A Phase 3 interventional study of intensive LDL-lowering therapy and standard statin monotherapy in Acute Coronary Artery Syndrome, sponsored by VA Office of Research and Development. Completed at 4 sites in United States. Open to participants aged 31 Years and older. Per ClinicalTrials.gov, last updated 2019-10-30.
Sponsored by VA Office of Research and Development · Phase 3, Interventional, and Prevention
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.
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:
97 studies on the registry are indexed under Plaque, Amyloid; 38 are open to participants now.
This study's enrollment of 270 is above the median of 111 across 70 interventional studies indexed under Plaque, Amyloid.
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Exclusion Criteria:
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 · Drug: standard statin monotherapy
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 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.
Also known as: LIPOSORBER LA-15 System
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.
Also known as: Atorvastatin or other equivalent types of statin
Change in the Total Atheroma Volume From Baseline to 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).
Time frame: 12 weeks
Change in % Necrotic Core Component of Atheroma
The %NC component of atheroma were obtained via IVUS-VH at 2 time points (baseline during index PCI and 90-day follow-up).
Time frame: 12 weeks
Endothelial Progenitor Cell Colony Forming Units/ml 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, 30-day follow-up, and 90-day follow-up).
Time frame: 12 weeks
Major Adverse CV 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.
Time frame: 6 months
Subject recruitment for Phase II pivotal study started on March 30, 2015, and the first participant was randomized on April 9, 2015. The recruitment period stopped in July 2017. For all 4 participating sites, Dallas, Nashville, Oklahoma City, and Denver randomized 80, 5, 38, and 6 participants, respectively.
| Milestone | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) |
|---|---|---|
| Started | 63 | 66 |
| Completed | 56 | 58 |
| Not completed | 7 | 8 |
| Withdrew: Death | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 |
| Withdrew: Lost to follow-up | 2 | 2 |
| Withdrew: Refuse follow-up visit | 1 | 5 |
| Withdrew: No visit due to illness | 2 | 1 |
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).
| mm^3 | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) |
|---|---|---|
| Change in the Total Atheroma Volume From Baseline to 12 Weeks | -7.63 ± 23.78 | -3.10 ± 17.74 |
The %NC component of atheroma were obtained via IVUS-VH at 2 time points (baseline during index PCI and 90-day follow-up).
| percentage of atheroma component | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) |
|---|---|---|
| Change in % Necrotic Core Component of Atheroma | 0.44 ± 6.81 | 0.94 ± 9.89 |
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).
| colonies/ml | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) |
|---|---|---|
| baseline pre-PCI | 11.85 ± 9.24 | 11.99 ± 11.37 |
| baseline post-PCI | 15.30 ± 10.96 | 17.89 ± 16.91 |
| 30-day | 21.60 ± 14.78 | 20.40 ± 17.87 |
| 90-day | 16.32 ± 13.29 | 15.06 ± 14.33 |
The number of patients who experienced major adverse cardiovascular endpoints (MACE) including death, myocardial infarction, coronary revascularization, and stroke during the follow-up periods.
| Participants | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) |
|---|---|---|
| Major Adverse CV Events | 5 | 2 |
Collected over AE/SAE/UADE were monitored at the study sites throughout the whole period of the study at each clinic visit and telephone contact, beginning as soon as a study participant signs the Informed Consent and continuing through end-of-study for each participant. Most participants were followed for around 6 months for AE/SAE/UADE.. Non-serious events are listed at a 3% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Intensive LDL-lowering Therapy (ILLT) | 2/63 (3.2%) | 28/63 (44.4%) | 42/63 (66.7%) |
| Standard Statin Monotherapy (SMT) | 0/66 (0%) | 28/66 (42.4%) | 39/66 (59.1%) |
| Event | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) |
|---|---|---|
| Cardiac failure congestiveCardiac disorders | 0/63 | 7/66 |
| Coronary artery diseaseCardiac disorders | 5/63 | 2/66 |
| Chest painGeneral disorders | 5/63 | 5/66 |
| Coronary artery stenosisCardiac disorders | 0/63 | 5/66 |
| Vascular stent restenosisGeneral disorders | 3/63 | 4/66 |
| Atrial fibrillationCardiac disorders | 3/63 | 1/66 |
| Myocardial infarctionCardiac disorders | 1/63 | 3/66 |
| Cerebrovascular accidentNervous system disorders | 2/63 | 1/66 |
| PneumoniaInfections and infestations | 2/63 | 0/66 |
| Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders | 2/63 | 0/66 |
| Event | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) |
|---|---|---|
| Chest painGeneral disorders | 7/63 | 6/66 |
| Procedural hypotensionInjury, poisoning and procedural complications | 7/63 | 0/66 |
| HypotensionVascular disorders | 7/63 | 1/66 |
| FlushingVascular disorders | 6/63 | 0/66 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 5/63 | 2/66 |
| Procedural nauseaInjury, poisoning and procedural complications | 4/63 | 0/66 |
| EpistaxisRespiratory, thoracic and mediastinal disorders | 4/63 | 3/66 |
| VertigoEar and labyrinth disorders | 4/63 | 2/66 |
| Diabetes mellitus inadequate controlMetabolism and nutrition disorders | 1/63 | 3/66 |
| Musculoskeletal painMusculoskeletal and connective tissue disorders | 0/63 | 3/66 |
| Age, Continuous(years) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| Mean | 64.2 ± 9.4 | 67.3 ± 7.7 | 65.8 ± 8.7 |
| Sex: Female, Male(Participants) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| Female | 1 | 1 | 2 |
| Male | 62 | 65 | 127 |
| Race (NIH/OMB)(Participants) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 1 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 13 | 14 | 27 |
| White | 48 | 52 | 100 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(Participants) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| United States | 63 | 66 | 129 |
| Weight(pounds) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| Mean | 225.0 ± 56.7 | 221.7 ± 46.7 | 223.3 ± 51.6 |
| Height(inches) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| Mean | 69.9 ± 2.7 | 70.0 ± 2.9 | 70.0 ± 2.8 |
| Heart Rate(beats/min) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| Mean | 79.0 ± 16.0 | 71.8 ± 13.6 | 75.3 ± 15.2 |
| Systolic BP(mmHg) | Intensive LDL-lowering Therapy (ILLT) | Standard Statin Monotherapy (SMT) | Total |
|---|---|---|---|
| Mean | 140.0 ± 22.1 | 141.8 ± 23.9 | 140.9 ± 22.9 |
2 further baseline measures are reported on the registry.
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