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

NCT ID: NCT01004406

Last Updated: 2019-07-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 59 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2013-03-31

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.

Conditions

Acute Coronary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

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

Group Type: EXPERIMENTAL

intensive LDL-lowering therapy

Intervention Type: DEVICE

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

standard statin monotherapy

Intervention Type: DRUG

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.

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

Group Type: ACTIVE_COMPARATOR

standard statin monotherapy

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: DEVICE

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.

Intervention Type: DRUG

Other Intervention Names

LIPOSORBER LA-15 System; Atorvastatin or other equivalent types of statin

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

• Minimum Eligible Age: 31 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Subhash Banerjee, MD

Role: PRINCIPAL_INVESTIGATOR

VA North Texas Health Care System, Dallas

Locations

Oklahoma City VA Medical Center, Oklahoma City, OK

Oklahoma City, Oklahoma, United States

VA North Texas Health Care System, Dallas

Dallas, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 32791950 (View on PubMed)

Other Identifiers

CLIN-010-09S

Identifier Type: -

Identifier Source: org_study_id