<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/NCT01666223</url>
  </required_header>
  <id_info>
    <org_study_id>H-1-2012-049</org_study_id>
    <nct_id>NCT01666223</nct_id>
  </id_info>
  <brief_title>Effect of Bile Acids on GLP-1 Secretion</brief_title>
  <official_title>Effect of Bile Acids in the Gut on GLP-1 Secretion in Healthy Subjects and Patients With Type 2 Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Gentofte, Copenhagen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Gentofte, Copenhagen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to describe the physiological, pathophysiological and&#xD;
      potentially therapeutic implications of bile-induced glucagon-like peptide-1 (GLP-1)&#xD;
      secretion in human glucose homeostasis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators hypothesize that even modest increments in endogenous GLP-1 secretion will&#xD;
      elicit important antidiabetic effects of GLP-1. To evaluate whether bile acids have such&#xD;
      effects, the investigators plan to perform intraduodenal infusion of two different bile acids&#xD;
      and placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">June 2013</completion_date>
  <primary_completion_date type="Actual">June 2013</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in GLP-1</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in insulin</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in C-peptide</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in glucagon</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in glucagon-like-peptide 2 (GLP-2)</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in glucose-dependent insulinotropic polypeptide (GIP)</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in peptide YY (PYY)</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in oxyntomodulin</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in bile acids</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in gastrin</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in CCK</measure>
    <time_frame>At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in appetite, satiety and prospective food consumption</measure>
    <time_frame>At baseline, and 30, 60, 90, 120 and 180 minutes</time_frame>
    <description>Evaluated by Visual Analog Scale (VAS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in gallbladder volume</measure>
    <time_frame>-30, 0 (baseline), 30, 60, 120 og 180 minutes</time_frame>
    <description>Evaluated by ultrasound</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in basal metabolic rate</measure>
    <time_frame>At -30, 60 og 150 minutes</time_frame>
    <description>Evaluated by indirect calorimetry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in bile acid composition</measure>
    <time_frame>At -30, 0, 30, 60, 120 og 180 minutes</time_frame>
    <description>Evaluated by duodenal aspiration</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Type 2 Diabetes</condition>
  <condition>Obesity</condition>
  <arm_group>
    <arm_group_label>Colesevelam</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Chenodeoxycholic acid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Colesevelam + chenodeoxycholic acid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Colesevelam</intervention_name>
    <description>Colesevelam 3750 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.</description>
    <arm_group_label>Colesevelam</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chenodeoxycholic Acid</intervention_name>
    <description>1.250 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.</description>
    <arm_group_label>Chenodeoxycholic acid</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>saline</intervention_name>
    <description>100 ml saline</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Colesevelam 3750 mg + chenodeoxycholic acid 1250 mg</intervention_name>
    <description>Colesevelam and chenodeoxycholic acid dissolved in 100 ml saline, administered in a duodenal tube at time = 0.</description>
    <arm_group_label>Colesevelam + chenodeoxycholic acid</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Patients with type 2 diabetes&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  danish caucasian ethnicity&#xD;
&#xD;
          -  normal haemoglobin&#xD;
&#xD;
          -  BMI &gt; 25 kg/m2&#xD;
&#xD;
          -  HbA1c &lt; 9%&#xD;
&#xD;
          -  informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  liver disease(ALT and AST &gt; upper reference limit)&#xD;
&#xD;
          -  gastrointestinal disease&#xD;
&#xD;
          -  liver and biliary tract disease&#xD;
&#xD;
          -  nephropathy (serum creatinine &gt; 150 μM, and/or albuminuria)&#xD;
&#xD;
          -  treatment with insulin, glp-1 analogues and/ or DPP-4 inhibitors&#xD;
&#xD;
          -  treatment with medicine that can not be paused for 12 hours&#xD;
&#xD;
          -  previous abdominal surgery eg. cholecystectomy&#xD;
&#xD;
          -  BMI &lt; 18,5 kg/m2 or &gt; 35 kg/m2&#xD;
&#xD;
        Healthy Volunteers&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  danish caucasian ethnicity&#xD;
&#xD;
          -  normal haemoglobin&#xD;
&#xD;
          -  HbA1c &lt; 6,0 (American Diabetes Association guidelines)&#xD;
&#xD;
          -  informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  liver disease(ALT and AST &gt; upper reference limit)&#xD;
&#xD;
          -  gastrointestinal disease&#xD;
&#xD;
          -  liver and biliary tract disease&#xD;
&#xD;
          -  nephropathy (serum creatinine &gt; 150 μM, and/or albuminuria)&#xD;
&#xD;
          -  treatment with medicine that can not be paused for 12 hours&#xD;
&#xD;
          -  previous abdominal surgery eg. cholecystectomy&#xD;
&#xD;
          -  BMI &lt; 18,5 kg/m2 or &gt; 35 kg/m2&#xD;
&#xD;
          -  first degree relatives diagnosed with diabetes&#xD;
&#xD;
          -  previously diagnosed with diabetes, or treated with antidiabetic agents&#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_official>
    <last_name>Morten Hansen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen</name>
      <address>
        <city>Hellerup</city>
        <state>Copenhagen</state>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002 Nov 15;298(5):714-9. doi: 10.1016/s0006-291x(02)02550-0.</citation>
    <PMID>12419312</PMID>
  </reference>
  <reference>
    <citation>Adrian TE, Ballantyne GH, Longo WE, Bilchik AJ, Graham S, Basson MD, Tierney RP, Modlin IM. Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon. Gut. 1993 Sep;34(9):1219-24. doi: 10.1136/gut.34.9.1219.</citation>
    <PMID>8406158</PMID>
  </reference>
  <reference>
    <citation>Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005 Apr 1;329(1):386-90. doi: 10.1016/j.bbrc.2005.01.139.</citation>
    <PMID>15721318</PMID>
  </reference>
  <reference>
    <citation>Rafferty EP, Wylie AR, Hand KH, Elliott CE, Grieve DJ, Green BD. Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R(-/-) mice. Biol Chem. 2011 Apr;392(6):539-46. doi: 10.1515/BC.2011.050. Epub 2011 Apr 27.</citation>
    <PMID>21521075</PMID>
  </reference>
  <verification_date>December 2013</verification_date>
  <study_first_submitted>July 11, 2012</study_first_submitted>
  <study_first_submitted_qc>August 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 16, 2012</study_first_posted>
  <last_update_submitted>December 21, 2013</last_update_submitted>
  <last_update_submitted_qc>December 21, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 24, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Gentofte, Copenhagen</investigator_affiliation>
    <investigator_full_name>Morten Hansen</investigator_full_name>
    <investigator_title>MD, PhD Student</investigator_title>
  </responsible_party>
  <keyword>Type 2 diabetes</keyword>
  <keyword>GLP-1</keyword>
  <keyword>Bile acid</keyword>
  <keyword>TGR-5</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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>Chenodeoxycholic Acid</mesh_term>
    <mesh_term>Colesevelam Hydrochloride</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/NCT01666223
org study id: H-1-2012-049
nct id: NCT01666223
lead sponsor: 
has dmc: Yes
The purpose of this study is to describe the physiological, pathophysiological and
      potentially therapeutic implications of bile-induced glucagon-like peptide-1 (GLP-1)
      secretion in human glucose homeostasis.
The investigators hypothesize that even modest increments in endogenous GLP-1 secretion will
      elicit important antidiabetic effects of GLP-1. To evaluate whether bile acids have such
      effects, the investigators plan to perform intraduodenal infusion of two different bile acids
      and placebo.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change in GLP-1
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in insulin
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in C-peptide
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in glucagon
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in glucagon-like-peptide 2 (GLP-2)
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in glucose-dependent insulinotropic polypeptide (GIP)
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in peptide YY (PYY)
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in oxyntomodulin
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in bile acids
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in gastrin
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in CCK
time frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in appetite, satiety and prospective food consumption
time frame: At baseline, and 30, 60, 90, 120 and 180 minutes
description: Evaluated by Visual Analog Scale (VAS)
measure: Change in gallbladder volume
time frame: -30, 0 (baseline), 30, 60, 120 og 180 minutes
description: Evaluated by ultrasound
measure: Change in basal metabolic rate
time frame: At -30, 60 og 150 minutes
description: Evaluated by indirect calorimetry
measure: Change in bile acid composition
time frame: At -30, 0, 30, 60, 120 og 180 minutes
description: Evaluated by duodenal aspiration
arm group label: Colesevelam
arm group type: Experimental
arm group label: Chenodeoxycholic acid
arm group type: Experimental
arm group label: Colesevelam + chenodeoxycholic acid
arm group type: Experimental
arm group label: Placebo
arm group type: Experimental
intervention type: Drug
intervention name: Colesevelam
description: Colesevelam 3750 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.
arm group label: Colesevelam
intervention type: Drug
intervention name: Chenodeoxycholic Acid
description: 1.250 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.
arm group label: Chenodeoxycholic acid
intervention type: Other
intervention name: saline
description: 100 ml saline
arm group label: Placebo
intervention type: Drug
intervention name: Colesevelam 3750 mg + chenodeoxycholic acid 1250 mg
description: Colesevelam and chenodeoxycholic acid dissolved in 100 ml saline, administered in a duodenal tube at time = 0.
arm group label: Colesevelam + chenodeoxycholic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Morten Hansen, MD
role: Principal Investigator
affiliation: Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen
facility: 
country: Denmark
citation: Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002 Nov 15;298(5):714-9. doi: 10.1016/s0006-291x(02)02550-0.
PMID: 12419312
citation: Adrian TE, Ballantyne GH, Longo WE, Bilchik AJ, Graham S, Basson MD, Tierney RP, Modlin IM. Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon. Gut. 1993 Sep;34(9):1219-24. doi: 10.1136/gut.34.9.1219.
PMID: 8406158
citation: Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005 Apr 1;329(1):386-90. doi: 10.1016/j.bbrc.2005.01.139.
PMID: 15721318
citation: Rafferty EP, Wylie AR, Hand KH, Elliott CE, Grieve DJ, Green BD. Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R(-/-) mice. Biol Chem. 2011 Apr;392(6):539-46. doi: 10.1515/BC.2011.050. Epub 2011 Apr 27.
PMID: 21521075
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Gentofte, Copenhagen
investigator full name: Morten Hansen
investigator title: MD, PhD Student
mesh term: Diabetes Mellitus, Type 2
mesh term: Chenodeoxycholic Acid
mesh term: Colesevelam Hydrochloride