<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/NCT02192853</url>
  </required_header>
  <id_info>
    <org_study_id>H-2-2012-149</org_study_id>
    <nct_id>NCT02192853</nct_id>
  </id_info>
  <brief_title>Correlation Between Plasma- and Endothelial DPP-4 Activity</brief_title>
  <official_title>Plasma and Endothelial Activity of Dipeptidyl Peptidase 4 During Different Doses of Sitagliptin</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 investigators want to estimate both the endothelial and the plasma activity of dipeptidyl&#xD;
      peptidase 4 during different doses of sitagliptin in healthy subjects and patients with type&#xD;
      2 diabetes. Furthermore, the investigators want to investigate whether the current clinical&#xD;
      dose of 100 mg of sitagliptin is sufficient to inhibit both the plasma and the endothelial&#xD;
      activity of the enzyme dipeptidyl peptidase 4.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The two incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent&#xD;
      insulinotropic polypeptide (GIP) are secreted from the intestinal L- and K- cells,&#xD;
      respectively in response to ingestion of nutrients. The two hormones are able to lower blood&#xD;
      glucose levels during high glucose levels - by the so called incretin effect. GIP and GLP-1&#xD;
      are both rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4). The remaining&#xD;
      metabolites are without insulinotropic effects. The effect of DPP-4 inhibitors used in&#xD;
      treatment of type 2 diabetes relies on their impact on DPP-4 activity.&#xD;
&#xD;
      DPP-4 exists in a soluble form in plasma ad as a membrane-bound form in blood vessels and&#xD;
      other tissues. The impact of DPP-4 inhibitors on DPP-4 activity has only been evaluated in&#xD;
      plasma. We aim to investigate plasma and endothelial DPP-4 activity (i.e. whole-body DPP-4&#xD;
      activity) in patients with type 2 diabetes during different doses of the DPP-4 inhibitor&#xD;
      sitagliptin.&#xD;
&#xD;
      Both healthy control subjects and patients with type 2 diabetes are subjected to 4&#xD;
      experimental days (in a randomized order) with continuous infusion of GLP-1 and pre-treatment&#xD;
      with 25 mg sitagliptin, 100 mg sitagliptin, 200 mg sitagliptin and placebo, respectively.&#xD;
      Afterwards, we are going to measure the whole-body DPP-4 activity by comparing plasma levels&#xD;
      of active (intact) GLP-1 and total GLP-1, and relate to plasma DPP-4 activity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>May 2013</start_date>
  <completion_date type="Actual">March 2014</completion_date>
  <primary_completion_date type="Actual">February 2014</primary_completion_date>
  <phase>Phase 4</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>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>intervention was blinded for the participant and the investigator</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Correlation between the total and intact GLP-1 hormone during different doses of sitagliptin measured as total area under the curve (tAUC)</measure>
    <time_frame>GLP.1 total and GLP-1 intact will be calculated based on blood samples at time points: -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Differences in serum-/plasma concentrations of GLP-1 measured as total Area under the curve (tAUC)</measure>
    <time_frame>GLP-1 will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in glucose measured as total Area under the curve (tAUC)</measure>
    <time_frame>Glucose will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in Insulin measured as total Area under the curve (tAUC)</measure>
    <time_frame>Insulin will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Type 2 Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>Sitagliptin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with Type 2 Diabetes Mellitus and healthy control subjects are given tablets of sitagliptin in either a dosage of 25, 100 or 200 mg tablet in 3 different days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>sitagliptin</intervention_name>
    <description>In randomized order:&#xD;
Day 1: tablet of 25 mg of sitagliptin + i.v. GLP-1 infusion Day 2: tablet of 100 mg of sitagliptin + i.v. GLP-1 infusion Day 3: tablet of 200 mg of sitagliptin + i.v. GLP-1 infusion</description>
    <arm_group_label>Sitagliptin</arm_group_label>
    <other_name>Januvia</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Day 4: placebo tablet</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Caucasians with diet and/or metformin treated patients with type 2 diabetes (diagnosed&#xD;
             according to the criterias of the World Health Organization)&#xD;
&#xD;
          -  Normal Hemoglobin&#xD;
&#xD;
          -  Prior Informed Consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Nephropathy&#xD;
&#xD;
          -  Liver disease&#xD;
&#xD;
          -  Inflammatory bowel disease&#xD;
&#xD;
          -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Filip K Knop, MD PhD</last_name>
    <role>Study Director</role>
    <affiliation>Gentofte Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tina Vilsbøll, MD DMSc</last_name>
    <role>Study Chair</role>
    <affiliation>Gentofte Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Asger Lund, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Gentofte Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Camilla Andersen, Med.stud.</last_name>
    <role>Study Chair</role>
    <affiliation>Gentofte Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jens Juul Holst, MD DMSc</last_name>
    <role>Study Chair</role>
    <affiliation>Institute of biomedical sciences, University of Copenhagen</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Emilie Skytte Andersen, Med.stud.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gentofte Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Diabetes Research Division, Department of Endocrinology, Gentofte Hospital</name>
      <address>
        <city>Hellerup</city>
        <zip>2900</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Deacon CF, Hughes TE, Holst JJ. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes. 1998 May;47(5):764-9. doi: 10.2337/diabetes.47.5.764.</citation>
    <PMID>9588448</PMID>
  </reference>
  <reference>
    <citation>Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006.</citation>
    <PMID>17928588</PMID>
  </reference>
  <reference>
    <citation>Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):127-36. doi: 10.1016/j.mce.2008.08.012. Epub 2008 Aug 20.</citation>
    <PMID>18786605</PMID>
  </reference>
  <reference>
    <citation>Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. doi: 10.2337/diab.42.5.658.</citation>
    <PMID>8482423</PMID>
  </reference>
  <reference>
    <citation>Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, Hufner M, Schmiegel WH. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46. doi: 10.1210/jcem.87.3.8355.</citation>
    <PMID>11889194</PMID>
  </reference>
  <reference>
    <citation>Gutzwiller JP, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, Beglinger C. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999 May;276(5):R1541-4. doi: 10.1152/ajpregu.1999.276.5.R1541.</citation>
    <PMID>10233049</PMID>
  </reference>
  <reference>
    <citation>Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003 Jul 15;114(2-3):115-21. doi: 10.1016/s0167-0115(03)00111-3.</citation>
    <PMID>12832099</PMID>
  </reference>
  <reference>
    <citation>Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004 Nov-Dec;36(11-12):761-5. doi: 10.1055/s-2004-826160.</citation>
    <PMID>15655705</PMID>
  </reference>
  <reference>
    <citation>Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. doi: 10.1016/j.clpt.2005.09.002.</citation>
    <PMID>16338283</PMID>
  </reference>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>January 4, 2014</study_first_submitted>
  <study_first_submitted_qc>July 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 17, 2014</study_first_posted>
  <last_update_submitted>September 7, 2017</last_update_submitted>
  <last_update_submitted_qc>September 7, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Gentofte, Copenhagen</investigator_affiliation>
    <investigator_full_name>Emilie Skytte Andersen</investigator_full_name>
    <investigator_title>Research student</investigator_title>
  </responsible_party>
  <keyword>Diabetes Mellitus</keyword>
  <keyword>Glucagon-like peptide 1</keyword>
  <keyword>Dipeptidyl peptidase 4</keyword>
  <keyword>Dipeptidyl peptidase 4 inhibitor</keyword>
  <keyword>sitagliptin</keyword>
  <keyword>Enzyme activity</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 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sitagliptin Phosphate</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/NCT02192853
org study id: H-2-2012-149
nct id: NCT02192853
lead sponsor: 
has dmc: Yes
The investigators want to estimate both the endothelial and the plasma activity of dipeptidyl
      peptidase 4 during different doses of sitagliptin in healthy subjects and patients with type
      2 diabetes. Furthermore, the investigators want to investigate whether the current clinical
      dose of 100 mg of sitagliptin is sufficient to inhibit both the plasma and the endothelial
      activity of the enzyme dipeptidyl peptidase 4.
The two incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent
      insulinotropic polypeptide (GIP) are secreted from the intestinal L- and K- cells,
      respectively in response to ingestion of nutrients. The two hormones are able to lower blood
      glucose levels during high glucose levels - by the so called incretin effect. GIP and GLP-1
      are both rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4). The remaining
      metabolites are without insulinotropic effects. The effect of DPP-4 inhibitors used in
      treatment of type 2 diabetes relies on their impact on DPP-4 activity.

      DPP-4 exists in a soluble form in plasma ad as a membrane-bound form in blood vessels and
      other tissues. The impact of DPP-4 inhibitors on DPP-4 activity has only been evaluated in
      plasma. We aim to investigate plasma and endothelial DPP-4 activity (i.e. whole-body DPP-4
      activity) in patients with type 2 diabetes during different doses of the DPP-4 inhibitor
      sitagliptin.

      Both healthy control subjects and patients with type 2 diabetes are subjected to 4
      experimental days (in a randomized order) with continuous infusion of GLP-1 and pre-treatment
      with 25 mg sitagliptin, 100 mg sitagliptin, 200 mg sitagliptin and placebo, respectively.
      Afterwards, we are going to measure the whole-body DPP-4 activity by comparing plasma levels
      of active (intact) GLP-1 and total GLP-1, and relate to plasma DPP-4 activity.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: intervention was blinded for the participant and the investigator
measure: Correlation between the total and intact GLP-1 hormone during different doses of sitagliptin measured as total area under the curve (tAUC)
time frame: GLP.1 total and GLP-1 intact will be calculated based on blood samples at time points: -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days
measure: Differences in serum-/plasma concentrations of GLP-1 measured as total Area under the curve (tAUC)
time frame: GLP-1 will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days
measure: Differences in glucose measured as total Area under the curve (tAUC)
time frame: Glucose will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days
measure: Differences in Insulin measured as total Area under the curve (tAUC)
time frame: Insulin will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days
arm group label: Sitagliptin
arm group type: Experimental
description: Patients with Type 2 Diabetes Mellitus and healthy control subjects are given tablets of sitagliptin in either a dosage of 25, 100 or 200 mg tablet in 3 different days.
arm group label: placebo
arm group type: Placebo Comparator
intervention type: Drug
intervention name: sitagliptin
description: In randomized order:
Day 1: tablet of 25 mg of sitagliptin + i.v. GLP-1 infusion Day 2: tablet of 100 mg of sitagliptin + i.v. GLP-1 infusion Day 3: tablet of 200 mg of sitagliptin + i.v. GLP-1 infusion
arm group label: Sitagliptin
other name: Januvia
intervention type: Drug
intervention name: Placebo
description: Day 4: placebo tablet
arm group label: placebo
criteria: 
gender: All
minimum age: 35 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Filip K Knop, MD PhD
role: Study Director
affiliation: Gentofte Hospital
last name: Tina Vilsbøll, MD DMSc
role: Study Chair
affiliation: Gentofte Hospital
last name: Asger Lund, MD
role: Study Chair
affiliation: Gentofte Hospital
last name: Camilla Andersen, Med.stud.
role: Study Chair
affiliation: Gentofte Hospital
last name: Jens Juul Holst, MD DMSc
role: Study Chair
affiliation: Institute of biomedical sciences, University of Copenhagen
last name: Emilie Skytte Andersen, Med.stud.
role: Principal Investigator
affiliation: Gentofte Hospital
facility: 
country: Denmark
citation: Deacon CF, Hughes TE, Holst JJ. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes. 1998 May;47(5):764-9. doi: 10.2337/diabetes.47.5.764.
PMID: 9588448
citation: Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006.
PMID: 17928588
citation: Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):127-36. doi: 10.1016/j.mce.2008.08.012. Epub 2008 Aug 20.
PMID: 18786605
citation: Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. doi: 10.2337/diab.42.5.658.
PMID: 8482423
citation: Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, Hufner M, Schmiegel WH. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46. doi: 10.1210/jcem.87.3.8355.
PMID: 11889194
citation: Gutzwiller JP, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, Beglinger C. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999 May;276(5):R1541-4. doi: 10.1152/ajpregu.1999.276.5.R1541.
PMID: 10233049
citation: Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003 Jul 15;114(2-3):115-21. doi: 10.1016/s0167-0115(03)00111-3.
PMID: 12832099
citation: Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004 Nov-Dec;36(11-12):761-5. doi: 10.1055/s-2004-826160.
PMID: 15655705
citation: Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. doi: 10.1016/j.clpt.2005.09.002.
PMID: 16338283
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Gentofte, Copenhagen
investigator full name: Emilie Skytte Andersen
investigator title: Research student
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Sitagliptin Phosphate