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Effect of Evolocumab on Coronary Plaque Characteristics (YELLOW III)

Primary Purpose

Coronary Artery Disease

Status

Active

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Evolocumab Injections

About this trial

This is an interventional basic science trial for Coronary Artery Disease focused on measuring Coronary Artery Disease, Coronary Plaque, Optical Coherence Tomography, Near-Infrared Spectroscopy, Evolocumab, Statin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Mount Sinai Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

Evolocumab subcutaneously administered 140 mg every 2 weeks for 26 weeks

Outcomes

Primary Outcome Measures

Change in Minimal Fibrous Cap Thickness (FCT)

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.

Number of Participants With FCT <65 µm

Number of Participants With Increased Fibrous Cap

Change in maxNIRS4mm

Changes in maximal lipid-core burden index within 4 mm (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. Maximal lipid-core burden index is calculated as a fraction of yellow pixels (representing lipid) obtained from the NIRS chemogram multiplied by 1000. It ranges is from 0 to 1000 and represents the amount of lipid in the investigated segment with "0" corresponding to no lipid and "1000" representing all lipid lesion.

Number of Participants With Decreased maxLCBI4mm

Secondary Outcome Measures

Change in Maximal Lipid Arc

Change in Maximal lipid arc assessed by OCT and measured in degrees.

Change in Lipid Length

Change in Lipid length by OCT, measured in millimeters.

Change in Lipid Volume Index (LVI)

Change in Lipid Volume Length (LVI) calculated as the average lipid arc multiplied by lipid length assessed by OCT.

Change in Macrophage Accumulation

Change in the prevalence of Macrophage accumulation (maximum and average) by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.)

Change in Macrophage Volume Index

Change in the Macrophage Volume Index by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.)

Change in Macrophage Length

Change in Calcification Accumulation

Change in Calcification accumulation by OCT expressed as frequency of the presence of calcification in lesions.

Change in Calcium Length

Change in Percent Atheroma Volume (PAV)

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. The percent atheroma volume is calculated as the proportion of total vessel wall volume occupied by atherosclerotic plaque - plaque volume divided by vessel volume and multiplied by 100.

Change in Total Atheroma Volume (TAV)

Change in TAV assessed by IVUS. TAV characterizes the total volume of coronary plaque.

Change in PBMC Gene Expression

Change in PBMC gene expression. Messenger RNA sequencing data will be processed using statistical and bioinformatics analyses.

Full Information

NCT ID

NCT04710368

First Posted

January 12, 2021

Last Updated

April 27, 2023

Sponsor

Annapoorna Kini

1. Study Identification

Unique Protocol Identification Number

NCT04710368

Brief Title

Effect of Evolocumab on Coronary Plaque Characteristics

Acronym

YELLOW III

Official Title

Effect of Evolocumab on Coronary Plaque Characteristics: a Multimodality Imaging Study

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

May 4, 2021 (Actual)

Primary Completion Date

October 28, 2022 (Actual)

Study Completion Date

October 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Annapoorna Kini

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Coronary Artery Disease

Keywords

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

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

137 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

Evolocumab subcutaneously administered 140 mg every 2 weeks for 26 weeks

Intervention Type

Drug

Intervention Name(s)

Evolocumab Injections

Other Intervention Name(s)

Repatha

Intervention Description

Administered on day 1 (the day of the first treatment) and through week 26 with a personal injector or prefilled auto injector/pens.

Primary Outcome Measure Information:

Title

Change in Minimal Fibrous Cap Thickness (FCT)

Description

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.

Time Frame

Baseline and 26 Weeks

Title

Number of Participants With FCT <65 µm

Time Frame

Baseline and 26 Weeks

Title

Number of Participants With Increased Fibrous Cap

Time Frame

26 weeks

Title

Change in maxNIRS4mm

Description

Time Frame

Baseline and 26 Weeks

Title

Number of Participants With Decreased maxLCBI4mm

Time Frame

26 Weeks

Secondary Outcome Measure Information:

Title

Change in Maximal Lipid Arc

Description

Change in Maximal lipid arc assessed by OCT and measured in degrees.

Time Frame

Baseline and 26 Weeks

Title

Change in Lipid Length

Description

Change in Lipid length by OCT, measured in millimeters.

Time Frame

Baseline and 26 weeks

Title

Change in Lipid Volume Index (LVI)

Description

Change in Lipid Volume Length (LVI) calculated as the average lipid arc multiplied by lipid length assessed by OCT.

Time Frame

Baseline and 26 Weeks

Title

Change in Macrophage Accumulation

Description

Change in the prevalence of Macrophage accumulation (maximum and average) by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.)

Time Frame

Baseline and 26 Weeks

Title

Change in Macrophage Volume Index

Description

Change in the Macrophage Volume Index by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.)

Time Frame

Baseline and 26 Weeks

Title

Change in Macrophage Length

Time Frame

Baseline and 26 Weeks

Title

Change in Calcification Accumulation

Description

Change in Calcification accumulation by OCT expressed as frequency of the presence of calcification in lesions.

Time Frame

Baseline and 26 Weeks

Title

Change in Calcium Length

Time Frame

Baseline and 26 Weeks

Title

Change in Percent Atheroma Volume (PAV)

Description

Time Frame

Baseline and 26 weeks

Title

Change in Total Atheroma Volume (TAV)

Description

Change in TAV assessed by IVUS. TAV characterizes the total volume of coronary plaque.

Time Frame

Baseline and 26 Weeks

Title

Change in PBMC Gene Expression

Description

Change in PBMC gene expression. Messenger RNA sequencing data will be processed using statistical and bioinformatics analyses.

Time Frame

Baseline and 1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Annapoorna Kini, MD

Organizational Affiliation

Icahn School of Medicine at Mount Sinai

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mount Sinai Hospital

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

27039291

Citation

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Results Reference

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Citation

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.

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Results Reference

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PubMed Identifier

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Citation

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.

Results Reference

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PubMed Identifier

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Citation

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.

Results Reference

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Effect of Evolocumab on Coronary Plaque Characteristics

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