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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01004406
Recruitment Status : Completed
First Posted : October 30, 2009
Results First Posted : July 15, 2019
Last Update Posted : July 30, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE October 29, 2009
First Posted Date  ICMJE October 30, 2009
Results First Submitted Date  ICMJE June 18, 2019
Results First Posted Date  ICMJE July 15, 2019
Last Update Posted Date July 30, 2019
Study Start Date  ICMJE September 2011
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2019)
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) [ Time Frame: baseline and 12-week follow-up ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: October 29, 2009)
Change in the total atheroma volume within at least 20mm of the target coronary artery from baseline to 12 weeks post-PCI. The measurement will be done via IVUS-VH. [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2019)
  • Change in % Necrotic Core (NC) Component of Atheroma From Baseline to 12 Weeks Post-PCI as Assessed Via IVUS-VH [ Time Frame: baseline and 12-week follow-up ]
    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 [ Time Frame: pre-PCI, post-PCI, 4-week follow-up, and 12-week follow-up ]
    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 [ Time Frame: 6 months ]
    The number of patients who experienced major adverse cardiovascular endpoints (MACE) including death, myocardial infarction, coronary revascularization, and stroke during the follow-up periods.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 29, 2009)
  • % necrotic core component of atheroma [ Time Frame: 6 months ]
  • Endothelial progenitor cell colony forming units/ml of peripheral blood [ Time Frame: 6 months ]
  • Major adverse CV events during the follow-up periods [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase I
Official Title  ICMJE Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER)
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:

  1. The first stage will enroll 30 patients with a 2:1 randomization favoring LDL-apheresis. the safety data will be submitted to the FDA.
  2. The enrollment of the second stage of the study will be contingent to the recommendations of the FDA.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Acute Coronary Syndrome
Intervention  ICMJE
  • Device: intensive LDL-lowering therapy
    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
    Other Name: LIPOSORBER LA-15 System
  • Drug: standard statin monotherapy
    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.
    Other Name: Atorvastatin or other equivalent types of statin
Study Arms  ICMJE
  • Experimental: intensive LDL-lowering therapy (ILLT)
    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
    Interventions:
    • Device: intensive LDL-lowering therapy
    • Drug: standard statin monotherapy
  • Active Comparator: standard statin monotherapy (SMT)
    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: Drug: standard statin monotherapy
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 18, 2019)
59
Original Estimated Enrollment  ICMJE
 (submitted: October 29, 2009)
128
Actual Study Completion Date  ICMJE March 2013
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 31 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01004406
Other Study ID Numbers  ICMJE CLIN-010-09S
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party VA Office of Research and Development
Original Responsible Party Banerjee, Subhash - Principal Investigator, Department of Veterans Affairs
Current Study Sponsor  ICMJE VA Office of Research and Development
Original Study Sponsor  ICMJE US Department of Veterans Affairs
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Subhash Banerjee, MD VA North Texas Health Care System, Dallas
PRS Account VA Office of Research and Development
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP