<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/NCT04449198</url>
  </required_header>
  <id_info>
    <org_study_id>1595933</org_study_id>
    <nct_id>NCT04449198</nct_id>
  </id_info>
  <brief_title>Type 1 Diabetes, Endothelin, and Skeletal Muscle Mitochondrial Dysfunction: The Role of Sirtuin-1</brief_title>
  <acronym>T-St1M</acronym>
  <official_title>Type 1 Diabetes, Endothelin, and Skeletal Muscle Mitochondrial Dysfunction: The Role of Sirtuin-1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Augusta University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Augusta University</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The proposed study is designed to test the hypothesis that treatment of resveratrol for 12&#xD;
      weeks will improve both endothelin-B receptor (aim 1) and skeletal muscle mitochondrial&#xD;
      function (aim 2) in people with type 1 diabetes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Preliminary data from the investigators' laboratory demonstrate a negative relationship&#xD;
      between hemoglobin A1c (HbA1c) and ETBR function, supporting ETBR may be dysfunctional in the&#xD;
      presence of T1D. Using near infrared spectroscopy (NIRS) to non-invasively assess muscle&#xD;
      function, the investigators have also observed reduced skeletal muscle mitochondrial function&#xD;
      in people with T1D compared to healthy controls. In addition, reduced circulating Sirt1 is&#xD;
      associated with both ETBR and skeletal muscle mitochondrial dysfunction in the general&#xD;
      population. For the current application, the investigators propose to utilize intradermal&#xD;
      microdialysis and NIRS as unique, novel, and minimally invasive methods to investigate ETBR&#xD;
      and skeletal muscle mitochondrial function, respectively, in people with T1D. Accordingly,&#xD;
      the central hypothesis is that increasing circulating Sirt1 with oral supplementation of&#xD;
      resveratrol will improve both ETBR function and mitochondrial skeletal muscle function,&#xD;
      reducing overall CVD risk (Figure 1). The investigators will test this hypothesis with the&#xD;
      following specific aims:&#xD;
&#xD;
      Aim 1: To test the hypothesis that an increase in Sirt1 will improve ETBR function in people&#xD;
      with T1D. The investigators will evaluate ETBR function and circulating Sirt1 at baseline and&#xD;
      after a 12-week treatment of resveratrol or placebo. Based on preliminary data, the&#xD;
      investigators predict that people with T1D will have ETBR dysfunction compared to controls.&#xD;
      In addition, the investigators predict that increasing Sirt1 following resveratrol treatment&#xD;
      will improve ETBR function, whereas no change will occur with placebo.&#xD;
&#xD;
      Aim 2: To test the hypothesis that an increase in Sirt1 will improve skeletal muscle&#xD;
      mitochondrial function and lower HbA1c in people with T1D. A non-invasive assessment of&#xD;
      skeletal muscle function will be performed on people with T1D before and after 12-weeks of&#xD;
      treatment with resveratrol or placebo. Compared to controls, the investigators predict that&#xD;
      people with T1D will have skeletal muscle dysfunction. Following 12 weeks of resveratrol, the&#xD;
      investigators predict that the increase in circulating Sirt1 will improve skeletal muscle&#xD;
      function. Additionally, the investigators predict the improved skeletal muscle function will&#xD;
      contribute to a subsequent decrease in HbA1c in people with T1D.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 14, 2020</start_date>
  <completion_date type="Anticipated">July 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2025</primary_completion_date>
  <phase>Early Phase 1</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>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in AUC for ET-1 + BQ-123</measure>
    <time_frame>Measure taken at Baseline and post 12 weeks</time_frame>
    <description>Change in Area Under the Curve (AUC) for Cutaneous Vascular Conductance (CVC) in response to co-perfusion of ET-1 + BQ-123 at 12 weeks. Measured using intradermal microdialysis technique in conjunction with Laser Speckle Contrast Imaging (Moor FLPI-2) and beat-by-beat blood pressure monitoring (Finapres NOVA).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Skeletal Muscle Mitochondrial Function</measure>
    <time_frame>Measure taken at Baseline and post 12 weeks</time_frame>
    <description>Change in Skeletal Muscle Mitochondrial Function at 12 weeks. Measured using Near Infrared Spectroscopy (NIRS). Values are an index of phosphocreatine recovery expressed as a rate constant (min-1)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Percentage Flow-Mediated Dilation (FMD)</measure>
    <time_frame>Measure taken at Baseline and post 12 weeks</time_frame>
    <description>Change in Percentage FMD at 12 weeks. Measured via ultrasound in conjunction with edge detection software. Expressed as %</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pulse Wave Velocity (PWV)</measure>
    <time_frame>Measure taken at Baseline and post 12 weeks</time_frame>
    <description>Change in PWV at 12 weeks. Measured by Shygmocor Xcel in m/s.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Post Occlusive Reactive Hyperemia (PORH)</measure>
    <time_frame>Baseline and post 12 weeks</time_frame>
    <description>Change in PORH at 12 weeks. Measured by Laser Speckle Contrast Imager (Moor FLPI-2) in perfusion units (PU). Represents the maximal dilatory response in the microcirculation post 5 minute occlusion.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">24</enrollment>
  <condition>Type 1 Diabetes</condition>
  <arm_group>
    <arm_group_label>Individuals with type 1 diabetes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Individuals with type 1 diabetes will be randomly assigned to 1 of the 2 interventions (Resveratrol or placebo)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Healthy individuals who participate will receive no intervention and serve as controls.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Resveratrol</intervention_name>
    <description>500 mg of oral trans-resveratrol twice daily (in the morning and evening) for 12-weeks</description>
    <arm_group_label>Individuals with type 1 diabetes</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>placebo for 12 weeks</description>
    <arm_group_label>Individuals with type 1 diabetes</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and premenopausal women&#xD;
&#xD;
          -  All races&#xD;
&#xD;
          -  Clinical diagnosis of insulin-dependent type 1 diabetes (patients only)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Clinical diagnosis of hepatic, cardiovascular, or renal disease&#xD;
&#xD;
          -  Uncontrolled diabetes (HbA1C &gt;12%)&#xD;
&#xD;
          -  Diabetic complications (i.e. neuropathy)&#xD;
&#xD;
          -  Uncontrolled hypertension (&gt;140/90 mm Hg on therapy)&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Use of vasoactive medications&#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_contact>
    <last_name>Ryan A Harris, PhD, CEP</last_name>
    <phone>7067215998</phone>
    <email>ryharris@augusta.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jacob Looney, MS</last_name>
    <phone>7067215483</phone>
    <email>jlooney@augusta.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Augusta University/Georgia Prevention Institute/ Laboratory of Integrative and Exercise Physiology</name>
      <address>
        <city>Augusta</city>
        <state>Georgia</state>
        <zip>30912</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ryan Harris, PhD, CEP</last_name>
      <phone>706-721-5998</phone>
      <email>ryharris@augusta.edu</email>
    </contact>
    <contact_backup>
      <last_name>Casey Derella, BS</last_name>
      <phone>706-721-5483</phone>
      <email>cderella@augusta.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>June 11, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 26, 2020</study_first_posted>
  <last_update_submitted>July 18, 2023</last_update_submitted>
  <last_update_submitted_qc>July 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 20, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Augusta University</investigator_affiliation>
    <investigator_full_name>Ryan Harris</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>diabetes</keyword>
  <keyword>heart disease</keyword>
  <keyword>muscle function</keyword>
  <keyword>blood vessels</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</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/NCT04449198
org study id: 1595933
nct id: NCT04449198
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The proposed study is designed to test the hypothesis that treatment of resveratrol for 12
      weeks will improve both endothelin-B receptor (aim 1) and skeletal muscle mitochondrial
      function (aim 2) in people with type 1 diabetes.
Preliminary data from the investigators' laboratory demonstrate a negative relationship
      between hemoglobin A1c (HbA1c) and ETBR function, supporting ETBR may be dysfunctional in the
      presence of T1D. Using near infrared spectroscopy (NIRS) to non-invasively assess muscle
      function, the investigators have also observed reduced skeletal muscle mitochondrial function
      in people with T1D compared to healthy controls. In addition, reduced circulating Sirt1 is
      associated with both ETBR and skeletal muscle mitochondrial dysfunction in the general
      population. For the current application, the investigators propose to utilize intradermal
      microdialysis and NIRS as unique, novel, and minimally invasive methods to investigate ETBR
      and skeletal muscle mitochondrial function, respectively, in people with T1D. Accordingly,
      the central hypothesis is that increasing circulating Sirt1 with oral supplementation of
      resveratrol will improve both ETBR function and mitochondrial skeletal muscle function,
      reducing overall CVD risk (Figure 1). The investigators will test this hypothesis with the
      following specific aims:

      Aim 1: To test the hypothesis that an increase in Sirt1 will improve ETBR function in people
      with T1D. The investigators will evaluate ETBR function and circulating Sirt1 at baseline and
      after a 12-week treatment of resveratrol or placebo. Based on preliminary data, the
      investigators predict that people with T1D will have ETBR dysfunction compared to controls.
      In addition, the investigators predict that increasing Sirt1 following resveratrol treatment
      will improve ETBR function, whereas no change will occur with placebo.

      Aim 2: To test the hypothesis that an increase in Sirt1 will improve skeletal muscle
      mitochondrial function and lower HbA1c in people with T1D. A non-invasive assessment of
      skeletal muscle function will be performed on people with T1D before and after 12-weeks of
      treatment with resveratrol or placebo. Compared to controls, the investigators predict that
      people with T1D will have skeletal muscle dysfunction. Following 12 weeks of resveratrol, the
      investigators predict that the increase in circulating Sirt1 will improve skeletal muscle
      function. Additionally, the investigators predict the improved skeletal muscle function will
      contribute to a subsequent decrease in HbA1c in people with T1D.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change in AUC for ET-1 + BQ-123
time frame: Measure taken at Baseline and post 12 weeks
description: Change in Area Under the Curve (AUC) for Cutaneous Vascular Conductance (CVC) in response to co-perfusion of ET-1 + BQ-123 at 12 weeks. Measured using intradermal microdialysis technique in conjunction with Laser Speckle Contrast Imaging (Moor FLPI-2) and beat-by-beat blood pressure monitoring (Finapres NOVA).
measure: Skeletal Muscle Mitochondrial Function
time frame: Measure taken at Baseline and post 12 weeks
description: Change in Skeletal Muscle Mitochondrial Function at 12 weeks. Measured using Near Infrared Spectroscopy (NIRS). Values are an index of phosphocreatine recovery expressed as a rate constant (min-1)
measure: Change in Percentage Flow-Mediated Dilation (FMD)
time frame: Measure taken at Baseline and post 12 weeks
description: Change in Percentage FMD at 12 weeks. Measured via ultrasound in conjunction with edge detection software. Expressed as %
measure: Change in Pulse Wave Velocity (PWV)
time frame: Measure taken at Baseline and post 12 weeks
description: Change in PWV at 12 weeks. Measured by Shygmocor Xcel in m/s.
measure: Change in Post Occlusive Reactive Hyperemia (PORH)
time frame: Baseline and post 12 weeks
description: Change in PORH at 12 weeks. Measured by Laser Speckle Contrast Imager (Moor FLPI-2) in perfusion units (PU). Represents the maximal dilatory response in the microcirculation post 5 minute occlusion.
arm group label: Individuals with type 1 diabetes
arm group type: Experimental
description: Individuals with type 1 diabetes will be randomly assigned to 1 of the 2 interventions (Resveratrol or placebo)
arm group label: Healthy Controls
arm group type: No Intervention
description: Healthy individuals who participate will receive no intervention and serve as controls.
intervention type: Drug
intervention name: Resveratrol
description: 500 mg of oral trans-resveratrol twice daily (in the morning and evening) for 12-weeks
arm group label: Individuals with type 1 diabetes
intervention type: Other
intervention name: Placebo
description: placebo for 12 weeks
arm group label: Individuals with type 1 diabetes
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Ryan A Harris, PhD, CEP
phone: 7067215998
email: ryharris@augusta.edu
last name: Jacob Looney, MS
phone: 7067215483
email: jlooney@augusta.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Augusta University
investigator full name: Ryan Harris
investigator title: Associate Professor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Resveratrol