YELLOW II Study: Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering

Coronary Artery Disease Clinical Trial

Official title:

YELLOW II Study: Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01837823
• Other study ID #: GCO 12-1507
• Secondary ID: HS#: 12-00741
• Status: Completed
• Phase: Phase 2
• First received: April 5, 2013
• Last updated: January 16, 2018
• Start date: July 2013
• Est. completion date: April 2015

Study information

• Verified date: January 2018
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Coronary artery disease (CAD) remains a leading cause of death in most countries. It is well known that the reduction of cholesterol levels by statin therapy is associated with significant decreases in plaque burden. REVERSAL, ASTEROID, and more recently the SATURN II trial showed that in patients with CAD, lipid lowering with atorvastatin or rosuvastatin respectively reduced progression of coronary atherosclerosis, even causing plaque regression of some lesions. CAD clinical events are related to plaque instability due to lipid content and activity within the atherosclerotic plaque. The investigators recently completed the YELLOW I study, and identified that intensive statin therapy (rosuvastatin 40mg) was associated with a reduction in the amount of lipid in obstructive coronary plaques, as measured by near-infrared spectroscopy (NIRS). The YELLOW II study is designed to expand and build upon these results, and to provide mechanistic insights into the potential benefits of intensive statin therapy on atherosclerotic plaques.

Description:

YELLOW II is a single site study and will assess the regression of plaque lipid content and changes in plaque morphology from atherosclerotic lesions after high-dose statin therapy by utilizing NIRS, IVUS and optical coherency tomography (OCT) imaging modalities in the coronary arteries. We propose to image non-culprit coronary lesions using these modalities in patients with two or three diseased coronary vessels deemed to warrant intervention on clinical grounds. Thus, at the time of enrolment patients will undergo Percutaneous Coronary Intervention (PCI) of a non-study culprit lesion, and triple-modality imaging of the potential non-culprit ('YELLOW') lesion. If there is high baseline lipid content in the non-culprit YELLOW lesion (max 4mm LCBI > 150), patients will be formally entered into this study. Following this, all enrolled subjects will receive high-dose lipid lowering therapy (rosuvastatin 40mg daily). The non-culprit YELLOW lesion will undergo staged intervention 8-12 weeks following study enrolment and baseline imaging. At this time the YELLOW lesion will be reimaged to determine whether high-dose statin therapy caused a reduction in lipid content as assessed by NIRS, and other altered plaque morphology as assessed by OCT and IVUS. In addition, both at baseline and at the time of final non-culprit YELLOW lesion PCI, blood samples will be drawn during baseline and follow-up procedure to characterize reverse cholesterol transport by ability of patient HDL to accept cholesterol from cholesterol-laden (mouse J774) macrophage (cholesterol efflux) and the effect of patient HDL and apolipoprotein A1 on macrophage gene expression and migration.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 91
• Est. completion date: April 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients >18 years of age and willing to participate.

• Fluency in either English or Spanish.

• Stable patients who will undergo cardiac catheterization and PCI (intent to stent).

• Patient is willing to go on high-dose cholesterol lowering medication for the duration of the study

• Signed written Informed Consent.

• Women of childbearing potential must agree to be on an acceptable method of birth control/contraceptive such as barrier method (condoms/diaphragm); hormonal contraceptives (birth control pills, implants (Norplant) or injections (Depo-Provera)); Intrauterine Device.

• Proposed non-culprit YELLOW study lesion with max 4mm LCBI = 150.

Exclusion Criteria:

• Patients who have acute myocardial infarction (ST-segment elevation presentation, new Q waves or non-ST segment elevation with CK-MB > 5 times above the upper normal (31.5 ng/ml) within 72 hours).

• Patients who are in cardiogenic shock.

• Patients requiring coronary artery bypass graft surgery.

• 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.

• Active autoimmune disease.

• Nursing mothers

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Inflammation
• Myocardial Ischemia
• Obstructive Coronary Artery Disease

Intervention

Drug:
• rosuvastatin
All subjects will receive rosuvastatin 40mg/day for 8-12 weeks

Locations

Country	Name	City	State
United States	Icahn School of Medicine at Mount Sinai	New York	New York

Sponsors (4)

Lead Sponsor	Collaborator
Icahn School of Medicine at Mount Sinai	AstraZeneca, InfraReDx (indirect), Texas Heart Institute (Wafic Said Molecular Cardiology Research Lab)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Correlation Between Plaque Morphology and HDL Functionality	Correlation between the changes in plaque morphology composition by intravascular imaging with changes in HDL functionality. HDL functionality is measured by the Cholesterol Efflux Capacity (CEC). Plaque morphology is represented by the Fibrous Cap Thickness.	baseline and 8-12 weeks
Primary	Correlation Between the Change in Fibrous Cap Thickness and Hs-CRP	Correlation between the change in plaque morphology composition by intravascular imaging with inflammatory cell activity.	baseline and 8-12 weeks
Secondary	Maximal 4mm Lipid Core Burden Index (LCBI 4mm Max)	Maximum LCBI 4mm (?LCBI4mm max) of the non-culprit YELLOW lesion at baseline and 8-12 weeks thereafter.; LCBI4mm max : 4-mm long segment with maximum lipid core burden index (LCBI), where the LCBI is calculated as the fraction of yellow pixels on a chemogram x 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.	baseline and at 8-12 weeks
Secondary	Fibrous Cap Thickness (FCT) by OCT	?Fibrous Cap Thickness measured by OCT at baseline and at 8-12 weeks	baseline and at 8-12 weeks
Secondary	IVUS Imaging Measures	Correlation between ?LCBI4mm max will be related to ? values from baseline to 8-12 weeks thereafter in specific IVUS (?Plaque burden) imaging measures. Plaque burden is Plaque + Media divided by Total Plaque Area in %.	Baseline and 8 weeks
Secondary	Inflammatory and Lipid Parameters	?LCBI4mm max will be related to ? values from baseline to 8-12 weeks thereafter in inflammatory and lipid parameters responses to patient-derived samples.	baseline and at 8-12 weeks
Secondary	Lesion LCBI	As related to other outcomes, change in LCBI measured across the entire lesion (rather than ?LCBI4mm max). The LCBI Score, computed as the fraction of valid pixels within the scanned region that exceeded a LCP probability of 0.6 multiplied by 1000, summarized the amount of LCP in the entire scanned region of the coronary vessel on a 0-to-1000 scale .	at baseline and at 8-12 weeks
Secondary	LCBI 4mm at Same Anatomical Site	As related to other outcomes, change in LCBI 4mm measured at the identical anatomical site at both time points, as defined by the LCBI4mm max site at baseline (rather than ?LCBI4mm max).; LCBI4mm: 4-mm long segment with maximum lipid core burden index (LCBI), where the LCBI is calculated as the fraction of yellow pixels on a chemogram x 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.	at baseline and at 8-12 weeks
Secondary	Change in Atheroma Volume	Change in total atheroma volume (TAV) and lumen cross sectional area on OCT.	baseline and at 8-12 weeks
Secondary	Biomarker Release	Post procedure CK-MB, Troponin-I release at final YELLOW lesion PCI.	within 24 hrs of PCI
Secondary	Correlation of Baseline Lipid Parameters With Baseline LCBI4mm Max	Correlation of baseline lipid parameters with baseline LCBI4mm max	baseline
Secondary	Plaque Morphology as Related to Haptoglobin	To relate changes in plaque lipid content and morphology to the patient haptoglobin genotype.	baseline and at 8-12 weeks
Secondary	Mechanism of Reverse Cholesterol Transport	To assess the mechanism of reverse cholesterol transport that arises with high-dose statin therapy, as related to changes in plaque lipid content and morphology, and systemic vascular inflammation. Reverse cholesterol transport (RCT) is a pathway by which accumulated cholesterol is transported from the vessel wall to the liver for excretion, thus preventing atherosclerosis.	baseline and at 8-12 weeks
Secondary	Correlation of Changes in Plaque Morphology	Correlation of changes in plaque morphology by OCT, IVUS and NIRS with the perturbations in peripheral blood mononuclear cell transcriptome using microarray analysis.; data not collected for this measure.	baseline and at 8-12 weeks
Secondary	MACE	Major Adverse Cardiac Events (MACE) defined as a combined clinical endpoint of death, MI (Q wave or non Q-wave with CK-MB >3 times above the upper normal limit (48 U/L), urgent revascularization or stroke at 30 days.	at 30 days
Secondary	MACE	Major Adverse Cardiac Events (MACE) defined as a combined clinical endpoint of death, MI (Q wave or non Q-wave with CK-MB >3 times above the upper normal limit (48 U/L), urgent revascularization or stroke at 1 year.	at 1 year