xml: <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/NCT06042517</url>
    </required_header>
    <id_info>
      <org_study_id>2000034954</org_study_id>
      <secondary_id>1R01DK131127-01A1</secondary_id>
      <nct_id>NCT06042517</nct_id>
    </id_info>
    <brief_title>Mechanisms of Ultrasound Neuromodulation Effects in Diabetes</brief_title>
    <official_title>Mechanisms of Ultrasound Neuromodulation Effects in Diabetes</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Yale University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
    </sponsors>
    <source>Yale University</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>Yes</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        This study aims to evaluate the effect of hepatic ultrasound treatment on changes from&#xD;
        baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE&#xD;
        Clamp).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Drop-outs will be replaced; data will be used as much as can be. Subjects will undergo a&#xD;
        Screening visit to assess eligibility and will then be scheduled to undergo 2 outpatient US&#xD;
        treatment visits.&#xD;
  &#xD;
        On day three subjects first undergo a third ultrasound session and then will either undergo&#xD;
        Oral Glucose Tolerance Test (OGTT) with carbon13 (13C-glucose) tracer administration and&#xD;
        subsequent NMR spectroscopy OR if enrolled into the HEC study arm will undergo euglycemic&#xD;
        clamp testing. Following these procedures there will be an approximately two-week follow-up&#xD;
        observational Period (with CGM). A two-week washout period will be followed by another cycle&#xD;
        of the same procedures of either OGTT/NMR or HEC study, respectively.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">September 2027</completion_date>
    <primary_completion_date type="Anticipated">September 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>For Cohort 4: T2DM subjects, age-, BMI- and HbA1c-matched to cohorts 1 and 2 will be recruited from the same pool of volunteers and selected according to the same inclusion and exclusion criteria outlined in the human subject protection plan.&#xD;
  5 additional subjects will be recruited to participate in cohort 3.</intervention_model_description>
      <primary_purpose>Other</primary_purpose>
      <masking>Single (Participant)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Insulin Sensitivity</measure>
      <time_frame>Measured during HE clamp.</time_frame>
      <description>Insulin Sensitivity calculated as Glucose disposal rate / insulin ratio during steady state (M/I) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Glucose disposal rate</measure>
      <time_frame>Measured during HE clamp.</time_frame>
      <description>Glucose disposal rate during steady state (M) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Glucose metabolic clearance rate</measure>
      <time_frame>Measured during HE clamp.</time_frame>
      <description>Glucose metabolic clearance rate during steady state (MCR) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Absolute glycogen level</measure>
      <time_frame>during glucose tolerance testing (for 180 minutes).</time_frame>
      <description>The effect of hepatic plexus-directed pFUS on absolute glycogen level by observing the metabolic fate of unlabeled glucose ingested during oral glucose tolerance testing measured by 13C liver NMR-spectroscopy.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Glycogen synthesis rates</measure>
      <time_frame>during glucose tolerance testing (for 180 minutes).</time_frame>
      <description>Glycogen synthesis rates are derived from plasma 13C -glucose levels achieved during the OGTT and subsequent appearance of 13C -tracer in liver glycogen</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change from baseline in blood glucose (BG) time spent in defined glucose ranges</measure>
      <time_frame>1 week</time_frame>
      <description>Change from baseline in blood glucose (BG) time spent in defined glucose ranges assessed using a continuous glucose monitoring system (CGMS)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Average daily glucose</measure>
      <time_frame>1 week</time_frame>
      <description>Average daily glucose assessed using a continuous glucose monitoring system (CGMS)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Low blood glucose index (LBGI)</measure>
      <time_frame>1 week</time_frame>
      <description>Frequency of low glucose events detected during continuous glucose measurement.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>High blood glucose index (HBGI)</measure>
      <time_frame>1 week</time_frame>
      <description>Frequency of high glucose events detected during continuous glucose measurement.</description>
    </secondary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">77</enrollment>
    <condition>Insulin Sensitivity</condition>
    <arm_group>
      <arm_group_label>Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Hepatic ultrasound during a hyperinsulinemic euglycemic clamp (HEC).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort 2: Ultrasound then NMR with unlabeled glucose.</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Hepatic ultrasound and subsequent NMR measurement of glycogen with unlabeled glucose.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Hepatic ultrasound and subsequent NMR measurement of glycogen with carbon13 labeled glucose.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Hepatoportal plexus + superior mesenteric plexus dual site ultrasound stimulation followed by CGM glucose recording alone.</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Ultrasound</intervention_name>
      <description>The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.</description>
      <arm_group_label>Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).</arm_group_label>
      <arm_group_label>Cohort 2: Ultrasound then NMR with unlabeled glucose.</arm_group_label>
      <arm_group_label>Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.</arm_group_label>
      <arm_group_label>Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>OGTT with unlabeled glucose and liver NMR</intervention_name>
      <description>Subjects will undergo an OGTT with unlabeled glucose to measure liver glycogen concentration by NMR spectroscopy.</description>
      <arm_group_label>Cohort 2: Ultrasound then NMR with unlabeled glucose.</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>OGTT with carbon-13 labeled glucose and liver NMR</intervention_name>
      <description>Subjects will undergo an OGTT with carbon-13 labeled glucose to measure liver glycogen synthesis rate by NMR spectroscopy.</description>
      <arm_group_label>Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>CGM glucose reading</intervention_name>
      <description>A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.</description>
      <arm_group_label>Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).</arm_group_label>
      <arm_group_label>Cohort 2: Ultrasound then NMR with unlabeled glucose.</arm_group_label>
      <arm_group_label>Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.</arm_group_label>
      <arm_group_label>Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>HEC - Hyperinsulinemic-Euglycemic-Clamp</intervention_name>
      <description>A constant i.v. insulin and variable glucose infusion will be used to determine insulin sensitivity of study participants.</description>
      <arm_group_label>Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Type 2 diabetic (T2D) subjects must be aged 18-80 and must be able to provide written&#xD;
               informed consent&#xD;
  &#xD;
            -  All subjects must have had T2D for at least 3 months prior to study enrollment. All&#xD;
               subjects must be either on diet and exercise or oral antidiabetic agents alone, not on&#xD;
               insulin or any form of insulin or GLP-1 receptor agonists.&#xD;
  &#xD;
            -  Subjects must demonstrate:&#xD;
  &#xD;
                 1. A past medical history of abnormal glucose control and carry a diagnosis of T2D&#xD;
                    according to current ADA criteria:&#xD;
  &#xD;
                      -  A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or&#xD;
  &#xD;
                      -  A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a&#xD;
                         75-g oral glucose tolerance test (OGTT), or&#xD;
  &#xD;
                      -  A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient&#xD;
                         with classic symptoms of hyperglycemia or hyperglycemic crisis or&#xD;
  &#xD;
                      -  A hemoglobin A1c (HbA1c) level of 6.5% or higher.&#xD;
  &#xD;
                 2. Be willing to carry a continuous glucose monitor for at least 10 days.&#xD;
  &#xD;
                 3. Be willing to follow all required instructions by study personnel and appear for&#xD;
                    the required laboratory assessments, including euglycemic clamps and OGTT.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  BMI &gt;40kg/m2.&#xD;
  &#xD;
            -  Untreated proliferative retinopathy&#xD;
  &#xD;
            -  Creatinine clearance &lt; 60 ml/min/1.73 m2.&#xD;
  &#xD;
            -  Serum creatinine ≥1.5 mg/dL&#xD;
  &#xD;
            -  Positive pregnancy test, or presently breast-feeding, or failure to follow effective&#xD;
               contraceptive measures&#xD;
  &#xD;
            -  Active infection including hepatitis C, hepatitis B, HIV,&#xD;
  &#xD;
            -  Any history of Active alcohol abuse&#xD;
  &#xD;
            -  History of non-adherence to prescribed regimens&#xD;
  &#xD;
            -  Baseline Hgb &lt; 10.5 g/dL in females, or &lt; 13 g/dL in males&#xD;
  &#xD;
            -  History of coagulopathy or medical condition requiring long-term anticoagulant therapy&#xD;
               (low-dose aspirin treatment is allowed)&#xD;
  &#xD;
            -  Co-existing cardiac disease with active medication titration. Patients on stable meds&#xD;
               without active cardiac complications permitted.&#xD;
  &#xD;
            -  Liver function tests outside of 3xUL of normal range&#xD;
  &#xD;
            -  GI disorders potentially interfering with the ability to absorb oral medications and&#xD;
               h/o upper GI surgery that might have changed anatomy in the target areas.&#xD;
  &#xD;
            -  Any medical condition or medication that, in the opinion of the investigators, will&#xD;
               interfere with the safe completion of the study or study outcomes.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Raimund Herzog, MD, MHS</last_name>
      <role>Principal Investigator</role>
      <affiliation>Yale University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Raimund Herzog, MD MHS</last_name>
      <phone>+1 (203) 737-4773</phone>
      <email>raimund.herzog@yale.edu</email>
    </overall_contact>
    <location>
      <facility>
        <name>Yale School of Medicine</name>
        <address>
          <city>New Haven</city>
          <state>Connecticut</state>
          <zip>06520</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 22, 2023</study_first_submitted>
    <study_first_submitted_qc>September 14, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 18, 2023</study_first_posted>
    <last_update_submitted>September 14, 2023</last_update_submitted>
    <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 18, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Insulin Resistance</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Liver Extracts</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06042517
  org study id: 2000034954
  secondary id: 1R01DK131127-01A1
  nct id: NCT06042517
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: Yes
  This study aims to evaluate the effect of hepatic ultrasound treatment on changes from
        baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE
        Clamp).
  Drop-outs will be replaced; data will be used as much as can be. Subjects will undergo a
        Screening visit to assess eligibility and will then be scheduled to undergo 2 outpatient US
        treatment visits.
  
        On day three subjects first undergo a third ultrasound session and then will either undergo
        Oral Glucose Tolerance Test (OGTT) with carbon13 (13C-glucose) tracer administration and
        subsequent NMR spectroscopy OR if enrolled into the HEC study arm will undergo euglycemic
        clamp testing. Following these procedures there will be an approximately two-week follow-up
        observational Period (with CGM). A two-week washout period will be followed by another cycle
        of the same procedures of either OGTT/NMR or HEC study, respectively.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: For Cohort 4: T2DM subjects, age-, BMI- and HbA1c-matched to cohorts 1 and 2 will be recruited from the same pool of volunteers and selected according to the same inclusion and exclusion criteria outlined in the human subject protection plan.
  5 additional subjects will be recruited to participate in cohort 3.
  primary purpose: Other
  masking: Single (Participant)
  measure: Insulin Sensitivity
  time frame: Measured during HE clamp.
  description: Insulin Sensitivity calculated as Glucose disposal rate / insulin ratio during steady state (M/I) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)
  measure: Glucose disposal rate
  time frame: Measured during HE clamp.
  description: Glucose disposal rate during steady state (M) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)
  measure: Glucose metabolic clearance rate
  time frame: Measured during HE clamp.
  description: Glucose metabolic clearance rate during steady state (MCR) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)
  measure: Absolute glycogen level
  time frame: during glucose tolerance testing (for 180 minutes).
  description: The effect of hepatic plexus-directed pFUS on absolute glycogen level by observing the metabolic fate of unlabeled glucose ingested during oral glucose tolerance testing measured by 13C liver NMR-spectroscopy.
  measure: Glycogen synthesis rates
  time frame: during glucose tolerance testing (for 180 minutes).
  description: Glycogen synthesis rates are derived from plasma 13C -glucose levels achieved during the OGTT and subsequent appearance of 13C -tracer in liver glycogen
  measure: Change from baseline in blood glucose (BG) time spent in defined glucose ranges
  time frame: 1 week
  description: Change from baseline in blood glucose (BG) time spent in defined glucose ranges assessed using a continuous glucose monitoring system (CGMS)
  measure: Average daily glucose
  time frame: 1 week
  description: Average daily glucose assessed using a continuous glucose monitoring system (CGMS)
  measure: Low blood glucose index (LBGI)
  time frame: 1 week
  description: Frequency of low glucose events detected during continuous glucose measurement.
  measure: High blood glucose index (HBGI)
  time frame: 1 week
  description: Frequency of high glucose events detected during continuous glucose measurement.
  arm group label: Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).
  arm group type: Experimental
  description: Hepatic ultrasound during a hyperinsulinemic euglycemic clamp (HEC).
  arm group label: Cohort 2: Ultrasound then NMR with unlabeled glucose.
  arm group type: Experimental
  description: Hepatic ultrasound and subsequent NMR measurement of glycogen with unlabeled glucose.
  arm group label: Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.
  arm group type: Experimental
  description: Hepatic ultrasound and subsequent NMR measurement of glycogen with carbon13 labeled glucose.
  arm group label: Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.
  arm group type: Experimental
  description: Hepatoportal plexus + superior mesenteric plexus dual site ultrasound stimulation followed by CGM glucose recording alone.
  intervention type: Device
  intervention name: Ultrasound
  description: The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.
  arm group label: Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).
  arm group label: Cohort 2: Ultrasound then NMR with unlabeled glucose.
  arm group label: Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.
  arm group label: Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.
  intervention type: Diagnostic Test
  intervention name: OGTT with unlabeled glucose and liver NMR
  description: Subjects will undergo an OGTT with unlabeled glucose to measure liver glycogen concentration by NMR spectroscopy.
  arm group label: Cohort 2: Ultrasound then NMR with unlabeled glucose.
  intervention type: Diagnostic Test
  intervention name: OGTT with carbon-13 labeled glucose and liver NMR
  description: Subjects will undergo an OGTT with carbon-13 labeled glucose to measure liver glycogen synthesis rate by NMR spectroscopy.
  arm group label: Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.
  intervention type: Diagnostic Test
  intervention name: CGM glucose reading
  description: A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.
  arm group label: Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).
  arm group label: Cohort 2: Ultrasound then NMR with unlabeled glucose.
  arm group label: Cohort 3: Ultrasound then NMR with carbon13 labeled glucose.
  arm group label: Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone.
  intervention type: Diagnostic Test
  intervention name: HEC - Hyperinsulinemic-Euglycemic-Clamp
  description: A constant i.v. insulin and variable glucose infusion will be used to determine insulin sensitivity of study participants.
  arm group label: Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC).
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: No
  last name: Raimund Herzog, MD, MHS
  role: Principal Investigator
  affiliation: Yale University
  last name: Raimund Herzog, MD MHS
  phone: +1 (203) 737-4773
  email: raimund.herzog@yale.edu
  facility: 
  country: United States
  responsible party type: Sponsor
  mesh term: Insulin Resistance
  mesh term: Liver Extracts
  sharing ipd: No