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Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase I (PREMIER)

Primary Purpose

Acute Coronary Syndrome

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
intensive LDL-lowering therapy
standard statin monotherapy
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Acute Coronary Syndrome focused on measuring plaque, LDL, statin, endothelial, apheresis, acute coronary syndrome

Eligibility Criteria

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

Inclusion Criteria:

  • Willing and able to provide informed consent (including HIPAA)
  • Age >30 years
  • Presenting with acute coronary syndrome (ACS), manifested as unstable angina or non-ST-elevation myocardial infarction
  • Referred for clinically-indicated, non-emergent (the procedure is not required to be performed within 3 hours after patient presentation) coronary angiography and PCI with IVUS-VH of target coronary artery for ACS
  • Successful placement of two large bore IV cannulas in bilateral upper extremities
  • Fasting (>= 12 hours) LDL >= 100mg/dl while on <= 80mg Atorvastatin or equivalent dose of other statin, performed at time of admission or 3 months prior to PCI.

Exclusion Criteria:

  • Known allergy to aspirin, clopidogrel, statins, or iodinated contrast
  • Positive pregnancy test, planning to become pregnant, or breast-feeding
  • Coexisting conditions that limit life expectancy to less than six months or affect patient compliance
  • Uncontrolled fasting (>= 12 hours) triglyceride levels (>= 500mg/dl)
  • Already participating in an investigational device or drug study
  • History of heparin induced thrombocytopenia (HIT)
  • Persons with estimated glomerular filtration rate (eGFR) less than 60 ml/min if they are diabetic; persons with eGFR of less than 45 ml/min if they are not diabetic
  • ST-elevation myocardial infarction at admission
  • Abnormal liver function test (LFT) at time of admission or 3 month prior to PCI with abnormal LFT defined as any liver transaminases (ALT or AST) 3 times the upper limit of the normal laboratory reference
  • Pre-PCI or post-PCI left ventricular ejection fraction <25% by echo or cardiac catheterization done after admission
  • Pre-PCI, intra-PCI, or post-PCI hemodynamic instability with hypotension
  • Pre-PCI, intra-PCI, or post-PCI cardiac arrest
  • Pre-PCI or post-PCI heart failure with or without pulmonary edema
  • Intra-PCI or post-PCI sustained ventricular tachycardia
  • Complicated PCI, defined as PCI with any of the vascular access complications (large hematoma with lump > 5 cm or requiring medical treatment; arteriovenous (AV) fistula; pseudo aneurysm requiring treatment; retroperitoneal bleeding), or PCI with any of the procedural complications (abrupt vessel closure; no-reflow phenomenon; new angiographic thrombus; new major dissection with reduced flow; catheter-related thrombus), or PCI requiring further medical treatments (urgent coronary artery bypass grafting (CABG); endotracheal intubation; unplanned in-aortic balloon pump; left ventricular assist device (LVAD); covered stent; unplanned temporary pacemaker wire; administration of inotropes; CPR) , or PCI resulting in clinical events (death; stroke; myocardial infarction; stent thrombosis) during or within 24 hours after the index PCI
  • Post-PCI ongoing chest pain
  • Post-PCI severe groin pain and hematoma > 5cm in diameter
  • Persons whose hemoglobin is less than 9 grams following the index PCI/IVUS procedure, or who experience a drop in hemoglobin of greater than or equal to 2 grams following the procedure
  • Not able to comply with study protocol as determined by the investigators

Sites / Locations

  • Oklahoma City VA Medical Center, Oklahoma City, OK
  • VA North Texas Health Care System, Dallas

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

intensive LDL-lowering therapy (ILLT)

standard statin monotherapy (SMT)

Arm Description

Patient of acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is randomized to LDL-apheresis and an oral daily dose of 40-80mg of Atorvastatin or equivalent

Patient of acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is randomized to an oral daily dose of 40-80mg of Atorvastatin or equivalent without LDL-apheresis

Outcomes

Primary Outcome Measures

Change in the Total Atheroma Volume of the Target Coronary Artery From Baseline to 12 Weeks Post-PCI as Assessed Via Intravascular Ultrasound With Virtual Histology (IVUS-VH)
The primary effectiveness outcome measure was the change in the total atheroma volume within a ≥ 20 mm long segment of the target coronary artery from baseline to 12 weeks post-PCI. The measurement was done via IVUS-VH at 2 time points (baseline during index PCI and 12-week follow-up).

Secondary Outcome Measures

Change in % Necrotic Core (NC) Component of Atheroma From Baseline to 12 Weeks Post-PCI as Assessed Via IVUS-VH
The %NC component of atheroma were obtained via IVUS-VH at 2 time points (baseline during index PCI and 12-week follow-up).
Endothelial Progenitor Cell Colony Forming Units (EPC-CFU) Per Milliliter of Peripheral Blood Across Time
The cell culture assay and quantification of circulating EPC-CFU were performed for patients recruited at the Dallas VA center only. The assay were done at 4 time points (pre-PCI, post-PCI, 4-week follow-up, and 12-week follow-up).
Major Adverse Cardiovascular Events
The number of patients who experienced major adverse cardiovascular endpoints (MACE) including death, myocardial infarction, coronary revascularization, and stroke during the follow-up periods.

Full Information

First Posted
October 29, 2009
Last Updated
July 22, 2019
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT01004406
Brief Title
Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase I
Acronym
PREMIER
Official Title
Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
September 2011 (undefined)
Primary Completion Date
January 2013 (Actual)
Study Completion Date
March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this randomized, multi-site, clinical trial is to determine whether intensive therapy consisting of cholesterol-lowering statin drugs plus apheresis to cleanse the blood of low-density lipoprotein (LDL) cholesterol is more effective than statin therapy alone in reducing plaque volume in heart arteries of patients who have already suffered an acute coronary syndrome (ACS). The study will also investigate whether this intensive approach can help increase the presence of endothelial progenitor cells (EPC), stem cells that have been shown to reduce cardiovascular (CV) events in ACS patients. This study has II phases and FDA approval for phase II has been received.
Detailed Description
Using statins to lower blood cholesterol, and specifically LDL, is well established as a long-term strategy to reduce CVs and even death. But the most intensive pharmacologic lipid-lowering therapy with statins, though proven superior to standard dose regimens, is still associated with an unacceptably high rate of recurrent CV events early after an ACS. This study hypothesizes that for ACS patients undergoing percutaneous coronary intervention (PCI), intensive lipid-lowering therapy consisting of statins and LDL-apheresis (ILLT) will significantly reduce the total coronary atheroma volume of vulnerable plaque and augment mobilization of peripherally circulating EPC colony forming units, compared to guideline statin monotherapy (SMT). ILLT will lead to fewer CV events for these patients. Patients presenting at two VA sites with ACS will be screened and consented before undergoing uncomplicated PCI (balloons or stents) and intravascular ultrasound with virtual histology (IVUS-VH). They will then be randomized into the ILLT arm or SMT arm of the study. The ILLT group will receive one treatment of LDL-apheresis plus a daily oral 80mg dose of Atorvastatin; the SMT group will only get the Atorvastatin. Patients will again undergo IVUS-VH 12 weeks after enrollment to measure atheroma volume; EPC level will also be checked. The four-year duration of the study includes 24 months of accrual, six months of follow-up, and 12 months of study closure and data analysis. A two-sample t-test of mean difference with 90% power and 0.65 Cohen's D effect size provides a total sample size estimate of 102. Counting 20% drop-out rate, the sample size increases to 128. The recent FDA recommendations regarding the design of the study has been included in the revised study protocol: The first stage will enroll 30 patients with a 2:1 randomization favoring LDL-apheresis. the safety data will be submitted to the FDA. The enrollment of the second stage of the study will be contingent to the recommendations of the FDA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Coronary Syndrome
Keywords
plaque, LDL, statin, endothelial, apheresis, acute coronary syndrome

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
59 (Actual)

8. Arms, Groups, and Interventions

Arm Title
intensive LDL-lowering therapy (ILLT)
Arm Type
Experimental
Arm Description
Patient of acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is randomized to LDL-apheresis and an oral daily dose of 40-80mg of Atorvastatin or equivalent
Arm Title
standard statin monotherapy (SMT)
Arm Type
Active Comparator
Arm Description
Patient of acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is randomized to an oral daily dose of 40-80mg of Atorvastatin or equivalent without LDL-apheresis
Intervention Type
Device
Intervention Name(s)
intensive LDL-lowering therapy
Other Intervention Name(s)
LIPOSORBER LA-15 System
Intervention Description
The intensive LDL-lowering therapy uses LDL-apheresis in addition to the standard statin therapy. The device used in this study is the LIPOSORBER LA-15 System, manufactured by Kaneka Pharma America LLC. A filter separates plasma from whole blood, the Liposorber -columns remove LDL from the plasma. The system recombines plasma and blood cells and returns them into the patient's body. This procedure typically takes about 3 hours. The procedure provides an immediate reduction in a patient's lipid levels. A single apheresis treatment can lower LDL by more than 80%, but levels return to baseline within 3 weeks
Intervention Type
Drug
Intervention Name(s)
standard statin monotherapy
Other Intervention Name(s)
Atorvastatin or other equivalent types of statin
Intervention Description
The standard statin therapy of 40-80mg oral daily dose of Atorvastatin or other equivalent types of statin to lower LDL in blood for both randomized groups.
Primary Outcome Measure Information:
Title
Change in the Total Atheroma Volume of the Target Coronary Artery From Baseline to 12 Weeks Post-PCI as Assessed Via Intravascular Ultrasound With Virtual Histology (IVUS-VH)
Description
The primary effectiveness outcome measure was the change in the total atheroma volume within a ≥ 20 mm long segment of the target coronary artery from baseline to 12 weeks post-PCI. The measurement was done via IVUS-VH at 2 time points (baseline during index PCI and 12-week follow-up).
Time Frame
baseline and 12-week follow-up
Secondary Outcome Measure Information:
Title
Change in % Necrotic Core (NC) Component of Atheroma From Baseline to 12 Weeks Post-PCI as Assessed Via IVUS-VH
Description
The %NC component of atheroma were obtained via IVUS-VH at 2 time points (baseline during index PCI and 12-week follow-up).
Time Frame
baseline and 12-week follow-up
Title
Endothelial Progenitor Cell Colony Forming Units (EPC-CFU) Per Milliliter of Peripheral Blood Across Time
Description
The cell culture assay and quantification of circulating EPC-CFU were performed for patients recruited at the Dallas VA center only. The assay were done at 4 time points (pre-PCI, post-PCI, 4-week follow-up, and 12-week follow-up).
Time Frame
pre-PCI, post-PCI, 4-week follow-up, and 12-week follow-up
Title
Major Adverse Cardiovascular Events
Description
The number of patients who experienced major adverse cardiovascular endpoints (MACE) including death, myocardial infarction, coronary revascularization, and stroke during the follow-up periods.
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
31 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Willing and able to provide informed consent (including HIPAA) Age >30 years Presenting with acute coronary syndrome (ACS), manifested as unstable angina or non-ST-elevation myocardial infarction Referred for clinically-indicated, non-emergent (the procedure is not required to be performed within 3 hours after patient presentation) coronary angiography and PCI with IVUS-VH of target coronary artery for ACS Successful placement of two large bore IV cannulas in bilateral upper extremities Fasting (>= 12 hours) LDL >= 100mg/dl while on <= 80mg Atorvastatin or equivalent dose of other statin, performed at time of admission or 3 months prior to PCI. Exclusion Criteria: Known allergy to aspirin, clopidogrel, statins, or iodinated contrast Positive pregnancy test, planning to become pregnant, or breast-feeding Coexisting conditions that limit life expectancy to less than six months or affect patient compliance Uncontrolled fasting (>= 12 hours) triglyceride levels (>= 500mg/dl) Already participating in an investigational device or drug study History of heparin induced thrombocytopenia (HIT) Persons with estimated glomerular filtration rate (eGFR) less than 60 ml/min if they are diabetic; persons with eGFR of less than 45 ml/min if they are not diabetic ST-elevation myocardial infarction at admission Abnormal liver function test (LFT) at time of admission or 3 month prior to PCI with abnormal LFT defined as any liver transaminases (ALT or AST) 3 times the upper limit of the normal laboratory reference Pre-PCI or post-PCI left ventricular ejection fraction <25% by echo or cardiac catheterization done after admission Pre-PCI, intra-PCI, or post-PCI hemodynamic instability with hypotension Pre-PCI, intra-PCI, or post-PCI cardiac arrest Pre-PCI or post-PCI heart failure with or without pulmonary edema Intra-PCI or post-PCI sustained ventricular tachycardia Complicated PCI, defined as PCI with any of the vascular access complications (large hematoma with lump > 5 cm or requiring medical treatment; arteriovenous (AV) fistula; pseudo aneurysm requiring treatment; retroperitoneal bleeding), or PCI with any of the procedural complications (abrupt vessel closure; no-reflow phenomenon; new angiographic thrombus; new major dissection with reduced flow; catheter-related thrombus), or PCI requiring further medical treatments (urgent coronary artery bypass grafting (CABG); endotracheal intubation; unplanned in-aortic balloon pump; left ventricular assist device (LVAD); covered stent; unplanned temporary pacemaker wire; administration of inotropes; CPR) , or PCI resulting in clinical events (death; stroke; myocardial infarction; stent thrombosis) during or within 24 hours after the index PCI Post-PCI ongoing chest pain Post-PCI severe groin pain and hematoma > 5cm in diameter Persons whose hemoglobin is less than 9 grams following the index PCI/IVUS procedure, or who experience a drop in hemoglobin of greater than or equal to 2 grams following the procedure Not able to comply with study protocol as determined by the investigators
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Subhash Banerjee, MD
Organizational Affiliation
VA North Texas Health Care System, Dallas
Official's Role
Principal Investigator
Facility Information:
Facility Name
Oklahoma City VA Medical Center, Oklahoma City, OK
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
VA North Texas Health Care System, Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75216
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32791950
Citation
Banerjee S, Luo P, Reda DJ, Latif F, Hastings JL, Armstrong EJ, Bagai J, Abu-Fadel M, Baskar A, Kamath P, Lippe D, Wei Y, Scrymgeour A, Gleason TC, Brilakis ES. Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER). Circ Cardiovasc Interv. 2020 Aug;13(8):e008933. doi: 10.1161/CIRCINTERVENTIONS.119.008933. Epub 2020 Aug 14. Erratum In: Circ Cardiovasc Interv. 2020 Oct;13(10):e000078.
Results Reference
derived

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Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase I

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