<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/NCT01729299</url>
  </required_header>
  <id_info>
    <org_study_id>12070904</org_study_id>
    <nct_id>NCT01729299</nct_id>
  </id_info>
  <brief_title>Ghrelin Effect on Beta Cell Function in Health and Disease</brief_title>
  <official_title>Ghrelin Effect on Beta Cell Function in Health and Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>David Dalessio</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Cincinnati</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine the role of nutrient status on ghrelin regulation of insulin secretion. We&#xD;
      hypothesize that ghrelin and glucagon-like peptide-1 (GLP-1)(both are hormones made in the&#xD;
      gut,) have differential effects on β-cell function in the fed state. We will compare insulin&#xD;
      secretion and glucose turnover during meal ingestion using a dual glucose tracer and mixed&#xD;
      meal protocol in subjects receiving ghrelin or saline. We will also determine the role of&#xD;
      ghrelin-stimulated GLP-1 levels in this process using the GLP-1 receptor (GLP-1R) antagonist&#xD;
      Exendin(9-39) (Ex-9).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      We plan to study 20 healthy subjects on 4 occasions where they will receive ghrelin,&#xD;
      ghrelin+Ex-9, Ex-9 or saline infusion after an overnight fast in a randomized order; Ex-9&#xD;
      will be used to block GLP-1 action. A 240-minute meal tolerance test (MTT) using a dual&#xD;
      glucose tracer method will serve as the foundation of each study visit. One tracer,&#xD;
      [6,6-2H2]glucose will be infused intravenously before and during the test meal to quantify&#xD;
      fasting endogenous glucose production (EGP), and glucose disappearance during the meal. A&#xD;
      second tracer, [U-13C]glucose, will be included in the meal to trace the appearance of oral&#xD;
      glucose. The systemic appearance rates of both ingested tracer and total (i.e., ingested and&#xD;
      endogenously produced) glucose will be calculated. Using this protocol, we will be able to&#xD;
      evaluate a) insulin secretion in response to mixed-meal ingestion, b) glucose appearance and&#xD;
      glucose disappearance during meal ingestion, c) the ghrelin effect on these parameters&#xD;
      without GLP-1, and d) the effect of GLP-1 in the response based on the effects with and&#xD;
      without Ex-9.&#xD;
&#xD;
      This dual-tracer method has been used to assess the ability of an individual to dispose of an&#xD;
      oral glucose load, and accurately fractionates the appearance of ingested glucose in plasma&#xD;
      (Ra meal), EGP, and peripheral glucose disposal (Rd) in this setting 41-42. The&#xD;
      [6,6-2H2]glucose and [U-13C]glucose are stable-isotope tracers and are different from&#xD;
      radioactive-isotope tracers in that they do not emit radiation.&#xD;
&#xD;
      All procedures will be performed at the CTRC at the Cincinnati Children's Hospital Medical&#xD;
      Center (CCHMC).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>April 2013</start_date>
  <completion_date type="Anticipated">April 2014</completion_date>
  <primary_completion_date type="Anticipated">April 2014</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>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>post-prandial insulin secretion</measure>
    <time_frame>1 year</time_frame>
    <description>Postprandial insulin secretion (ISR-meal) will be derived from plasma C-peptide concentrations during MTT using deconvolution with population estimates of C-peptide clearance.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>endogenous GLP-1 contribution to postprandial insulin secretion</measure>
    <time_frame>1 year</time_frame>
    <description>The endogenous GLP-1 contribution to postprandial insulin secretion (GLP-1 effect) will be calculated as the difference in ISR-meal with and without Ex-9.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>β-cell response to glucose</measure>
    <time_frame>1 year</time_frame>
    <description>An index of β-cell response to glucose will be calculated as the incremental insulin/glucose (I/G) AUC (ΔAUCI/G).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>insulin sensitivity</measure>
    <time_frame>1 year</time_frame>
    <description>Whole body insulin sensitivity will be estimated using the Matsuda Index that has been well validated in large cohort studies and has demonstrated a good correlation with IVGTT or hyperinsulinemic-euglycemic clamp derived measures of insulin sensitivity. β-cell function (DI-meal) will be calculated as ΔAUCI/G x Matsuda Index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>fasting EGP</measure>
    <time_frame>1 year</time_frame>
    <description>Fasting EGP will be calculated as the ratio of 6,6-[2H2]glucose infusion rate to plasma tracer enrichment (tracer-to-tracee ratio [TTR]6,6 from measurements obtained in the last 20 min of the basal tracer equilibration period, when plasma glucose concentration and 6,6-[2H2]glucose enrichment are stable).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>glucose appearance</measure>
    <time_frame>1 year</time_frame>
    <description>Total rates of glucose appearance after meal ingestion (total Ra) will be calculated by modeling 6,6-[2H2] enrichment ([TTR]6,6) using both a two-compartment model and Steele's equation42. Meal glucose appearance will be determined from the analysis of [U-13C]-glucose fluxes. The meal will be labeled to 2.66% with U-13C]-glucose (TTRmeal). From the measurement of plasma [TTR]13C, we will calculate the exogenous (meal) glucose concentrations, [Gmeal] , from total glucose concentrations, [Gtot] , using the formula [Gmeal] = [Gtot] x [TTR]13C / TTRmeal as previously described 42,45. Endogenous glucose concentration [Gend] will be calculated as [Gend] = [Gtot] - [Gmeal].</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EGP during MTT</measure>
    <time_frame>1 year</time_frame>
    <description>EGP during MTT will be calculated using model analysis of TTR of endogenous glucose ([TTR]end) and calculated as [TTR]end = [TTR]6,6 x [Gtot] / [Gend]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>exogenous glucose rate of appearance</measure>
    <time_frame>1 year</time_frame>
    <description>Exogenous glucose rate of appearance, Ra meal, will be calculated by subtracting EGP during meal from total Ra (Ra meal = total Ra - EGP).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>metabolic glucose clearance</measure>
    <time_frame>1 year</time_frame>
    <description>As for indexes of peripheral insulin sensitivity, we will calculate metabolic glucose clearance during MTT using peripheral glucose disposal (Rd) divided by glucose concentration (expressed as ml/min/kg) where Rd is calculated by subtracting the rate of change of plasma glucose mass from total Ra.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>area under the curve</measure>
    <time_frame>1 year</time_frame>
    <description>AUC for glucagon, GLP-1, GIP, and free fatty acids (FFA), a measure of lipolysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ghrelin measures</measure>
    <time_frame>1 year</time_frame>
    <description>AG and total ghrelin levels will be measured during clamp-MTT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>gastric emptying</measure>
    <time_frame>1 year</time_frame>
    <description>Gastric emptying estimated by the gastric half-emptying time calculated from the emptying curve as the time when 50% of the total cumulated dose of acetaminophen has been eliminated46.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Diabetes</condition>
  <arm_group>
    <arm_group_label>saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Saline: 0.9% saline solution</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ghrelin and exendin (9-39)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ghrelin+Ex-9: Combination of ghrelin and Ex-9,</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Exendin (9-39)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Exendin (9-39) (25 µg/kg) bolus over 1 min followed by a continuous infusion of 2.5 µg/kg/min</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ghrelin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>synthetic human Acyl Ghrelin (0.28 μg/kg) bolus over 1 min followed by 2 μg/kg/h continuous infusion,</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Exendin (9-39)</intervention_name>
    <arm_group_label>Exendin (9-39)</arm_group_label>
    <arm_group_label>ghrelin and exendin (9-39)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>acyl ghrelin</intervention_name>
    <arm_group_label>ghrelin</arm_group_label>
    <arm_group_label>ghrelin and exendin (9-39)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>saline</intervention_name>
    <arm_group_label>saline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy men and women&#xD;
&#xD;
          2. Ages between 18 and 45 years&#xD;
&#xD;
          3. BMI between 18 and 29 kg/m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History or clinical evidence of impaired fasting glucose or diabetes mellitus,&#xD;
             myocardial infarction within the past year, history or symptoms of congestive heart&#xD;
             failure, uncontrolled hypertension, history or active liver or renal disease (AST or&#xD;
             ALT &gt;2x upper limits of normal, calculated glomerular filtration rate [GFR] &lt;60).&#xD;
&#xD;
          2. History of pituitary or adrenal disorders or neuroendocrine tumor.&#xD;
&#xD;
          3. Anemia defined as hematocrit &lt;33%.&#xD;
&#xD;
          4. Use of medications that alter glucose metabolism&#xD;
&#xD;
          5. Pregnancy or lactation.&#xD;
&#xD;
          6. Abnormal Electrocardiogram (ECG): evidence of ischemia or arrhythmia.&#xD;
&#xD;
          7. Women who have a positive pregnancy test at any time during the study period.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jenny Tong, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Cincinnati</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jenny Tong, MD, MPH</last_name>
    <phone>513-558-4446</phone>
    <email>jenny.tong@uc.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Cincinnati</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45267</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jenny Tong, MD, MPH</last_name>
      <phone>513-558-4446</phone>
      <email>jenny.tong@uc.edu</email>
    </contact>
    <contact_backup>
      <last_name>Ahrar Haque, MD</last_name>
      <phone>513-558-3923</phone>
      <email>haqueau@uc.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Jenny Tong, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital and Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ahrar Haque, MD</last_name>
      <phone>513-558-3923</phone>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2013</verification_date>
  <study_first_submitted>November 13, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 20, 2012</study_first_posted>
  <last_update_submitted>April 2, 2013</last_update_submitted>
  <last_update_submitted_qc>April 2, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 4, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Cincinnati</investigator_affiliation>
    <investigator_full_name>David Dalessio</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>ghrelin</keyword>
  <keyword>glucose control</keyword>
  <keyword>GLP-1</keyword>
  <keyword>Exendin (9-39)</keyword>
  <keyword>insulin</keyword>
  <!-- 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/NCT01729299
org study id: 12070904
nct id: NCT01729299
lead sponsor: 
collaborator: 
has dmc: Yes
To determine the role of nutrient status on ghrelin regulation of insulin secretion. We
      hypothesize that ghrelin and glucagon-like peptide-1 (GLP-1)(both are hormones made in the
      gut,) have differential effects on β-cell function in the fed state. We will compare insulin
      secretion and glucose turnover during meal ingestion using a dual glucose tracer and mixed
      meal protocol in subjects receiving ghrelin or saline. We will also determine the role of
      ghrelin-stimulated GLP-1 levels in this process using the GLP-1 receptor (GLP-1R) antagonist
      Exendin(9-39) (Ex-9).
We plan to study 20 healthy subjects on 4 occasions where they will receive ghrelin,
      ghrelin+Ex-9, Ex-9 or saline infusion after an overnight fast in a randomized order; Ex-9
      will be used to block GLP-1 action. A 240-minute meal tolerance test (MTT) using a dual
      glucose tracer method will serve as the foundation of each study visit. One tracer,
      [6,6-2H2]glucose will be infused intravenously before and during the test meal to quantify
      fasting endogenous glucose production (EGP), and glucose disappearance during the meal. A
      second tracer, [U-13C]glucose, will be included in the meal to trace the appearance of oral
      glucose. The systemic appearance rates of both ingested tracer and total (i.e., ingested and
      endogenously produced) glucose will be calculated. Using this protocol, we will be able to
      evaluate a) insulin secretion in response to mixed-meal ingestion, b) glucose appearance and
      glucose disappearance during meal ingestion, c) the ghrelin effect on these parameters
      without GLP-1, and d) the effect of GLP-1 in the response based on the effects with and
      without Ex-9.

      This dual-tracer method has been used to assess the ability of an individual to dispose of an
      oral glucose load, and accurately fractionates the appearance of ingested glucose in plasma
      (Ra meal), EGP, and peripheral glucose disposal (Rd) in this setting 41-42. The
      [6,6-2H2]glucose and [U-13C]glucose are stable-isotope tracers and are different from
      radioactive-isotope tracers in that they do not emit radiation.

      All procedures will be performed at the CTRC at the Cincinnati Children's Hospital Medical
      Center (CCHMC).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Single (Participant)
measure: post-prandial insulin secretion
time frame: 1 year
description: Postprandial insulin secretion (ISR-meal) will be derived from plasma C-peptide concentrations during MTT using deconvolution with population estimates of C-peptide clearance.
measure: endogenous GLP-1 contribution to postprandial insulin secretion
time frame: 1 year
description: The endogenous GLP-1 contribution to postprandial insulin secretion (GLP-1 effect) will be calculated as the difference in ISR-meal with and without Ex-9.
measure: β-cell response to glucose
time frame: 1 year
description: An index of β-cell response to glucose will be calculated as the incremental insulin/glucose (I/G) AUC (ΔAUCI/G).
measure: insulin sensitivity
time frame: 1 year
description: Whole body insulin sensitivity will be estimated using the Matsuda Index that has been well validated in large cohort studies and has demonstrated a good correlation with IVGTT or hyperinsulinemic-euglycemic clamp derived measures of insulin sensitivity. β-cell function (DI-meal) will be calculated as ΔAUCI/G x Matsuda Index
measure: fasting EGP
time frame: 1 year
description: Fasting EGP will be calculated as the ratio of 6,6-[2H2]glucose infusion rate to plasma tracer enrichment (tracer-to-tracee ratio [TTR]6,6 from measurements obtained in the last 20 min of the basal tracer equilibration period, when plasma glucose concentration and 6,6-[2H2]glucose enrichment are stable).
measure: glucose appearance
time frame: 1 year
description: Total rates of glucose appearance after meal ingestion (total Ra) will be calculated by modeling 6,6-[2H2] enrichment ([TTR]6,6) using both a two-compartment model and Steele's equation42. Meal glucose appearance will be determined from the analysis of [U-13C]-glucose fluxes. The meal will be labeled to 2.66% with U-13C]-glucose (TTRmeal). From the measurement of plasma [TTR]13C, we will calculate the exogenous (meal) glucose concentrations, [Gmeal] , from total glucose concentrations, [Gtot] , using the formula [Gmeal] = [Gtot] x [TTR]13C / TTRmeal as previously described 42,45. Endogenous glucose concentration [Gend] will be calculated as [Gend] = [Gtot] - [Gmeal].
measure: EGP during MTT
time frame: 1 year
description: EGP during MTT will be calculated using model analysis of TTR of endogenous glucose ([TTR]end) and calculated as [TTR]end = [TTR]6,6 x [Gtot] / [Gend]
measure: exogenous glucose rate of appearance
time frame: 1 year
description: Exogenous glucose rate of appearance, Ra meal, will be calculated by subtracting EGP during meal from total Ra (Ra meal = total Ra - EGP).
measure: metabolic glucose clearance
time frame: 1 year
description: As for indexes of peripheral insulin sensitivity, we will calculate metabolic glucose clearance during MTT using peripheral glucose disposal (Rd) divided by glucose concentration (expressed as ml/min/kg) where Rd is calculated by subtracting the rate of change of plasma glucose mass from total Ra.
measure: area under the curve
time frame: 1 year
description: AUC for glucagon, GLP-1, GIP, and free fatty acids (FFA), a measure of lipolysis.
measure: ghrelin measures
time frame: 1 year
description: AG and total ghrelin levels will be measured during clamp-MTT.
measure: gastric emptying
time frame: 1 year
description: Gastric emptying estimated by the gastric half-emptying time calculated from the emptying curve as the time when 50% of the total cumulated dose of acetaminophen has been eliminated46.
arm group label: saline
arm group type: Placebo Comparator
description: Saline: 0.9% saline solution
arm group label: ghrelin and exendin (9-39)
arm group type: Experimental
description: Ghrelin+Ex-9: Combination of ghrelin and Ex-9,
arm group label: Exendin (9-39)
arm group type: Experimental
description: Exendin (9-39) (25 µg/kg) bolus over 1 min followed by a continuous infusion of 2.5 µg/kg/min
arm group label: ghrelin
arm group type: Experimental
description: synthetic human Acyl Ghrelin (0.28 μg/kg) bolus over 1 min followed by 2 μg/kg/h continuous infusion,
intervention type: Drug
intervention name: Exendin (9-39)
arm group label: Exendin (9-39)
arm group label: ghrelin and exendin (9-39)
intervention type: Drug
intervention name: acyl ghrelin
arm group label: ghrelin
arm group label: ghrelin and exendin (9-39)
intervention type: Drug
intervention name: saline
arm group label: saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jenny Tong, MD, MPH
role: Principal Investigator
affiliation: University of Cincinnati
last name: Jenny Tong, MD, MPH
phone: 513-558-4446
email: jenny.tong@uc.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Cincinnati
investigator full name: David Dalessio
investigator title: Professor