Coronary Artery Disease
Conditions
Keywords
Coronary Artery Disease, Coronary Plaque, Optical Coherence Tomography, Near-Infrared Spectroscopy, Evolocumab, Statin
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.
Interventions
DRUGEvolocumab Injections
Administered on day 1 (the day of the first treatment) and through week 26 with a personal injector or prefilled auto injector/pens.
Sponsors
Annapoorna Kini
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Minimal Fibrous Cap Thickness (FCT) | 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. |
| Number of Participants With FCT <65 µm | Baseline and 26 Weeks | — |
| Number of Participants With Increased Fibrous Cap | 26 weeks | — |
| Change in maxNIRS4mm | Baseline and 26 Weeks | 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 | 26 Weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Macrophage Length | Baseline and 26 Weeks | — |
| Change in Calcification Accumulation | Baseline and 26 Weeks | Change in Calcification accumulation by OCT expressed as frequency of the presence of calcification in lesions. |
| Change in Calcium Length | Baseline and 26 Weeks | — |
| Change in Maximal Lipid Arc | Baseline and 26 Weeks | Change in Maximal lipid arc assessed by OCT and measured in degrees. |
| Change in Total Atheroma Volume (TAV) | Baseline and 26 Weeks | Change in TAV assessed by IVUS. TAV characterizes the total volume of coronary plaque. |
| Change in PBMC Gene Expression | Baseline and 1 year | Change in PBMC gene expression. Messenger RNA sequencing data will be processed using statistical and bioinformatics analyses. |
| Change in Percent Atheroma Volume (PAV) | 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. 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 Lipid Length | Baseline and 26 weeks | Change in Lipid length by OCT, measured in millimeters. |
| Change in Lipid Volume Index (LVI) | Baseline and 26 Weeks | Change in Lipid Volume Length (LVI) calculated as the average lipid arc multiplied by lipid length assessed by OCT. |
| Change in Macrophage Accumulation | Baseline and 26 Weeks | 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 | Baseline and 26 Weeks | Change in the Macrophage Volume Index by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.) |
Countries
United States
Participant flow
Recruitment details
329 Patients were screened with 137 enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Evolocumab subcutaneously administered 140 mg every 2 weeks for 26 weeks
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. | 137 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Lost to Follow-up | 4 |
| Overall Study | Patient preference | 11 |
| Overall Study | Treatment discontinuation | 1 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Treatment | — |
|---|---|---|
| Age, Continuous | 66.0 years STANDARD_DEVIATION 9.7 | — |
| Baseline statin use High intensity | 91 Participants | — |
| Baseline statin use Low intensity | 0 Participants | — |
| Baseline statin use Moderate intensity | 38 Participants | — |
| Body Mass Index (BMI) | 31.6 kg/m^2 STANDARD_DEVIATION 19.3 | — |
| Current smoking | 14 Participants | — |
| Diabetes | 74 Participants | — |
| Diseased Coronary Vessel Type LAD - Left Anterior Descending Artery | 29 Participants | — |
| Diseased Coronary Vessel Type LCX - Left Circumflex Artery | 36 Participants | — |
| Diseased Coronary Vessel Type RCA - Right Coronary Artery | 70 Participants | — |
| Diseased Coronary Vessel Type RI - Ramus Intermedius Artery | 2 Participants | — |
| History of smoking | 51 Participants | — |
| Hypertension | 127 Participants | — |
| Number of diseased vessels 0 | 19 Participants | — |
| Number of diseased vessels 1 | 83 Participants | — |
| Number of diseased vessels 2 | 31 Participants | — |
| Number of diseased vessels 3 | 4 Participants | — |
| Previous Myocardial Infarction (MI) | 32 Participants | — |
| Previous Percutaneous coronary intervention (PCI) | 97 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 39 Participants | — |
| Sex: Female, Male Male | 98 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 110 |
| other Total, other adverse events | 30 / 110 |
| serious Total, serious adverse events | 5 / 110 |
Outcome results
Primary
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.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in maxNIRS4mm | Baseline | 306.8 index | Standard Deviation 177.6 |
| Treatment | Change in maxNIRS4mm | 26 Weeks | 213.1 index | Standard Deviation 168 |
Primary
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.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Minimal Fibrous Cap Thickness (FCT) | Baseline | 70.9 µm | Standard Deviation 21.7 |
| Treatment | Change in Minimal Fibrous Cap Thickness (FCT) | 26 Weeks | 97.7 µm | Standard Deviation 31.1 |
Primary
Number of Participants With Decreased maxLCBI4mm
Time frame: 26 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Decreased maxLCBI4mm | 86 Participants |
Primary
Number of Participants With FCT <65 µm
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment | Number of Participants With FCT <65 µm | Baseline | 53 Participants |
| Treatment | Number of Participants With FCT <65 µm | 26 weeks | 14 Participants |
Primary
Number of Participants With Increased Fibrous Cap
Time frame: 26 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Increased Fibrous Cap | 88 Participants |
Secondary
Change in Calcification Accumulation
Change in Calcification accumulation by OCT expressed as frequency of the presence of calcification in lesions.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Calcification Accumulation | Maximum calcium arc Baseline | 98.6 degrees | Standard Deviation 55.7 |
| Treatment | Change in Calcification Accumulation | Maximum calcium arc 26 Weeks | 98.6 degrees | Standard Deviation 54.6 |
| Treatment | Change in Calcification Accumulation | Average calcium arc Baseline | 61.1 degrees | Standard Deviation 26.1 |
| Treatment | Change in Calcification Accumulation | Average calcium arc 26 Weeks | 61.2 degrees | Standard Deviation 25.1 |
Secondary
Change in Calcium Length
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Calcium Length | Baseline | 6.4 mm | Standard Deviation 4.9 |
| Treatment | Change in Calcium Length | 26 Weeks | 6.7 mm | Standard Deviation 4.7 |
Secondary
Change in Lipid Length
Change in Lipid length by OCT, measured in millimeters.
Time frame: Baseline and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Lipid Length | Baseline | 10.4 mm | Standard Deviation 6 |
| Treatment | Change in Lipid Length | 26 Weeks | 8.9 mm | Standard Deviation 5.6 |
Secondary
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.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Lipid Volume Index (LVI) | Baseline | 1259.4 mm*degrees | Standard Deviation 994.5 |
| Treatment | Change in Lipid Volume Index (LVI) | 26 Weeks | 972.0 mm*degrees | Standard Deviation 855.7 |
Secondary
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.)
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Macrophage Accumulation | Maximum macrophage arc Baseline | 148.2 degrees | Standard Deviation 72.5 |
| Treatment | Change in Macrophage Accumulation | Maximum macrophage arc 26 Weeks | 122.1 degrees | Standard Deviation 67.7 |
| Treatment | Change in Macrophage Accumulation | Average macrophage arc Baseline | 83.4 degrees | Standard Deviation 36.5 |
| Treatment | Change in Macrophage Accumulation | Average macrophage arc 26 Weeks | 71.2 degrees | Standard Deviation 32 |
Secondary
Change in Macrophage Length
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Macrophage Length | Baseline | 9.6 mm | Standard Deviation 5.7 |
| Treatment | Change in Macrophage Length | 26 Weeks | 7.6 mm | Standard Deviation 5.2 |
Secondary
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.)
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Macrophage Volume Index | Baseline | 876.4 mm*degrees | Standard Deviation 757.6 |
| Treatment | Change in Macrophage Volume Index | 26 Weeks | 590.0 mm*degrees | Standard Deviation 557.3 |
Secondary
Change in Maximal Lipid Arc
Change in Maximal lipid arc assessed by OCT and measured in degrees.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Maximal Lipid Arc | Baseline | 189.1 degrees | Standard Deviation 73.4 |
| Treatment | Change in Maximal Lipid Arc | 26 Weeks | 161.6 degrees | Standard Deviation 68.7 |
Secondary
Change in PBMC Gene Expression
Change in PBMC gene expression. Messenger RNA sequencing data will be processed using statistical and bioinformatics analyses.
Time frame: Baseline and 1 year
Secondary
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.
Time frame: Baseline and 26 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Percent Atheroma Volume (PAV) | Baseline | 51.6 percent atheroma volume | Standard Deviation 8.9 |
| Treatment | Change in Percent Atheroma Volume (PAV) | 26 Weeks | 50.2 percent atheroma volume | Standard Deviation 8.7 |
Secondary
Change in Total Atheroma Volume (TAV)
Change in TAV assessed by IVUS. TAV characterizes the total volume of coronary plaque.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Change in Total Atheroma Volume (TAV) | Baseline | 137.2 mm^3 | Standard Deviation 72.8 |
| Treatment | Change in Total Atheroma Volume (TAV) | 26 Weeks | 131.2 mm^3 | Standard Deviation 71.8 |