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Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase II (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: NCT02347098
Recruitment Status : Completed
First Posted : January 27, 2015
Results First Posted : July 10, 2019
Last Update Posted : October 30, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

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 two phases and FDA approval for phase II has been received and all information has been updated to reflect PREMIER Phase II.

Condition or disease Intervention/treatment Phase
Acute Coronary Artery Syndrome Device: intensive LDL-lowering therapy Drug: standard statin monotherapy Phase 3

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 four VA sites with ACS will be screened and consented before undergoing uncomplicated PCI (balloons or stents) and intravascular ultrasound with virtual histology (IVUS-HS). 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 40- 80mg dose of Atorvastatin or equivalent statin; the SMT group will only get 40-80mg Atorvastatin or equivalent. Patients will again undergo IVUS-HS 12 weeks after enrollment to measure atheroma volume; EPC level will also be checked.

The three-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 have been included in the revised study protocol:

  1. The safety data will be submitted to the FDA.
  2. Patients will be randomized to both LDL-apheresis and an oral daily dose of 40-80mg Atorvastatin or equivalent statin (Intensive LDL-lowering therapy/ILLT) or a daily dose of 40-80mg of Atorvastatin or equivalent statin without LDL-apheresis (standard statin monotherapy/SMT) following an uncomplicated PCI.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 270 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase II
Actual Study Start Date : March 30, 2015
Actual Primary Completion Date : February 28, 2018
Actual Study Completion Date : September 30, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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

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
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




Primary Outcome Measures :
  1. Change in the Total Atheroma Volume From Baseline to 12 Weeks [ Time Frame: 12 weeks ]
    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 90-day follow-up).


Secondary Outcome Measures :
  1. Change in % Necrotic Core Component of Atheroma [ Time Frame: 12 weeks ]
    The %NC component of atheroma were obtained via IVUS-VH at 2 time points (baseline during index PCI and 90-day follow-up).

  2. Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time [ Time Frame: 12 weeks ]
    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, 30-day follow-up, and 90-day follow-up).

  3. Major Adverse CV 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   31 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 Intravascular Ultrasound with Virtual Histology (IVUS-VH) of target coronary artery for ACS
  • Successful placement of two large bore IV cannulas in bilateral upper extremities
  • Fasting (12 hrs.) LDL 70mg/dl while on less than or equal to 80mg Atorvastatin or equivalent dose of other statin, performed at time of admission or 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 hrs.) 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) of less than 45 ml/min
  • ST-elevation myocardial infarction at admission
  • Abnormal liver function test (LFT) at time of admission or 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 acute 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 graft (CABG); endotracheal intubation; unplanned in-aortic balloon pump; left ventricular assist device (LVAD); covered stent; unplanned temporary pacemaker wire; administration of inotropes; cardiopulmonary resuscitation (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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02347098


Locations
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United States, Colorado
VA Eastern Colorado Health Care System, Denver, CO
Denver, Colorado, United States, 80220
United States, Oklahoma
Oklahoma City VA Medical Center, Oklahoma City, OK
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
Nashville, Tennessee, United States, 37212-2637
United States, Texas
VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
Dallas, Texas, United States, 75216
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Subhash Banerjee, MD VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
  Study Documents (Full-Text)

Documents provided by VA Office of Research and Development:
Study Protocol  [PDF] June 22, 2016
Statistical Analysis Plan  [PDF] September 30, 2014

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02347098    
Other Study ID Numbers: CLIN-010-09S-1
First Posted: January 27, 2015    Key Record Dates
Results First Posted: July 10, 2019
Last Update Posted: October 30, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Keywords provided by VA Office of Research and Development:
plaque
LDL
statin
endothelial
apheresis
acute coronary artery syndrome
Additional relevant MeSH terms:
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Syndrome
Disease
Pathologic Processes
Atorvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Enzyme Inhibitors