<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/NCT03260881</url>
  </required_header>
  <id_info>
    <org_study_id>20170684</org_study_id>
    <nct_id>NCT03260881</nct_id>
  </id_info>
  <brief_title>Liraglutide Effects on Epicardial Fat Inflammatory Genes</brief_title>
  <official_title>Effects of Liraglutide on Epicardial Fat Pro-Inflammatory Genes in Type 2 Diabetes and Coronary Artery Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Miami</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novo Nordisk A/S</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Miami</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Epicardial adipose tissue (EAT) is the visceral fat of the heart. EAT could locally affect&#xD;
      the coronary arteries through local secretion of pro-inflammatory cytokines. EAT plays a role&#xD;
      in the development of the coronary artery disease (CAD). EAT is a highly enriched with genes&#xD;
      involved in inflammation. Given its rapid metabolism and simple measurability, as first&#xD;
      developed by Iacobellis, EAT serves as target for medications targeting the fat.&#xD;
      Glucagon-like peptide-1 agonists (GLP-1A) are anti-diabetic medications with recently&#xD;
      suggested cardio-protective properties. Liraglutide, a GLP-1A, has recently shown to reduce&#xD;
      the cardiovascular risk. Iacobellis'group found that EAT thickness decreased by an&#xD;
      unprecedented 36% after 12 weeks of treatment with liraglutide. Remarkably, Iacobellis'group&#xD;
      found for the first time that human EAT express GLP-1 Receptor (GLP-1R). GLP-1A effects may&#xD;
      be therefore visceral fat specific and target EAT. Based on these preliminary data, we&#xD;
      hypothesize that treatment with liraglutide will significantly and rapidly reduce EAT&#xD;
      inflammation. Decreased EAT inflammation can reduce the burden of the coronary plaques. We&#xD;
      will test our hypothesis in a 12-week randomized, double-blind, placebo-controlled,&#xD;
      interventional study in 40 patients with type 2 diabetes mellitus (T2DM), and CAD, with an&#xD;
      acceptable glycemic control on their current diabetes regimen who require elective coronary&#xD;
      artery bypass graft (CABG) regardless of their participation in the study. A minimum time&#xD;
      frame of 4-week treatment will be considered to detect significant changes in the study&#xD;
      endpoints. Inclusion criteria for body fat markers will rule out the confounding effect of&#xD;
      different body fast distribution at baseline. Study subjects will be randomized in two groups&#xD;
      of 20 patients to receive additional liraglutide or to remain on current treatment/ placebo&#xD;
      prior to cardiac surgery. CAD subjects not allocated to liraglutide will be started on a&#xD;
      supervised low calorie diet (LCD) to achieve approximately 5% of weight loss after from a&#xD;
      minimum of 4 weeks up to 12 weeks to avoid the confounding effect of weight loss on the study&#xD;
      outcomes. EAT samples will be collected during cardiac surgery and processed for analysis of&#xD;
      mRNA and protein expression of EAT inflammatory genes such as Tumor Necrosis Factor-alpha&#xD;
      (TNF-α) and Interleukin 6 (IL-6), and GLP-1R.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 1, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Double-blind, parallel group, placebo controlled study.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>This will be a double-blind, parallel group, placebo controlled study. The method of allocation generation will be a computerized random-number generator. The sequence will be generated by the process of restricted randomization. Computer-based randomization process will be managed by the UM Research pharmacy.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>EAT inflammation</measure>
    <time_frame>from a minimum of 4 weeks up to 12 weeks</time_frame>
    <description>EAT inflammation as measured by mRNA and protein expression of Tumor Necrosis Factor (TNF)-Alpha and Interleukin (IL)-6 from blood sample.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>EAT thickness</measure>
    <time_frame>from a minimum of 4 weeks up to 12 weeks</time_frame>
    <description>EAT thickness as measured via ultrasound</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SAT inflammation</measure>
    <time_frame>from a minimum of 4 weeks up to 12 weeks</time_frame>
    <description>Subcutaneous Adipose Tissue (SAT) inflammation as measured by mRNA and protein expression of Tumor Necrosis Factor (TNF)-Alpha and Interleukin (IL)-6 from blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EAT GLP-1R</measure>
    <time_frame>from a minimum of 4 weeks up to 12 weeks</time_frame>
    <description>EAT Glucagon-like Peptide-1 Receptor (GLP-1R) mRNA and protein expression from blood sample</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Type2 Diabetes</condition>
  <condition>Coronary Artery Disease</condition>
  <arm_group>
    <arm_group_label>L-group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>• L-group will be started on liraglutide. Liraglutide will be started and administered for from a minimum of 4 weeks up to 12 weeks prior to CABG with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). The dose of 1.8 mg daily will be maintained until the end of the 12-week study. Other and current diabetes treatment will be continued</description>
  </arm_group>
  <arm_group>
    <arm_group_label>D-group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo will be administered in addition to current treatment prior to the CABG with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). D-group will be started on a supervised low calorie diet (LCD) to achieve approximately 5% of weight loss after from a minimum of 4 weeks up to 12 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liraglutide Pen Injector [Victoza]</intervention_name>
    <description>Study subjects will be randomized in two groups of 20 patients to receive additional liraglutide, (L-group) or to remain on current treatment or placebo (D-group).</description>
    <arm_group_label>L-group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>matching liraglutide-placebo pre-filled pens</intervention_name>
    <description>Study subjects will be randomized in two groups of 20 patients to receive additional liraglutide, (L-group) or to remain on current treatment or placebo (D-group).</description>
    <arm_group_label>D-group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  T2DM as defined by American Diabetes Association (ADA) criteria&#xD;
&#xD;
          -  Adult patients with T2DM who are indicated to receive liraglutide, not as first-line&#xD;
             therapy, in addition to diet and exercise to improve glycemic control&#xD;
&#xD;
          -  Hemoglobin A1c (HbA1c) ≤ 9%&#xD;
&#xD;
          -  Age ≥ 18 years old&#xD;
&#xD;
          -  Body mass index (BMI) ≥ 27 Kg/m2 and/or waist circumference ≥ 102 cm (40 inches) in&#xD;
             men and 88 cm (35 inches) in women, respectively.&#xD;
&#xD;
          -  Clinically and angiographically stable CAD who requires CABG as part of the standard&#xD;
             medical care, as CAD does not represent a contraindication for using liraglutide. The&#xD;
             stability of the CAD further warranties that study patients will not be exposed to&#xD;
             higher risk by using liraglutide&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with a personal or family history of medullary thyroid carcinoma or patients&#xD;
             with Multiple Endocrine Neoplasia syndrome type 2&#xD;
&#xD;
          -  Patients with a prior serious hypersensitivity reaction to liraglutide&#xD;
&#xD;
          -  Other contra-indications to liraglutide in accordance with risks and safety&#xD;
             information included in the latest updated prescribing information&#xD;
&#xD;
          -  Type 1 diabetes, as defined by ADA criteria&#xD;
&#xD;
          -  Current use of other GLP-1A, dipeptidyl peptidase 4 (DPP4) or Sodium Glucose&#xD;
             transporters 2 (SGLT2) inhibitors, thiazolidinediones (TZDs), pramlintide and fixed&#xD;
             prandial insulin.&#xD;
&#xD;
          -  Patients with unstable CAD, assessed by the Cardiology team and defined as new onset&#xD;
             angina, rest angina, rapidly increasing or crescendo angina&#xD;
&#xD;
          -  History of diabetic ketoacidosis, pancreas or beta-cell transplantation, or diabetes&#xD;
             secondary to pancreatitis or pancreatectomy; acute or chronic infective diseases,&#xD;
             cancer or chemotherapy, history of pulmonary, renal or liver diseases, and drug abuse&#xD;
&#xD;
          -  Patients with chronic and acute inflammatory conditions such as sepsis, rheumatoid&#xD;
             arthritis, ectopic dermatitis, asthma, ulcerative colitis.&#xD;
&#xD;
          -  Current use of systemic corticosteroids in the 3 months prior this study.&#xD;
&#xD;
          -  Pregnant or breast-feeding women&#xD;
&#xD;
          -  Females of childbearing potential who are not using adequate contraceptive methods (as&#xD;
             required by local law or practice)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gianluca Iacobellis, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Miami</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Gianluca Iacobellis, MD PhD</last_name>
    <phone>3052433636</phone>
    <email>giacobellis@med.miami.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gianluca Iacobellis, MD PhD</last_name>
      <phone>305-243-3636</phone>
      <email>giacobellis@med.miami.edu</email>
    </contact>
    <investigator>
      <last_name>Gianluca Iacobellis, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 24, 2017</study_first_posted>
  <last_update_submitted>November 4, 2022</last_update_submitted>
  <last_update_submitted_qc>November 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Miami</investigator_affiliation>
    <investigator_full_name>Gianluca Iacobellis</investigator_full_name>
    <investigator_title>Professor of Clinical</investigator_title>
  </responsible_party>
  <keyword>Epicardial Fat</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liraglutide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03260881
org study id: 20170684
nct id: NCT03260881
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Epicardial adipose tissue (EAT) is the visceral fat of the heart. EAT could locally affect
      the coronary arteries through local secretion of pro-inflammatory cytokines. EAT plays a role
      in the development of the coronary artery disease (CAD). EAT is a highly enriched with genes
      involved in inflammation. Given its rapid metabolism and simple measurability, as first
      developed by Iacobellis, EAT serves as target for medications targeting the fat.
      Glucagon-like peptide-1 agonists (GLP-1A) are anti-diabetic medications with recently
      suggested cardio-protective properties. Liraglutide, a GLP-1A, has recently shown to reduce
      the cardiovascular risk. Iacobellis'group found that EAT thickness decreased by an
      unprecedented 36% after 12 weeks of treatment with liraglutide. Remarkably, Iacobellis'group
      found for the first time that human EAT express GLP-1 Receptor (GLP-1R). GLP-1A effects may
      be therefore visceral fat specific and target EAT. Based on these preliminary data, we
      hypothesize that treatment with liraglutide will significantly and rapidly reduce EAT
      inflammation. Decreased EAT inflammation can reduce the burden of the coronary plaques. We
      will test our hypothesis in a 12-week randomized, double-blind, placebo-controlled,
      interventional study in 40 patients with type 2 diabetes mellitus (T2DM), and CAD, with an
      acceptable glycemic control on their current diabetes regimen who require elective coronary
      artery bypass graft (CABG) regardless of their participation in the study. A minimum time
      frame of 4-week treatment will be considered to detect significant changes in the study
      endpoints. Inclusion criteria for body fat markers will rule out the confounding effect of
      different body fast distribution at baseline. Study subjects will be randomized in two groups
      of 20 patients to receive additional liraglutide or to remain on current treatment/ placebo
      prior to cardiac surgery. CAD subjects not allocated to liraglutide will be started on a
      supervised low calorie diet (LCD) to achieve approximately 5% of weight loss after from a
      minimum of 4 weeks up to 12 weeks to avoid the confounding effect of weight loss on the study
      outcomes. EAT samples will be collected during cardiac surgery and processed for analysis of
      mRNA and protein expression of EAT inflammatory genes such as Tumor Necrosis Factor-alpha
      (TNF-α) and Interleukin 6 (IL-6), and GLP-1R.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Double-blind, parallel group, placebo controlled study.
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: This will be a double-blind, parallel group, placebo controlled study. The method of allocation generation will be a computerized random-number generator. The sequence will be generated by the process of restricted randomization. Computer-based randomization process will be managed by the UM Research pharmacy.
measure: EAT inflammation
time frame: from a minimum of 4 weeks up to 12 weeks
description: EAT inflammation as measured by mRNA and protein expression of Tumor Necrosis Factor (TNF)-Alpha and Interleukin (IL)-6 from blood sample.
measure: EAT thickness
time frame: from a minimum of 4 weeks up to 12 weeks
description: EAT thickness as measured via ultrasound
measure: SAT inflammation
time frame: from a minimum of 4 weeks up to 12 weeks
description: Subcutaneous Adipose Tissue (SAT) inflammation as measured by mRNA and protein expression of Tumor Necrosis Factor (TNF)-Alpha and Interleukin (IL)-6 from blood sample
measure: EAT GLP-1R
time frame: from a minimum of 4 weeks up to 12 weeks
description: EAT Glucagon-like Peptide-1 Receptor (GLP-1R) mRNA and protein expression from blood sample
arm group label: L-group
arm group type: Active Comparator
description: • L-group will be started on liraglutide. Liraglutide will be started and administered for from a minimum of 4 weeks up to 12 weeks prior to CABG with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). The dose of 1.8 mg daily will be maintained until the end of the 12-week study. Other and current diabetes treatment will be continued
arm group label: D-group
arm group type: Placebo Comparator
description: placebo will be administered in addition to current treatment prior to the CABG with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). D-group will be started on a supervised low calorie diet (LCD) to achieve approximately 5% of weight loss after from a minimum of 4 weeks up to 12 weeks.
intervention type: Drug
intervention name: Liraglutide Pen Injector [Victoza]
description: Study subjects will be randomized in two groups of 20 patients to receive additional liraglutide, (L-group) or to remain on current treatment or placebo (D-group).
arm group label: L-group
intervention type: Drug
intervention name: matching liraglutide-placebo pre-filled pens
description: Study subjects will be randomized in two groups of 20 patients to receive additional liraglutide, (L-group) or to remain on current treatment or placebo (D-group).
arm group label: D-group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gianluca Iacobellis, MD PhD
role: Principal Investigator
affiliation: University of Miami
last name: Gianluca Iacobellis, MD PhD
phone: 3052433636
email: giacobellis@med.miami.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Miami
investigator full name: Gianluca Iacobellis
investigator title: Professor of Clinical
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Diabetes Mellitus, Type 2
mesh term: Liraglutide
sharing ipd: No