Effect of Evolocumab on Coronary Plaque Characteristics (YELLOW III)

• ClinicalTrials.gov Identifier: NCT04710368
• Recruitment Status: Active, not recruiting
• First Posted: January 14, 2021
• Last Update Posted: March 10, 2023
• Sponsor: Annapoorna Kini
• Information provided by (Responsible Party): Annapoorna Kini, Icahn School of Medicine at Mount Sinai

Study Description

Brief Summary:

The aim of the study is to assess the effect of evolocumab on coronary plaque morphology using intravascular imaging and gene expression analysis of peripheral blood mononuclear cells (PBMC) in patients with stable CAD on maximally tolerated statin therapy. The study combines multi-modality intravascular imaging approaches and transcriptomic based machine learning algorithms to uncover molecular mechanisms responsible for the beneficial changes in atherosclerotic lesions of patients treated with evolocumab. The primary end-points are the changes from baseline to follow-up in (1) the minimal fibrous cap thickness (FCT) assessed by optical coherence tomography (OCT) and (2) maxLCBI4mm assessed by near-infrared spectroscopy (NIRS) after 26 weeks of evolocumab. The secondary endpoints are the changes in (1) the maximal lipid arc, lipid length, lipid volume index, macrophage accumulation and calcification by OCT; (2) PAV and TAV defined by intravascular ultrasound (IVUS) and (3) Changes in PBMC gene expression.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease	Drug: Evolocumab Injections	Phase 4

Detailed Description:

The single center single arm study will be performed in the Cardiac Catheterization laboratory of the Mount Sinai Hospital, New York, NY. After informed consent, patients undergoing clinically indicated elective PCI with a non-obstructive lesion and optimal background statin therapy will be eligible screening. Non-obstructive lesions (30-50% stenosis) identified by angiography in a non-culprit vessel with lipid-rich plaque will be studied. Subjects will receive evolocumab (Repatha) 140 mg subcutaneously every 2 weeks for 26 weeks. Serial NIRS/IVUS and OCT imaging will be performed in the non-obstructive lesions, first during PCI and subsequently after 26 weeks. A total of 25ml of blood will be drawn from the sheath during angiography for transcriptomic profiling of PBMC.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 137 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: The study team will screen patients scheduled for elective PCI, who are receiving statin therapy for at least 4 weeks with acceptable LDL-C levels. Patients with non-obstructive lesion (30-50% stenosis) by angiography and lipid-rich plaque with lipid arc >90° and minimal fibrous cap thickness ≤ 120 µm detected by OCT will comprise the final study population. Serial NIRS/IVUS and OCT imaging will be performed in a non-target lesions, first during PCI and subsequently after 26 weeks.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Effect of Evolocumab on Coronary Plaque Characteristics: a Multimodality Imaging Study
• Actual Study Start Date: May 4, 2021
• Actual Primary Completion Date: October 28, 2022
• Estimated Study Completion Date: October 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment; Evolocumab subcutaneously administered 140 mg every 2 weeks for 26 weeks	Drug: Evolocumab Injections; Administered on day 1 (the day of the first treatment) and through week 26 with a personal injector or prefilled auto injector/pens.; Other Name: Repatha

Outcome Measures

Primary Outcome Measures :

1. Change in Minimal Fibrous Cap Thickness (FCT) [ Time Frame: Baseline and 26 Weeks ]
   Changes in the minimal Minimal Fibrous Cap Thickness (FCT) is assessed by Optical Coherence Tomography (OCT) imaging and measured in microns. FCT describes plaque morphology composition
2. Change in maxNIRS4mm [ Time Frame: Baseline and 26 Weeks ]
   Changes in maxLCBI4mm. LCBI4mm is assessed by NIRS and calculated as the fraction of yellow pixels on a chemogram multiplied by 1000. Each pixel on the chemogram represents a probability of lipid presence in the given region; pixels are color-coded on a red-to-yellow color scale, with the low probability of lipid shown as red and the high probability of lipid shown as yellow.

Secondary Outcome Measures :

1. Change in Maximal Lipid Arc [ Time Frame: Baseline and 26 Weeks ]
   Change in Maximal lipid arc assessed by OCT and measured in degrees.
2. Change in Lipid Length [ Time Frame: Baseline and 26 weeks ]
   Change in Lipid length by OCT, measured in millimeters.
3. Change in Lipid Volume Index (LVI) [ Time Frame: Baseline and 26 Weeks ]
   Change in Lipid Volume Length (LVI) calculated as the average lipid arc multiplied by lipid length assessed by OCT.
4. Change in Macrophage Accumulation [ Time Frame: Baseline and 26 Weeks ]
   Change in the prevalence of Macrophage accumulation by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.)
5. Change in Calcification accumulation [ Time Frame: Baseline and 26 Weeks ]
   Change in Calcification accumulation by OCT expressed as frequency of the presence of calcification in lesions.
6. Change in Percent Atheroma Volume (PAV) [ Time Frame: Baseline and 26 weeks ]
   Change in PAV assessed by Intravascular Ultrasound (IVUS). PAV characterizes coronary plaque burden and calculated as the proportion of total vessel wall volume occupied by atherosclerotic plaque.
7. Change in Total Atheroma Volume (TAV) [ Time Frame: Baseline and 26 Weeks ]
   Change in TAV assessed by IVUS. TAV characterizes the total volume of coronary plaque.
8. Change in PBMC Gene Expression [ Time Frame: Baseline and 26 Weeks ]
   Change in PBMC gene expression. Messenger RNA sequencing data will be processed using statistical and bioinformatics analyses.

Eligibility Criteria

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

Criteria

Inclusion criteria:

• Men or women aged 18 years or older at screening who signed written Informed Consent
• Patients with coronary artery disease undergoing cardiac catheterization and PCI for a target lesion and also have a non-obstructive lesion (30-50% stenosis) identified by angiography
• Patients who are not candidates for PCI or CABG currently or over the next 12 months, in the opinion of the investigator
• Patients treated with statins for at least 4 weeks with LDL-C level ≥ 80 mg/dL for low- or moderate -intensity statin use and ≥ 60 mg/dL for high-dose statin. Patients with history of statin intolerance and LDL-C ≥ 100 mg/dL.
• Angiographic criteria: 30-50% reduction of lumen diameter in addition to the target lesion accessible by the OCT catheter. The target segment should not have a history of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and may not be a bypass graft.
• OCT criteria: target segment should have a lipid-rich plaque with lipid arc >90° and fibrous cap thickness ≤120 µm.
• Women of childbearing potential must agree to be on an acceptable method of birth control/contraceptive

Exclusion criteria:

• Patients who have acute myocardial infarction (Q wave or non-Q wave with CK-MB > 5 times above the upper normal (31.5 ng/ml) within 72 hours)
• Patients who are in cardiogenic shock
• Patients with left main disease, in-stent restenotic lesions or patients requiring coronary artery bypass graft surgery
• Patients with elevated CK-MB (>6.3 ng/ml) or Tnl (>0.5 ng/ml)
• Patients with platelet count < 100,000 cell/mm3
• Patients who have co-morbidity which reduces life expectancy to one year
• Patients who are currently participating in another investigational drug/device study
• Patients with liver disease
• Patient with creatinine > 2.0 mg/dL
• Pregnant women and women of childbearing potential who intend to have children during the duration of the trial
• Patients having undergone heart transplantation, or those that may undergo heart transplantation during the study period
• Patients with active autoimmune disease

Contacts and Locations

Locations

United States, New York

Mount Sinai Hospital

New York, New York, United States, 10029

Sponsors and Collaborators

Annapoorna Kini

Investigators

• Principal Investigator: Annapoorna Kini, MD; Icahn School of Medicine at Mount Sinai

More Information

Publications:

Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, Preiss D, Bruckert E, Ceska R, Lepor N, Ballantyne CM, Gouni-Berthold I, Elliott M, Brennan DM, Wasserman SM, Somaratne R, Scott R, Stein EA; GAUSS-3 Investigators. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016 Apr 19;315(15):1580-90. doi: 10.1001/jama.2016.3608.

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.

Connolly CK. Lung function testing. Respir Med. 1994 Nov;88(10):795-6. doi: 10.1016/s0954-6111(05)80207-0. No abstract available.

Kini AS, Vengrenyuk Y, Shameer K, Maehara A, Purushothaman M, Yoshimura T, Matsumura M, Aquino M, Haider N, Johnson KW, Readhead B, Kidd BA, Feig JE, Krishnan P, Sweeny J, Milind M, Moreno P, Mehran R, Kovacic JC, Baber U, Dudley JT, Narula J, Sharma S. Intracoronary Imaging, Cholesterol Efflux, and Transcriptomes After Intensive Statin Treatment: The YELLOW II Study. J Am Coll Cardiol. 2017 Feb 14;69(6):628-640. doi: 10.1016/j.jacc.2016.10.029. Epub 2016 Oct 29.

Johnson KW, Glicksberg BS, Shameer K, Vengrenyuk Y, Krittanawong C, Russak AJ, Sharma SK, Narula JN, Dudley JT, Kini AS. A transcriptomic model to predict increase in fibrous cap thickness in response to high-dose statin treatment: Validation by serial intracoronary OCT imaging. EBioMedicine. 2019 Jun;44:41-49. doi: 10.1016/j.ebiom.2019.05.007. Epub 2019 May 22.

• Responsible Party: Annapoorna Kini, Professor of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT04710368
• Other Study ID Numbers: GCO 20-2935
• First Posted: January 14, 2021
• Last Update Posted: March 10, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Annapoorna Kini, Icahn School of Medicine at Mount Sinai:

Coronary Artery Disease; Coronary Plaque; Optical Coherence Tomography; Near-Infrared Spectroscopy; Evolocumab; Statin

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Evolocumab; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents