Assessment of Atherosclerotic Plaque Characteristics Change by DCE-MRI With Alirocumab

April 24, 2019 updated by: Norman Lepor, MD, Westside Medical Associates of Los Angeles

Assessment of Atherosclerotic Plaque Characteristics Change by DCE-MRI With Alirocumab - a Pilot Study

Aim 1: To determine whether therapy with Alirocumab, compared to pre-treatment, will effectively improve carotid atherosclerotic plaque characteristics by reducing Ktrans and LRNC size. To achieve this goal, we will (a) enroll 30 subjects who are intolerant to high intensity statin therapy and only able to tolerate low potency statin or low weekly dose of high potency statin and have LDL-C ≥70 mg/dl; (b) initiate alirocumab at 150mg subcutaneously injection every 2 weeks; (c) perform carotid DCE-MRI scans at baseline, 3, 6 and 12 months; (d) perform quantitative analysis for vascular inflammation and plaque LRNC volume and other plaque characteristics; (e) compare vascular inflammation and LRNC volume between pre- and post-alirocumab at 3, 6 and 12 months.

Aim 2: To examine associations between reductions in atherogenic lipids (LDL-C, Lp(a), non-HDL-C) and changes in atherosclerotic plaque characteristics. To achieve this goal, we will (a) perform laboratory assessments of lipids, lipoproteins and apo-lipoproteins at baseline and during the study; (b) compare lipids, lipoproteins and apo-lipoproteins levels between pre- and post-alirocumab; (c) correlate reductions in atherogenic lipids with changes atherosclerotic plaque characteristics.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Acute ischemic events caused by atherosclerosis cardiovascular disease (ASCVD) are primarily due to plaque rupture/erosion determined by plaque morphologic characteristics, local composition and inflammation, which can be directly assessed using magnetic resonance imaging (MRI). Prospective carotid MRI studies have demonstrated: (1) plaques with thin or ruptured cap, intraplaque hemorrhage (IPH), neovascularization, or larger lipid-rich necrotic core (LRNC) are strongly associated with occurrence of cerebrovascular and coronary events, (2) increased LRNC size is significantly associated with increased risk for systemic ASCVD events after adjusting for LDL-C or Non-HDL-C levels, (3) increased permeability of adventitial vasa vasorum is associated with presence of IPH which increases plaque burden and LRNC progression that appears to be resistant to conventional doses of statins, (4) intensive lipid therapy decreases carotid LRNC and vascular inflammation, (5) multicenter carotid studies can be conducted with good reproducibility and feasibility.

Unlike previous clinical trials evaluating carotid artery disease using ultrasound based technology that showed a weak relationship to systemic and coronary vascular events, recent studies have demonstrated predictive value of carotid plaque tissue characteristics for subsequent systemic ASCVD events including coronary events. Hellings and colleagues found that carotid plaque composition by histology in 818 patients who underwent endarterectomy is an independent predictor of future cardiovascular events during long-term post-operative follow-up. Specifically, those with carotid IPH and increased neovascularization were at significantly higher risk for ASCVD events. The Atherosclerosis Risk in Communities study investigators reported that carotid LRNC (HR=1.9, p=0.014) and minimum cap thickness (HR=0.67, p=0.03), as identified by MRI, were significantly associated with development of ASCVD including coronary events after adjusting for all clinical risk factors, treatment variables and biomarkers. The carotid MRI sub-study in AIM-HIGH showed that higher Lp(a) levels are associated with high-risk plaque features which are prevalent in subjects with established vascular disease and "well-controlled" LDL-C and blood pressure. Thin or ruptured cap and a larger LRNC are predictive of systemic ASCVD events that include 83% (15/18) of the coronary events in AIM-HIGH, meanwhile, none of the clinical risk factors and lipids were predictive of future events.

Alirocumab has shown substantial lowering in LDL-C, non-HDL-C and Lp(a), with or without concomitant statin treatment [43]. It has the potential to be a therapy that can improve plaque characteristics leading to reduction of ASCVD events. We propose to conduct a carotid MRI pilot study to demonstrate that adding alirocumab for 12 months, in comparison to pre-alirocumab therapy, in 30 subjects with documented carotid artery plaques who are not able to tolerate high intensity statin therapy and have LDL-C ≥70 mg/dl would improve atherosclerotic plaque characteristics by reducing Ktrans and LRNC size.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
35

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Beverly Hills, California, United States, 90211
        • Westside Medical Associates of Los Angeles

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Men and women ≥18 years of age.
  • Subjects with documented inability to consistently take or tolerate high intensity statin therapy and LDL-C ≥70 mg/dL.
  • Subjects are only able or allowed to take lower potency statin or low weekly dose of high potency statin due to concern of drug-to-drug interactions or lack of tolerance (pravastatin ≤140 mg, pitavastatin ≤14 mg, simvastatin ≤140 mg, atorvastatin ≤70 mg, or rosuvastatin ≤70 mg, weekly) or intolerant of all statin doses and with fasting LDL-C ≥100 mg/dL.
  • Subjects must have significant carotid artery plaque with maximum wall thickness ≥2 mm on ultrasound performed within twelve months of screening.
  • Subject must present with a LRNC on baseline MRI scan.
  • Subjects must show an adequate image quality for MRI analysis.
  • Medically stable.
  • Willing to participate and sign informed consent.

Exclusion Criteria:

  • Contraindication to MRI.
  • Have immediate plans for bilateral carotid endarterectomy.
  • Had received 2 or more doses of treatment with a PCSK9 inhibitor in the past 4 months.
  • GFR ≤45 mL/min/1.73 m2 prior to MRI scan.
  • Claustrophobia.
  • Pregnant women; breastfeeding women; men and women of childbearing potential who are unwilling or unable to use a highly effective method of contraception.
  • TIA or stroke within the preceding twelve months

  • Severe carotid stenosis in an asymptomatic patient defined as any one of the following:

    1. Greater than or equal to 70% luminal narrowing on any imaging modality
    2. Peak systolic velocity greater than or equal to 250 cm/second
    3. End diastolic velocity greater than or equal to 100 cm/second
    4. Systolic volume ratio greater than or equal to 3.5

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Open Label
All enrolled patients will receive open label Praluent (Alirocumab).
Drug: Alirocumab
Injectable prescription medicine called a PCSK9 inhibitor.
Other Names:
  • Praluent

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Changes in carotid atherosclerotic plaque characteristics as evidenced by effect on the volume transfer constant( Ktrans) and lipid-rich necrotic core (LRNC) size.
Time Frame: 52 weeks
To determine whether therapy with Alirocumab, compared to pre-treatment, will effectively improve carotid atherosclerotic plaque characteristics by reducing Ktrans and LRNC size. To achieve this goal, we will (a) enroll 30 subjects who are intolerant to high intensity statin therpay and only able to tolerate low potency statin or low weekly dose of high potency statin and have LDL-C ≥100 mg/dl; (b) initiate alirocumab at 150mg subcutaneously injection every 2 weeks; (c) perform carotid DCE-MRI scans at baseline, 3, 6 and 12 months; (d) perform quantitative analysis for vascular inflammation (Ktrans) and plaque LRNC volume and other plaque characteristics; (e) compare Ktrans and LRNC volume between pre- and post-alirocumab at 3, 6 and 12 months.
52 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Associations between reductions in atherogenic lipids and changes in atherosclerotic plaque characteristics
Time Frame: 52 weeks
To examine associations between reductions in atherogenic lipids (LDL-C, Lp(a), non-HDL-C) and changes in atherosclerotic plaque characteristics. To achieve this goal, we will (a) perform laboratory assessments of lipids, lipoproteins and apo-lipoproteins at baseline and during the study; (b) compare lipids, lipoproteins and apo-lipoproteins levels between pre- and post-alirocumab; (c) correlate reductions in atherogenic lipids with changes atherosclerotic plaque characteristics.
52 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Westside Medical Associates of Los Angeles

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Regeneron Pharmaceuticals
University of Washington

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Norman Lepor, MD, Westside Medical Associates of Los Angeles

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2016

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 1, 2019

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 1, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 30, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 9, 2016

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 14, 2016

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 26, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 24, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • WMALA-99-032

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings