<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02992301</url>
  </required_header>
  <id_info>
    <org_study_id>WMALA-99-032</org_study_id>
    <nct_id>NCT02992301</nct_id>
  </id_info>
  <brief_title>Assessment of Atherosclerotic Plaque Characteristics Change by DCE-MRI With Alirocumab</brief_title>
  <official_title>Assessment of Atherosclerotic Plaque Characteristics Change by DCE-MRI With Alirocumab - a Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Westside Medical Associates of Los Angeles</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Regeneron Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Westside Medical Associates of Los Angeles</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aim 1: To determine whether therapy with Alirocumab, compared to pre-treatment, will&#xD;
      effectively improve carotid atherosclerotic plaque characteristics by reducing Ktrans and&#xD;
      LRNC size. To achieve this goal, we will (a) enroll 30 subjects who are intolerant to high&#xD;
      intensity statin therapy and only able to tolerate low potency statin or low weekly dose of&#xD;
      high potency statin and have LDL-C ≥70 mg/dl; (b) initiate alirocumab at 150mg subcutaneously&#xD;
      injection every 2 weeks; (c) perform carotid DCE-MRI scans at baseline, 3, 6 and 12 months;&#xD;
      (d) perform quantitative analysis for vascular inflammation and plaque LRNC volume and other&#xD;
      plaque characteristics; (e) compare vascular inflammation and LRNC volume between pre- and&#xD;
      post-alirocumab at 3, 6 and 12 months.&#xD;
&#xD;
      Aim 2: To examine associations between reductions in atherogenic lipids (LDL-C, Lp(a),&#xD;
      non-HDL-C) and changes in atherosclerotic plaque characteristics. To achieve this goal, we&#xD;
      will (a) perform laboratory assessments of lipids, lipoproteins and apo-lipoproteins at&#xD;
      baseline and during the study; (b) compare lipids, lipoproteins and apo-lipoproteins levels&#xD;
      between pre- and post-alirocumab; (c) correlate reductions in atherogenic lipids with changes&#xD;
      atherosclerotic plaque characteristics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute ischemic events caused by atherosclerosis cardiovascular disease (ASCVD) are primarily&#xD;
      due to plaque rupture/erosion determined by plaque morphologic characteristics, local&#xD;
      composition and inflammation, which can be directly assessed using magnetic resonance imaging&#xD;
      (MRI). Prospective carotid MRI studies have demonstrated: (1) plaques with thin or ruptured&#xD;
      cap, intraplaque hemorrhage (IPH), neovascularization, or larger lipid-rich necrotic core&#xD;
      (LRNC) are strongly associated with occurrence of cerebrovascular and coronary events, (2)&#xD;
      increased LRNC size is significantly associated with increased risk for systemic ASCVD events&#xD;
      after adjusting for LDL-C or Non-HDL-C levels, (3) increased permeability of adventitial vasa&#xD;
      vasorum is associated with presence of IPH which increases plaque burden and LRNC progression&#xD;
      that appears to be resistant to conventional doses of statins, (4) intensive lipid therapy&#xD;
      decreases carotid LRNC and vascular inflammation, (5) multicenter carotid studies can be&#xD;
      conducted with good reproducibility and feasibility.&#xD;
&#xD;
      Unlike previous clinical trials evaluating carotid artery disease using ultrasound based&#xD;
      technology that showed a weak relationship to systemic and coronary vascular events, recent&#xD;
      studies have demonstrated predictive value of carotid plaque tissue characteristics for&#xD;
      subsequent systemic ASCVD events including coronary events. Hellings and colleagues found&#xD;
      that carotid plaque composition by histology in 818 patients who underwent endarterectomy is&#xD;
      an independent predictor of future cardiovascular events during long-term post-operative&#xD;
      follow-up. Specifically, those with carotid IPH and increased neovascularization were at&#xD;
      significantly higher risk for ASCVD events. The Atherosclerosis Risk in Communities study&#xD;
      investigators reported that carotid LRNC (HR=1.9, p=0.014) and minimum cap thickness&#xD;
      (HR=0.67, p=0.03), as identified by MRI, were significantly associated with development of&#xD;
      ASCVD including coronary events after adjusting for all clinical risk factors, treatment&#xD;
      variables and biomarkers. The carotid MRI sub-study in AIM-HIGH showed that higher Lp(a)&#xD;
      levels are associated with high-risk plaque features which are prevalent in subjects with&#xD;
      established vascular disease and &quot;well-controlled&quot; LDL-C and blood pressure. Thin or ruptured&#xD;
      cap and a larger LRNC are predictive of systemic ASCVD events that include 83% (15/18) of the&#xD;
      coronary events in AIM-HIGH, meanwhile, none of the clinical risk factors and lipids were&#xD;
      predictive of future events.&#xD;
&#xD;
      Alirocumab has shown substantial lowering in LDL-C, non-HDL-C and Lp(a), with or without&#xD;
      concomitant statin treatment [43]. It has the potential to be a therapy that can improve&#xD;
      plaque characteristics leading to reduction of ASCVD events. We propose to conduct a carotid&#xD;
      MRI pilot study to demonstrate that adding alirocumab for 12 months, in comparison to&#xD;
      pre-alirocumab therapy, in 30 subjects with documented carotid artery plaques who are not&#xD;
      able to tolerate high intensity statin therapy and have LDL-C ≥70 mg/dl would improve&#xD;
      atherosclerotic plaque characteristics by reducing Ktrans and LRNC size.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">November 2016</start_date>
  <completion_date type="Anticipated">November 2019</completion_date>
  <primary_completion_date type="Anticipated">November 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in carotid atherosclerotic plaque characteristics as evidenced by effect on the volume transfer constant( Ktrans) and lipid-rich necrotic core (LRNC) size.</measure>
    <time_frame>52 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Associations between reductions in atherogenic lipids and changes in atherosclerotic plaque characteristics</measure>
    <time_frame>52 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Atherosclerosis</condition>
  <condition>Hyperlipidemia</condition>
  <arm_group>
    <arm_group_label>Open Label</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All enrolled patients will receive open label Praluent (Alirocumab).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alirocumab</intervention_name>
    <description>Injectable prescription medicine called a PCSK9 inhibitor.</description>
    <arm_group_label>Open Label</arm_group_label>
    <other_name>Praluent</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women ≥18 years of age.&#xD;
&#xD;
          -  Subjects with documented inability to consistently take or tolerate high intensity&#xD;
             statin therapy and LDL-C ≥70 mg/dL.&#xD;
&#xD;
          -  Subjects are only able or allowed to take lower potency statin or low weekly dose of&#xD;
             high potency statin due to concern of drug-to-drug interactions or lack of tolerance&#xD;
             (pravastatin ≤140 mg, pitavastatin ≤14 mg, simvastatin ≤140 mg, atorvastatin ≤70 mg,&#xD;
             or rosuvastatin ≤70 mg, weekly) or intolerant of all statin doses and with fasting&#xD;
             LDL-C ≥100 mg/dL.&#xD;
&#xD;
          -  Subjects must have significant carotid artery plaque with maximum wall thickness ≥2 mm&#xD;
             on ultrasound performed within twelve months of screening.&#xD;
&#xD;
          -  Subject must present with a LRNC on baseline MRI scan.&#xD;
&#xD;
          -  Subjects must show an adequate image quality for MRI analysis.&#xD;
&#xD;
          -  Medically stable.&#xD;
&#xD;
          -  Willing to participate and sign informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to MRI.&#xD;
&#xD;
          -  Have immediate plans for bilateral carotid endarterectomy.&#xD;
&#xD;
          -  Had received 2 or more doses of treatment with a PCSK9 inhibitor in the past 4 months.&#xD;
&#xD;
          -  GFR ≤45 mL/min/1.73 m2 prior to MRI scan.&#xD;
&#xD;
          -  Claustrophobia.&#xD;
&#xD;
          -  Pregnant women; breastfeeding women; men and women of childbearing potential who are&#xD;
             unwilling or unable to use a highly effective method of contraception.&#xD;
&#xD;
          -  TIA or stroke within the preceding twelve months&#xD;
&#xD;
          -  Severe carotid stenosis in an asymptomatic patient defined as any one of the&#xD;
             following:&#xD;
&#xD;
               1. Greater than or equal to 70% luminal narrowing on any imaging modality&#xD;
&#xD;
               2. Peak systolic velocity greater than or equal to 250 cm/second&#xD;
&#xD;
               3. End diastolic velocity greater than or equal to 100 cm/second&#xD;
&#xD;
               4. Systolic volume ratio greater than or equal to 3.5&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Norman Lepor, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Westside Medical Associates of Los Angeles</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Westside Medical Associates of Los Angeles</name>
      <address>
        <city>Beverly Hills</city>
        <state>California</state>
        <zip>90211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>November 30, 2016</study_first_submitted>
  <study_first_submitted_qc>December 9, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <last_update_submitted>April 24, 2019</last_update_submitted>
  <last_update_submitted_qc>April 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Westside Medical Associates of Los Angeles</investigator_affiliation>
    <investigator_full_name>Norman Lepor, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atherosclerosis</mesh_term>
    <mesh_term>Hyperlipidemias</mesh_term>
    <mesh_term>Plaque, Atherosclerotic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alirocumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02992301
org study id: WMALA-99-032
nct id: NCT02992301
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 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
description: 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.
measure: Associations between reductions in atherogenic lipids and changes in atherosclerotic plaque characteristics
time frame: 52 weeks
description: 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.
arm group label: Open Label
arm group type: Experimental
description: All enrolled patients will receive open label Praluent (Alirocumab).
intervention type: Drug
intervention name: Alirocumab
description: Injectable prescription medicine called a PCSK9 inhibitor.
arm group label: Open Label
other name: Praluent
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Norman Lepor, MD
role: Principal Investigator
affiliation: Westside Medical Associates of Los Angeles
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Westside Medical Associates of Los Angeles
investigator full name: Norman Lepor, MD
investigator title: Principal Investigator
mesh term: Atherosclerosis
mesh term: Hyperlipidemias
mesh term: Plaque, Atherosclerotic
mesh term: Alirocumab
sharing ipd: Undecided