<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/NCT03762096</url>
  </required_header>
  <id_info>
    <org_study_id>1095584</org_study_id>
    <nct_id>NCT03762096</nct_id>
  </id_info>
  <brief_title>Short Interval Resveratrol Trial in Cardiovascular Surgery</brief_title>
  <acronym>SIRT-CVS</acronym>
  <official_title>Short Interval Resveratrol Trial in Cardiovascular Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MaineHealth</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>American Heart Association</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>MaineHealth</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Major Problem&#xD;
&#xD;
      People with diabetes have an increased risk of heart disease, heart failure, and death from a&#xD;
      cardiovascular cause. Diabetes prevents efficient metabolism of fuel, causes inflammation and&#xD;
      vascular disease that blocks normal blood flow, and inhibits the function of the heart after&#xD;
      injury. These changes make diabetics more susceptible to heart attacks and heart failure.&#xD;
&#xD;
      Resveratrol is found in grapes and red wine and has been shown to have beneficial effects in&#xD;
      diabetic patients. In previous studies the investigators have shown that resveratrol can&#xD;
      improve heart metabolism and function in pigs with diabetes and chronic lack of blood flow to&#xD;
      the heart.&#xD;
&#xD;
      Questions&#xD;
&#xD;
      The investigators believe resveratrol will help reverse the negative effects of diabetes on&#xD;
      the heart. The questions are: 1.How does the molecular machinery in the hearts of patients&#xD;
      with diabetes differ from patients without diabetes? 2.Will resveratrol have an effect on&#xD;
      heart metabolism, intracellular signaling, inflammation and blood vessel function? 3.Will&#xD;
      resveratrol improve the number and function of cardiac stem cells, cells involved in heart&#xD;
      repair? The investigators have been safely collecting tissue from the hearts of patients&#xD;
      undergoing heart surgery. Preliminary studies show the investigators can isolate and study&#xD;
      cells. The investigators have collected and assessed the function of endothelial cells, a&#xD;
      measure of vascular health and can measure the level of endothelial injury and have studied&#xD;
      the make-up of caveolae, structures on the cell membrane that are important for cell&#xD;
      signaling and are negatively impacted by diabetes. This study is a unique collaboration among&#xD;
      cardiologists, cardiac surgeons, and basic scientists.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with diabetes and metabolic diseases such as obesity, hypertension and dyslipidemia&#xD;
      have a myocardial environment that results in endothelial dysfunction, altered metabolism and&#xD;
      little potential for regeneration by intrinsic or extrinsically delivered therapies. Based&#xD;
      upon work in animal and cell culture models of human disease, caveolae, lipid rafts found on&#xD;
      the cell membrane of endothelial cells and myocytes, are important in cell signaling and&#xD;
      metabolism. A growing body of literature suggests that disruption of membrane lipid&#xD;
      microdomains in diabetes can lead to altered signaling that contributes to cardiovascular&#xD;
      pathology. One possible method to improve the &quot;endothelial health&quot; of the heart could involve&#xD;
      normalizing metabolic processes and decreasing signals that lead to inflammation and pathways&#xD;
      that lead to fibrosis in the myocardium. This presents an opportunity to improve outcomes in&#xD;
      our diabetic patients and improve the success of future therapies aimed at improving&#xD;
      endothelial function.&#xD;
&#xD;
      Resveratrol, a polyphenol found in abundance in red wine, activates sirtuin 1 (SIRT1), an&#xD;
      NAD+-dependent deacetylase, which influences a diverse array of metabolic pathways. Studies&#xD;
      in cultured cells, small animal models, and humans demonstrate that SIRT1 is involved in&#xD;
      endothelial function, mitochondrial biogenesis, insulin production, inflammation, and glucose&#xD;
      and lipid homeostasis. These processes are often dysfunctional in patients with diabetes and&#xD;
      other metabolic diseases.&#xD;
&#xD;
      The central hypothesis of this proposal is that molecular pathology of diabetes on cardiac&#xD;
      endothelium can be corrected with orally supplemented resveratrol.&#xD;
&#xD;
      The investigators propose to test this hypothesis in by first assessing endothelial function,&#xD;
      lipidomic signatures, and cell signaling in patients with and without diabetes mellitus&#xD;
      undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). The&#xD;
      second Aim of this proposal is a pilot placebo-controlled, double-blind clinical trial that&#xD;
      will assess the effects of supplemental resveratrol in diabetic patients undergoing CABG with&#xD;
      CPB. The goal will be to better understand the influence of resveratrol on key molecular&#xD;
      signals that determine endothelial function, calveolar makeup and function, as well as&#xD;
      cytoprotective signaling and responses in the heart.&#xD;
&#xD;
      The Specific Aims of this proposal are to:&#xD;
&#xD;
      Aim 1: Define the molecular pathology of diabetes on cardiac cells and tissues in&#xD;
      non-diabetic and diabetic patients undergoing surgical revascularization. We will assess the&#xD;
      effects of DM on endothelial function and damage, lipidomics, caveolar expression, disrupted&#xD;
      receptor expression and neuregulin signaling.&#xD;
&#xD;
      Aim 2: Determine the effect of resveratrol on the microvascular function of diabetic patients&#xD;
      undergoing surgical revascularization. Through a pilot randomized placebo-controlled clinical&#xD;
      trial, the investigators will evaluate the effect of resveratrol on endothelial damage at the&#xD;
      time of cardiopulmonary bypass, endothelial function, and cell signaling.&#xD;
&#xD;
      This study will further our understanding of how resveratrol impacts patients in a controlled&#xD;
      setting, and will allow for a thorough and complete investigation of how the supplement&#xD;
      affects this patient population clinically and on a molecular level. The data will inform the&#xD;
      development of larger studies examining the benefits of resveratrol in diabetes and metabolic&#xD;
      syndrome. Finally, the investigators successful completion of this trial will inform the&#xD;
      study of other therapeutics where direct myocardial effects are being considered.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 6, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Actual">April 16, 2021</primary_completion_date>
  <phase>N/A</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>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in endothelial function</measure>
    <time_frame>6 weeks</time_frame>
    <description>Serum levels of nitric oxide (ELISA assay)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in endothelial function</measure>
    <time_frame>14 days</time_frame>
    <description>Nitric oxide synthase levels in heart tissue (Western blot assay)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Effects of resveratrol on caveolar function</measure>
    <time_frame>14 days</time_frame>
    <description>Lipidomic changes in cell membranes (Mass spectrometry)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects of resveratrol on molecular signaling</measure>
    <time_frame>14 days</time_frame>
    <description>Serum and tissue levels of pathways associated with glucose metabolism (Western blot assay)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>Coronary Artery Disease</condition>
  <arm_group>
    <arm_group_label>Resveratrol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Trans-resveratrol</intervention_name>
    <description>1 gram, twice a day by mouth Transmax (Biotivia)</description>
    <arm_group_label>Resveratrol</arm_group_label>
    <other_name>resveratrol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients (age &gt;18 years)&#xD;
&#xD;
          -  Type 2 diabetes (controlled by either oral agents or insulin)&#xD;
&#xD;
          -  Coronary artery disease referred for elective CABG with CPB&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known decompensated congestive heart failure or systolic heart failure with an&#xD;
             ejection fraction &lt; 45% at the time of evaluation&#xD;
&#xD;
          -  Liver Function Tests (LFT) greater than 2 times normal&#xD;
&#xD;
          -  Renal dysfunction (GFR less than 60 mL/min)&#xD;
&#xD;
          -  Abnormal coagulation profile (PT/PTT and INR)&#xD;
&#xD;
          -  Alcohol consumption more than 3 grams (equivalent to 2.5 glasses of wine) daily&#xD;
&#xD;
          -  Positive HIV, Hepatitis B or C testing&#xD;
&#xD;
          -  Severe ventricular arrhythmias&#xD;
&#xD;
          -  Significant hypotension (SBP &lt; 90 mmHg) at the time of enrollment&#xD;
&#xD;
          -  Patients who are pregnant&#xD;
&#xD;
          -  Known malignancy other than non-melanoma skin cancers&#xD;
&#xD;
          -  Expected survival less than one year.&#xD;
&#xD;
          -  Allergy or intolerance to the ingredients of the supplement or the placebo&#xD;
&#xD;
          -  Inability to comply with the study requirements.&#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>Douglas Sawyer</last_name>
    <role>Principal Investigator</role>
    <affiliation>Maine Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Maine Medical Center</name>
      <address>
        <city>Portland</city>
        <state>Maine</state>
        <zip>04102</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>November 30, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <last_update_submitted>March 24, 2023</last_update_submitted>
  <last_update_submitted_qc>March 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>MaineHealth</investigator_affiliation>
    <investigator_full_name>Douglas B. Sawyer</investigator_full_name>
    <investigator_title>Chief Academic Officer</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery 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>Resveratrol</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03762096
org study id: 1095584
nct id: NCT03762096
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Major Problem

      People with diabetes have an increased risk of heart disease, heart failure, and death from a
      cardiovascular cause. Diabetes prevents efficient metabolism of fuel, causes inflammation and
      vascular disease that blocks normal blood flow, and inhibits the function of the heart after
      injury. These changes make diabetics more susceptible to heart attacks and heart failure.

      Resveratrol is found in grapes and red wine and has been shown to have beneficial effects in
      diabetic patients. In previous studies the investigators have shown that resveratrol can
      improve heart metabolism and function in pigs with diabetes and chronic lack of blood flow to
      the heart.

      Questions

      The investigators believe resveratrol will help reverse the negative effects of diabetes on
      the heart. The questions are: 1.How does the molecular machinery in the hearts of patients
      with diabetes differ from patients without diabetes? 2.Will resveratrol have an effect on
      heart metabolism, intracellular signaling, inflammation and blood vessel function? 3.Will
      resveratrol improve the number and function of cardiac stem cells, cells involved in heart
      repair? The investigators have been safely collecting tissue from the hearts of patients
      undergoing heart surgery. Preliminary studies show the investigators can isolate and study
      cells. The investigators have collected and assessed the function of endothelial cells, a
      measure of vascular health and can measure the level of endothelial injury and have studied
      the make-up of caveolae, structures on the cell membrane that are important for cell
      signaling and are negatively impacted by diabetes. This study is a unique collaboration among
      cardiologists, cardiac surgeons, and basic scientists.
Patients with diabetes and metabolic diseases such as obesity, hypertension and dyslipidemia
      have a myocardial environment that results in endothelial dysfunction, altered metabolism and
      little potential for regeneration by intrinsic or extrinsically delivered therapies. Based
      upon work in animal and cell culture models of human disease, caveolae, lipid rafts found on
      the cell membrane of endothelial cells and myocytes, are important in cell signaling and
      metabolism. A growing body of literature suggests that disruption of membrane lipid
      microdomains in diabetes can lead to altered signaling that contributes to cardiovascular
      pathology. One possible method to improve the "endothelial health" of the heart could involve
      normalizing metabolic processes and decreasing signals that lead to inflammation and pathways
      that lead to fibrosis in the myocardium. This presents an opportunity to improve outcomes in
      our diabetic patients and improve the success of future therapies aimed at improving
      endothelial function.

      Resveratrol, a polyphenol found in abundance in red wine, activates sirtuin 1 (SIRT1), an
      NAD+-dependent deacetylase, which influences a diverse array of metabolic pathways. Studies
      in cultured cells, small animal models, and humans demonstrate that SIRT1 is involved in
      endothelial function, mitochondrial biogenesis, insulin production, inflammation, and glucose
      and lipid homeostasis. These processes are often dysfunctional in patients with diabetes and
      other metabolic diseases.

      The central hypothesis of this proposal is that molecular pathology of diabetes on cardiac
      endothelium can be corrected with orally supplemented resveratrol.

      The investigators propose to test this hypothesis in by first assessing endothelial function,
      lipidomic signatures, and cell signaling in patients with and without diabetes mellitus
      undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). The
      second Aim of this proposal is a pilot placebo-controlled, double-blind clinical trial that
      will assess the effects of supplemental resveratrol in diabetic patients undergoing CABG with
      CPB. The goal will be to better understand the influence of resveratrol on key molecular
      signals that determine endothelial function, calveolar makeup and function, as well as
      cytoprotective signaling and responses in the heart.

      The Specific Aims of this proposal are to:

      Aim 1: Define the molecular pathology of diabetes on cardiac cells and tissues in
      non-diabetic and diabetic patients undergoing surgical revascularization. We will assess the
      effects of DM on endothelial function and damage, lipidomics, caveolar expression, disrupted
      receptor expression and neuregulin signaling.

      Aim 2: Determine the effect of resveratrol on the microvascular function of diabetic patients
      undergoing surgical revascularization. Through a pilot randomized placebo-controlled clinical
      trial, the investigators will evaluate the effect of resveratrol on endothelial damage at the
      time of cardiopulmonary bypass, endothelial function, and cell signaling.

      This study will further our understanding of how resveratrol impacts patients in a controlled
      setting, and will allow for a thorough and complete investigation of how the supplement
      affects this patient population clinically and on a molecular level. The data will inform the
      development of larger studies examining the benefits of resveratrol in diabetes and metabolic
      syndrome. Finally, the investigators successful completion of this trial will inform the
      study of other therapeutics where direct myocardial effects are being considered.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in endothelial function
time frame: 6 weeks
description: Serum levels of nitric oxide (ELISA assay)
measure: Change in endothelial function
time frame: 14 days
description: Nitric oxide synthase levels in heart tissue (Western blot assay)
measure: Effects of resveratrol on caveolar function
time frame: 14 days
description: Lipidomic changes in cell membranes (Mass spectrometry)
measure: Effects of resveratrol on molecular signaling
time frame: 14 days
description: Serum and tissue levels of pathways associated with glucose metabolism (Western blot assay)
arm group label: Resveratrol
arm group type: Experimental
arm group label: Placebo
arm group type: Placebo Comparator
intervention type: Dietary Supplement
intervention name: Trans-resveratrol
description: 1 gram, twice a day by mouth Transmax (Biotivia)
arm group label: Resveratrol
other name: resveratrol
intervention type: Dietary Supplement
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Douglas Sawyer
role: Principal Investigator
affiliation: Maine Health
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: MaineHealth
investigator full name: Douglas B. Sawyer
investigator title: Chief Academic Officer
mesh term: Coronary Artery Disease
mesh term: Diabetes Mellitus, Type 2
mesh term: Resveratrol