<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/NCT04442451</url>
  </required_header>
  <id_info>
    <org_study_id>HR-2402</org_study_id>
    <nct_id>NCT04442451</nct_id>
  </id_info>
  <brief_title>Mechanisms of Fatigability With Diabetes</brief_title>
  <official_title>Mechanisms of Fatigability and the Protective Effects of Exercise in People With Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Marquette University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Illinois at Chicago</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Marquette University</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>
      Pre-diabetes (Pre-D) is a precursor to type 2 diabetes (T2D) and characterized by increased&#xD;
      exercise fatigability of lower limb muscles, that can impede exercise performance. The cause&#xD;
      for the increased fatigability in people with Pre-D is not known. Given the profound vascular&#xD;
      disease present in people who have had uncontrolled diabetes for several years, we will&#xD;
      determine whether dynamic, fatiguing contractions of the lower limb muscles in people with&#xD;
      Pre-D are limited by vascular dysfunction at multiple levels along the vascular tree&#xD;
      including the artery, arteriole, and/or capillary. This clinical trial involves a novel&#xD;
      exercise training regime involving blood flow restriction to the exercising limb will be used&#xD;
      as a probe to further understand the vascular mechanisms for increased fatigability in people&#xD;
      with Pre-D and T2D. The long-term goal is to better understand what limits exercise and&#xD;
      functional performance in people with diabetes to help develop targeted, more effective&#xD;
      exercise programs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The aim of the clinical trial is to determine the effectiveness of dynamic resistance&#xD;
      exercise training coupled with blood flow restriction to improve fatigability and vascular&#xD;
      function in people with Pre-D and T2D. People with Pre-D and T2D from Aim 1 will perform 8&#xD;
      weeks of dynamic unilateral resistance exercise training in which one leg is exercised with&#xD;
      freely perfused conditions and the other leg with blood flow restriction.&#xD;
&#xD;
      We will assess fatigability, skeletal muscle metabolism, capillary density, and vascular&#xD;
      function in people with Pre-D and T2D before and after a novel training intervention that&#xD;
      couples dynamic resistance training with blood flow restriction to the exercising limb. This&#xD;
      novel intervention has been shown to improve vascular function in young and older adults but&#xD;
      has not been investigated in people with Pre-D and T2D. Endothelial function in intact large&#xD;
      conduit arteries and arterioles isolated from skeletal muscle biopsies will be measured&#xD;
      before and after the training intervention to assess whether the novel training improves&#xD;
      vascular function along multiple levels of the vascular tree in people with Pre-D and T2D.&#xD;
      Skeletal muscle blood flow through the femoral artery will be quantified with Doppler&#xD;
      ultrasonography and skeletal muscle oxygenation will be measured with near infrared&#xD;
      spectroscopy (NIRS) during a dynamic fatiguing knee extension exercise. We will closely match&#xD;
      participant groups for physical activity levels, age, sex, and body mass index (BMI), because&#xD;
      these confounders are not typically controlled for in other human studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">October 1, 2024</start_date>
  <completion_date type="Anticipated">April 1, 2027</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2027</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>
    <intervention_model_description>Each participant will attend 3 sessions per week for 8 weeks. A training session will start with a 10-minute warm up on a bike ergometer. Each leg will then perform low-load resistance training (~20% of 1-RM) for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions while seated in a knee extension weight machine. One leg will be randomized to always perform the training with blood flow restriction (BFR leg) while the contralateral leg performs the exercise training without blood flow occlusion (Control leg).</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Fatigability - Reduction in Power</measure>
    <time_frame>One session before and then after 8 weeks of training</time_frame>
    <description>Reduction in limb power and maximal force in response to a dynamic fatiguing contraction.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Strength - 1 Repetition Maximum</measure>
    <time_frame>One session before and then after 8 weeks of training</time_frame>
    <description>Reduction in limb power and maximal force in response to a dynamic fatiguing contraction</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Strength - Maximal Voluntary Contraction (MVC)</measure>
    <time_frame>One session before and then after 8 weeks of training</time_frame>
    <description>Changes in MVC after 8 weeks resistance training. MVC is the greatest force generated during a brief isometric contraction.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Leg Blood Flow</measure>
    <time_frame>One session before and then after 8 weeks of training</time_frame>
    <description>Femoral artery mean blood velocity and femoral artery diameter will be measured using Doppler ultrasonography before and immediately after the fatiguing task in each leg.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Skeletal Muscle Oxygenation</measure>
    <time_frame>One session before and then after 8 weeks of training</time_frame>
    <description>Near-Infrared Spectroscopy recordings will be used to quantify blood flow kinetics of the knee extensor muscle tissue (rectus femoris and vastus lateralis) during the dynamic, fatiguing exercise in each leg.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vasodilation in Skeletal Muscle Arterioles</measure>
    <time_frame>One session before and then after 8 weeks of training</time_frame>
    <description>Vessel diameters of arterioles that are extracted and isolated from Skeletal muscle biopsies of the vastus lateralis will be measured in response to vasodilators and constrictors</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Muscle Metabolism - Phosphorus Nuclear Magnetic Resonance Spectroscopy (31P-MRS))</measure>
    <time_frame>One session before and then after 8 weeks of training</time_frame>
    <description>31P-MRS is used to noninvasively measure muscle metabolism by calculating intracellular ATP, ADP, phosphocreatine (PCr), inorganic phosphate (Pi), and pH in the quadriceps of participants. This measurement is conducted while participants perform fatiguing knee extensor exercise in the magnetic bore.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Capillary density</measure>
    <time_frame>One session before and after 8 weeks of training</time_frame>
    <description>Immunohistochemical analysis will be performed on muscle biopsy samples to determine the number and density of capillaries for each fiber type.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Pre-diabetes</condition>
  <condition>Type 2 Diabetes</condition>
  <arm_group>
    <arm_group_label>Control Exercise</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low-load knee extension resistance training (20% of 1-RM) without blood flow restriction. A 10-cm wide inflatable cuff will be placed around the upper portion of the thigh but not inflated.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Blood Flow Restriction Exercise</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low-load knee extension resistance training (20% of 1-RM) with blood flow restriction using a 10-cm wide inflatable cuff placed around the most proximal part of the exercising thigh. Blood flow will be restricted in the BFR leg at above the limb occlusion pressure of the and this will be determined prior to the exercise while the participant is seated in the knee extensor machine. The cuff pressure during the BFR protocol will be 10 mmHg above limb occlusion pressure.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Control Exercise</intervention_name>
    <description>Each participant will attend 3 sessions per week for 8 weeks. Participants will perform low-load knee extension resistance training (20% of 1-RM) without blood flow restriction on the designated leg for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions.</description>
    <arm_group_label>Control Exercise</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Blood Flow Restriction Exercise</intervention_name>
    <description>Each participant will attend 3 sessions per week for 8 weeks. Participants will perform low-load knee extension resistance training (20% of 1-RM) with blood flow restriction on the designated leg for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions.</description>
    <arm_group_label>Blood Flow Restriction Exercise</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women adults 30 years to 85 years or less&#xD;
&#xD;
          -  Pre-diabetes [glycosylated hemoglobin (HbA1c) of 5.7-6.4% and fasting plasma glucose&#xD;
             100-125 mg/dL at the time of initial screening]&#xD;
&#xD;
          -  Controls [normoglycemic with a HbA1c level ≤5.6% and fasting blood glucose ≤ 99 mg/dL&#xD;
             (5.5 mmol/L)]&#xD;
&#xD;
          -  Type 2 Diabetes Mellitus [elevated glycosylated hemoglobin (HbA1c) &gt;6.5% and &lt;10%]&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Signs or symptoms of neuropathy&#xD;
&#xD;
          -  Medications associated with advanced stages of T2D including insulin&#xD;
&#xD;
          -  Poor glycemic control (HbA1c&gt;10%)&#xD;
&#xD;
          -  Peripheral edema&#xD;
&#xD;
          -  Severe obesity (BMI, &gt;45kg·m-2)&#xD;
&#xD;
          -  Untreated hypothyroidism&#xD;
&#xD;
          -  Smoking&#xD;
&#xD;
          -  Hypertension&#xD;
&#xD;
          -  Cardiovascular or musculoskeletal disease that preclude exercise testing&#xD;
&#xD;
          -  Hormone replacement drugs or vasoactive medications&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Sandra K Hunter, PhD</last_name>
    <phone>414-288-6673</phone>
    <email>sandra.hunter@marquette.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mirae Mastrolonardo, BSc</last_name>
    <email>mirae.mastrolonardo@marquette.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Marquette University</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53201</zip>
        <country>United States</country>
      </address>
    </facility>
    <contact>
      <last_name>Sandra K Hunter, PhD</last_name>
      <phone>414-288-6673</phone>
      <email>sandra.hunter@marquette.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 22, 2020</study_first_posted>
  <last_update_submitted>August 22, 2023</last_update_submitted>
  <last_update_submitted_qc>August 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 24, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Pre-diabetes</keyword>
  <keyword>Fatigability</keyword>
  <keyword>Blood Flow Restriction Training</keyword>
  <keyword>Vascular Function</keyword>
  <keyword>Muscle Fatigue</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Prediabetic State</mesh_term>
    <mesh_term>Glucose Intolerance</mesh_term>
  </condition_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/NCT04442451
org study id: HR-2402
nct id: NCT04442451
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Pre-diabetes (Pre-D) is a precursor to type 2 diabetes (T2D) and characterized by increased
      exercise fatigability of lower limb muscles, that can impede exercise performance. The cause
      for the increased fatigability in people with Pre-D is not known. Given the profound vascular
      disease present in people who have had uncontrolled diabetes for several years, we will
      determine whether dynamic, fatiguing contractions of the lower limb muscles in people with
      Pre-D are limited by vascular dysfunction at multiple levels along the vascular tree
      including the artery, arteriole, and/or capillary. This clinical trial involves a novel
      exercise training regime involving blood flow restriction to the exercising limb will be used
      as a probe to further understand the vascular mechanisms for increased fatigability in people
      with Pre-D and T2D. The long-term goal is to better understand what limits exercise and
      functional performance in people with diabetes to help develop targeted, more effective
      exercise programs.
The aim of the clinical trial is to determine the effectiveness of dynamic resistance
      exercise training coupled with blood flow restriction to improve fatigability and vascular
      function in people with Pre-D and T2D. People with Pre-D and T2D from Aim 1 will perform 8
      weeks of dynamic unilateral resistance exercise training in which one leg is exercised with
      freely perfused conditions and the other leg with blood flow restriction.

      We will assess fatigability, skeletal muscle metabolism, capillary density, and vascular
      function in people with Pre-D and T2D before and after a novel training intervention that
      couples dynamic resistance training with blood flow restriction to the exercising limb. This
      novel intervention has been shown to improve vascular function in young and older adults but
      has not been investigated in people with Pre-D and T2D. Endothelial function in intact large
      conduit arteries and arterioles isolated from skeletal muscle biopsies will be measured
      before and after the training intervention to assess whether the novel training improves
      vascular function along multiple levels of the vascular tree in people with Pre-D and T2D.
      Skeletal muscle blood flow through the femoral artery will be quantified with Doppler
      ultrasonography and skeletal muscle oxygenation will be measured with near infrared
      spectroscopy (NIRS) during a dynamic fatiguing knee extension exercise. We will closely match
      participant groups for physical activity levels, age, sex, and body mass index (BMI), because
      these confounders are not typically controlled for in other human studies.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Each participant will attend 3 sessions per week for 8 weeks. A training session will start with a 10-minute warm up on a bike ergometer. Each leg will then perform low-load resistance training (~20% of 1-RM) for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions while seated in a knee extension weight machine. One leg will be randomized to always perform the training with blood flow restriction (BFR leg) while the contralateral leg performs the exercise training without blood flow occlusion (Control leg).
primary purpose: Basic Science
masking: None (Open Label)
measure: Fatigability - Reduction in Power
time frame: One session before and then after 8 weeks of training
description: Reduction in limb power and maximal force in response to a dynamic fatiguing contraction.
measure: Strength - 1 Repetition Maximum
time frame: One session before and then after 8 weeks of training
description: Reduction in limb power and maximal force in response to a dynamic fatiguing contraction
measure: Strength - Maximal Voluntary Contraction (MVC)
time frame: One session before and then after 8 weeks of training
description: Changes in MVC after 8 weeks resistance training. MVC is the greatest force generated during a brief isometric contraction.
measure: Leg Blood Flow
time frame: One session before and then after 8 weeks of training
description: Femoral artery mean blood velocity and femoral artery diameter will be measured using Doppler ultrasonography before and immediately after the fatiguing task in each leg.
measure: Skeletal Muscle Oxygenation
time frame: One session before and then after 8 weeks of training
description: Near-Infrared Spectroscopy recordings will be used to quantify blood flow kinetics of the knee extensor muscle tissue (rectus femoris and vastus lateralis) during the dynamic, fatiguing exercise in each leg.
measure: Vasodilation in Skeletal Muscle Arterioles
time frame: One session before and then after 8 weeks of training
description: Vessel diameters of arterioles that are extracted and isolated from Skeletal muscle biopsies of the vastus lateralis will be measured in response to vasodilators and constrictors
measure: Muscle Metabolism - Phosphorus Nuclear Magnetic Resonance Spectroscopy (31P-MRS))
time frame: One session before and then after 8 weeks of training
description: 31P-MRS is used to noninvasively measure muscle metabolism by calculating intracellular ATP, ADP, phosphocreatine (PCr), inorganic phosphate (Pi), and pH in the quadriceps of participants. This measurement is conducted while participants perform fatiguing knee extensor exercise in the magnetic bore.
measure: Capillary density
time frame: One session before and after 8 weeks of training
description: Immunohistochemical analysis will be performed on muscle biopsy samples to determine the number and density of capillaries for each fiber type.
arm group label: Control Exercise
arm group type: Experimental
description: Low-load knee extension resistance training (20% of 1-RM) without blood flow restriction. A 10-cm wide inflatable cuff will be placed around the upper portion of the thigh but not inflated.
arm group label: Blood Flow Restriction Exercise
arm group type: Experimental
description: Low-load knee extension resistance training (20% of 1-RM) with blood flow restriction using a 10-cm wide inflatable cuff placed around the most proximal part of the exercising thigh. Blood flow will be restricted in the BFR leg at above the limb occlusion pressure of the and this will be determined prior to the exercise while the participant is seated in the knee extensor machine. The cuff pressure during the BFR protocol will be 10 mmHg above limb occlusion pressure.
intervention type: Other
intervention name: Control Exercise
description: Each participant will attend 3 sessions per week for 8 weeks. Participants will perform low-load knee extension resistance training (20% of 1-RM) without blood flow restriction on the designated leg for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions.
arm group label: Control Exercise
intervention type: Other
intervention name: Blood Flow Restriction Exercise
description: Each participant will attend 3 sessions per week for 8 weeks. Participants will perform low-load knee extension resistance training (20% of 1-RM) with blood flow restriction on the designated leg for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions.
arm group label: Blood Flow Restriction Exercise
criteria: 
gender: All
minimum age: 30 Years
maximum age: 85 Years
healthy volunteers: No
last name: Sandra K Hunter, PhD
phone: 414-288-6673
email: sandra.hunter@marquette.edu
last name: Mirae Mastrolonardo, BSc
email: mirae.mastrolonardo@marquette.edu
facility: 
contact: 
country: United States
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Prediabetic State
mesh term: Glucose Intolerance