Icosapent Ethyl for High-Risk Coronary Plaques Assessed by 18F-NaF PET/CT (IPE-NaF)

A Randomized Controlled Trial Evaluating the Effect of Icosapent Ethyl on High-Risk Coronary Plaques Using 18F-Sodium Fluoride PET/CT

This randomized controlled study will evaluate whether icosapent ethyl (IPE) can improve and stabilize high-risk coronary plaques in patients receiving stable low-density lipoprotein cholesterol (LDL-C)-lowering therapy. Potential participants will have coronary plaques identified by coronary computed tomography angiography (CCTA), with 30% to 70% narrowing in at least one major coronary artery and at least one high-risk plaque feature.

After baseline imaging with fluorine-18 sodium fluoride positron emission tomography/computed tomography (18F-NaF PET/CT), eligible participants will be randomly assigned in a 1:1 ratio to receive either IPE 2 g twice daily plus standard LDL-C-lowering therapy or standard LDL-C-lowering therapy alone for 12 months. At the end of treatment, participants will undergo repeat CCTA and 18F-NaF PET/CT. Blood biomarkers and major adverse cardiovascular events will also be assessed during follow-up.

Study Overview

• Status: Not yet recruiting
• Conditions: Coronary Artery Disease; Coronary Atherosclerosis; Hypertriglyceridaemia; Hyperlipidaemia
• Intervention / Treatment: Drug: icosapent ethyl (IPE); Drug: Standard LDL-C-Lowering Therapy

Detailed Description

This study consists of three main stages. First, a screening cohort will be established using CCTA. Individuals with 30% to 70% diameter narrowing in at least one major coronary artery-the left anterior descending, left circumflex, or right coronary artery-and at least one high-risk plaque feature will be considered for further screening. High-risk plaque features assessed by experienced imaging specialists include increased pericoronary fat attenuation, low-attenuation plaque, positive remodeling, spotty calcification, and the napkin-ring sign. This screening process is intended to identify appropriate and reliably characterized candidates for the randomized study.

Eligible participants will undergo baseline 18F-NaF PET/CT imaging and then be randomly assigned in a 1:1 ratio using a centralized block randomization system. Participants in the intervention group will receive IPE 2 g twice daily for 12 months in addition to stable LDL-C-lowering therapy. Participants in the control group will continue stable LDL-C-lowering therapy without IPE. The LDL-C-lowering regimen should be stable for more than 4 weeks before randomization.

After 12 months, participants in both groups will undergo follow-up CCTA and 18F-NaF PET/CT to evaluate changes in coronary plaque characteristics and disease activity. Follow-up will also include measurements of relevant plasma biomarkers and monitoring for major adverse cardiovascular events. Imaging data will be acquired using standardized procedures and interpreted by experienced imaging specialists.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Naqiong Wu, Doctor; Phone Number: +86 13501139869; Email: fuwainaqiongwu@163.com
• Study Contact Backup: Name: Zheng Yin, Master; Phone Number: +8615359270767; Email: yinzheng@fuwai.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100037
      • Fuwai Hospital
      • Contact: Jianing Zhang, Master; Phone Number: +86 (010) 88398662; Email: Zhangjianing@fuwai.com
      • Principal Investigator: Naqiong Wu, Doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female participants aged 18 to 75 years.
• Ability to understand the study and provide written informed consent before enrollment.
• Receiving a stable lipid-lowering regimen before enrollment, with the type and dose of statin therapy remaining unchanged for at least 4 weeks.
• Fasting triglyceride level below 5.6 mmol/L.
• Presence of at least one of the following high-risk plaque features on coronary computed tomography angiography (CCTA):Pericoronary fat attenuation index greater than -70.1 Hounsfield units;
• Low-attenuation plaque below 30 Hounsfield units;
• Positive remodeling index greater than 1.1;
• Spotty calcification;
• or Napkin-ring sign, defined as a low-attenuation plaque core surrounded by a rim of higher attenuation.

Exclusion Criteria:

• Current participation in another investigational drug, device, or procedure study, or receipt of an investigational drug or device within 4 weeks before enrollment.
• Treatment with icosapent ethyl within 12 months before enrollment.
• Known intolerance or hypersensitivity to icosapent ethyl or fish oil.
• A previous diagnosis of homozygous familial hypercholesterolemia or hyperlipidemia requiring hemodialysis.
• Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, or stroke within 3 months before enrollment;
• Planned cardiac surgery, percutaneous coronary intervention, or carotid artery stenting, or planned major noncardiac surgery during the study.
• A known contraindication or limitation to PET/CT, including exceeding scanner weight limits or having a device, carotid or aortic stent, or vascular graft that may cause imaging artifacts.
• Autoimmune disease, vasculitis, or active inflammatory disease.
• Serious infection within 1 month before enrollment or a current infection requiring intravenous antibiotic treatment.
• Use within 6 weeks before enrollment or current use of medications that may significantly affect plaque inflammation, including oral, rectal, or injectable corticosteroids or immunosuppressive agents, such as cyclosporine, methotrexate, tacrolimus, azathioprine, antithymocyte globulin, sirolimus, anti-tumor necrosis factor agents such as infliximab, anti-interleukin-6 therapy such as tocilizumab, or anti-interleukin-1 therapy.
• Use within 6 weeks before enrollment or current use of aspirin at a dose greater than 325 mg/day or nonsteroidal anti-inflammatory drugs at a dose greater than 1,000 mg/day.
• Treatment within 12 months before enrollment with a cholesteryl ester transfer protein inhibitor, including anacetrapib, dalcetrapib, or evacetrapib, or with mipomersen or lomitapide.
• Known clinically significant systemic disease, including hepatic, renal, hematologic, or malignant disease, or any other clinically significant comorbidity that may interfere with study participation or study assessments.
• History of malignancy within the previous 5 years, except nonmelanoma skin cancer, cervical carcinoma in situ, ductal carcinoma in situ of the breast, or stage I prostate cancer.
• Inability or anticipated inability to complete all protocol-required visits or procedures, or any condition that may make the participant unreliable for study participation, including alcohol or other substance abuse within the previous year or a psychiatric disorder.
• Pregnancy or breastfeeding, or plans to become pregnant or breastfeed during study treatment or within 15 weeks after the last dose of study treatment.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Icosapent Ethyl Plus Standard LDL-C-Lowering Therapy; Participants will receive oral icosapent ethyl 2 g twice daily for 12 months in addition to their stable LDL-C-lowering therapy. CCTA and 18F-NaF PET/CT will be performed at baseline and after 12 months, together with biomarker and clinical event follow-up.	Drug: icosapent ethyl (IPE); Icosapent ethyl will be administered orally at a dose of 2 g twice daily (total daily dose of 4 g) for 12 months, in addition to stable LDL-C-lowering therapy.; Other Names: IPE; Ethyl Eicosapentaenoate; Eicosapentaenoic Acid Ethyl Ester; Drug: Standard LDL-C-Lowering Therapy; Participants will continue an individualized, stable LDL-C-lowering regimen throughout the 12-month study period. The LDL-C-lowering regimen must have remained stable for more than 4 weeks before randomization. This background therapy will be administered in both study arms.
Active Comparator: Standard LDL-C-Lowering Therapy Alone; Participants will continue their stable LDL-C-lowering therapy for 12 months without receiving icosapent ethyl. CCTA and 18F-NaF PET/CT will be performed at baseline and after 12 months, together with biomarker and clinical event follow-up.	Drug: Standard LDL-C-Lowering Therapy; Participants will continue an individualized, stable LDL-C-lowering regimen throughout the 12-month study period. The LDL-C-lowering regimen must have remained stable for more than 4 weeks before randomization. This background therapy will be administered in both study arms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Maximum Target-to-Background Ratio of the Target Coronary Lesion	The target lesion is defined as the coronary lesion with the highest maximum target-to-background ratio (TBRmax) at baseline. TBRmax is calculated as the maximum standardized uptake value (SUVmax) of the target lesion divided by the mean standardized uptake value (SUVmean) of the blood-pool background measured in the right atrium, superior vena cava, or inferior vena cava. Absolute change is calculated as the Month 12 TBRmax minus the baseline TBRmax.	Baseline and Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in TBRmax of the Target Coronary Lesion	The target lesion is the coronary lesion with the highest TBRmax at baseline. Percentage change is calculated as [(Month 12 TBRmax - baseline TBRmax) / baseline TBRmax] × 100%.	Baseline and Month 12
Change From Baseline in SUVmax of the Target Coronary Lesion	Change in the maximum standardized uptake value of the prespecified target coronary lesion, calculated as the Month 12 value minus the baseline value.	Baseline and Month 12
Change From Baseline in Total Volume of 18F-NaF-Positive Coronary Plaque	Total volume of coronary plaque demonstrating positive 18F-NaF uptake, defined as TBRmax greater than 1.25. Change is calculated as the Month 12 volume minus the baseline volume.	Baseline and Month 12
Change From Baseline in the Number of 18F-NaF-Positive Coronary Segments	Number of coronary artery segments with positive 18F-NaF uptake, defined as TBRmax greater than 1.25. Change is calculated as the Month 12 count minus the baseline count.	Baseline and Month 12
Change From Baseline in Pericoronary Fat Attenuation Index at the Target Plaque	Pericoronary fat attenuation index (FAI), measured in Hounsfield units using CCTA at the location of the target plaque. Change is calculated as the Month 12 value minus the baseline value.	Baseline and Month 12
Change From Baseline in Percent Atheroma Volume at the Target Plaque	Percent atheroma volume (PAV) will be measured using CCTA. Change is calculated as the Month 12 value minus the baseline value.	Baseline and Month 12
Change From Baseline in CCTA-Derived Coronary Plaque Component Volumes	CCTA will be used to measure changes in total plaque, noncalcified plaque, calcified plaque, and low-attenuation noncalcified plaque volumes. For each component, change is calculated as the Month 12 volume minus the baseline volume.	Baseline and Month 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma triglycerides Levels From Baseline to Month 12	Plasma levels of triglycerides (TG) will be measured.	Baseline and Month 12
Percentage Change From Baseline in Plasma High-Sensitivity C-Reactive Protein Level	Percentage change will be calculated as [(Month 12 hs-CRP - baseline hs-CRP) / baseline hs-CRP] × 100%.	Baseline and Month 12
Change in Plasma Eicosapentaenoic Acid Level From Baseline to Month 12	Plasma eicosapentaenoic acid (EPA) concentration will be measured and reported in its applicable concentration unit (e.g., μg/mL or % of total fatty acids, according to the laboratory assay).	Baseline and Month 12
Exploratory Incidence of Three-Point Major Adverse Cardiovascular Events	Number and percentage of participants experiencing a three-point major adverse cardiovascular event (3P-MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke.	From randomization through Month 12
Exploratory Incidence of Four-Point Major Adverse Cardiovascular Events	Number and percentage of participants experiencing a four-point major adverse cardiovascular event (4P-MACE), defined as 3P-MACE plus ischemia-driven coronary revascularization.	From randomization through Month 12

Collaborators and Investigators

• Sponsor: China National Center for Cardiovascular Diseases
• Collaborators: Beijing Chao Yang Hospital; Beijing Anzhen Hospital; Beijing Municipal Health Commission

Publications and helpful links

General Publications

• Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, Muhlestein JB, Le VT, May HT, Shaikh K, Shekar C, Roy SK, Tayek J, Nelson JR. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J. 2020 Oct 21;41(40):3925-3932. doi: 10.1093/eurheartj/ehaa652.
• Moss A, Daghem M, Tzolos E, Meah MN, Wang KL, Bularga A, Adamson PD, Kwiecinski J, Fletcher A, Dawson D, Arumugam P, Sabharwal N, Greenwood JP, Townend JN, Calvert PA, Rudd JHF, Berman D, Verjans J, Slomka P, Dey D, Forsyth L, Murdoch L, Lee RJ, Lewis S, Mills NL, van Beek EJR, Williams MC, Dweck MR, Newby DE; PREFFIR Investigators. Coronary Atherosclerotic Plaque Activity and Future Coronary Events. JAMA Cardiol. 2023 Aug 1;8(8):755-764. doi: 10.1001/jamacardio.2023.1729.
• Sayah N, Bhatt DL, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Jiao L, Pineda AL, Doyle RT Jr, Tardif JC, Ballantyne CM, Steg PG. Icosapent ethyl following acute coronary syndrome: the REDUCE-IT trial. Eur Heart J. 2024 Apr 1;45(13):1173-1176. doi: 10.1093/eurheartj/ehad889. No abstract available.
• Yang S, Hoshino M, Koo BK, Yonetsu T, Zhang J, Hwang D, Shin ES, Doh JH, Nam CW, Wang J, Chen S, Tanaka N, Matsuo H, Kubo T, Chang HJ, Kakuta T, Narula J. Relationship of Plaque Features at Coronary CT to Coronary Hemodynamics and Cardiovascular Events. Radiology. 2022 Dec;305(3):578-587. doi: 10.1148/radiol.213271. Epub 2022 Aug 16.
• Gallone G, Bellettini M, Gatti M, Tore D, Bruno F, Scudeler L, Cusenza V, Lanfranchi A, Angelini A, de Filippo O, Iannaccone M, Baldetti L, Audisio K, Demetres M, Risi G, Rizzello G, Porto I, Fonio P, Prati F, Williams MC, Koo BK, Pontone G, Depaoli A, Libby P, Stone GW, Narula J, de Ferrari GM, d'Ascenzo F. Coronary Plaque Characteristics Associated With Major Adverse Cardiovascular Events in Atherosclerotic Patients and Lesions: A Systematic Review and Meta-Analysis. JACC Cardiovasc Imaging. 2023 Dec;16(12):1584-1604. doi: 10.1016/j.jcmg.2023.08.006. Epub 2023 Oct 4.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: July 29, 2026
• First Submitted That Met QC Criteria: August 11, 2026
• First Posted (Actual): August 13, 2026

Study Record Updates

• Last Update Posted (Actual): August 13, 2026
• Last Update Submitted That Met QC Criteria: August 11, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Icosapent Ethyl; Coronary Computed Tomography Angiography; Coronary Atherosclerosis; CCTA; 18F-NaF PET/CT; Intermediate Coronary Stenosis; IPE; High-Risk Coronary Plaque; Coronary Plaque Stabilization; 18F-Sodium Fluoride PET/CT; Coronary Microcalcification; Pericoronary Fat Attenuation Index
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Metabolic Diseases; Dyslipidemias; Lipid Metabolism Disorders; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Ischemia; Nutritional and Metabolic Diseases; Coronary Artery Disease; Hypertriglyceridemia; Hyperlipidemias; eicosapentaenoic acid ethyl ester
• Other Study ID Numbers: 2026-3220

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared because of participant privacy and confidentiality considerations and applicable institutional ethics and data governance requirements. Deidentified aggregate study results may be reported in scientific publications and presentations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes