascular events; Intravascular ultrasound (IVUS); Coronary atherosclerotic plaques; Maximally tolerated statin therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: 20160184; 2017-003236-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (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
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No