<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/NCT02244164</url>
  </required_header>
  <id_info>
    <org_study_id>Incretine study</org_study_id>
    <nct_id>NCT02244164</nct_id>
  </id_info>
  <brief_title>Pathophysiological Study of the Increase in Pancreatic Volume in Type 2 Diabetes Treatments.</brief_title>
  <official_title>Pathophysiological Study of the Increase in Pancreatic Volume in Type 2 Diabetes Treatments.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Erasme University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Erasme University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Incretinomimetics and inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments for&#xD;
      diabetes. Previous retrospective studies have shown that these treatments induced an increase&#xD;
      in pancreatic mass with potentially a risk for pancreatitis and development of precancerous&#xD;
      lesions.&#xD;
&#xD;
      The aim of our study is to provide a better understanding of the pathophysiological&#xD;
      mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain&#xD;
      treatment of type 2 diabetes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The incretinomimetics and the inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments&#xD;
      for diabetes. The incretinomimetics are analogs of Glucagon Like Peptide 1 (GLP-1), secreted&#xD;
      from endocrine L-cells of the colon and terminal ileum peptide. Serum GLP-1 increase rapidly&#xD;
      after a meal. But its degradation is also fast. It acts on the hypothalamus by reducing&#xD;
      appetite and food intake, on the stomach by delaying gastric emptying and the level of beta&#xD;
      islet cells by inducing the synthesis and secretion of insulin (1). The incretinomimetics&#xD;
      currently marketed in Belgium (March 2014) are exenatide (Byetta ®), liraglutide (Victoza ®),&#xD;
      lixisenatide (Lyxumia ®) and very soon (April 2014) extended-release exenatide (Bydureon ®).&#xD;
      The DPP-4 prevent the degradation of GLP-1. The DPP-4 currently marketed (March 2014) are&#xD;
      sitagliptin (Januvia ®), vildagliptin (Galvus ®), saxagliptin (Onglyza ®) and (Trajenta ®)&#xD;
      linagliptin.&#xD;
&#xD;
      In diabetic patients, these treatments allow a significant reduction in fasting plasma&#xD;
      glucose and postprandial, with a low risk of hypoglycemia and no weight gain (and sometimes&#xD;
      weight loss) (2).&#xD;
&#xD;
      Their place in the management of type 2 diabetes is considered or in combination with&#xD;
      metformin, when diabetes is inadequately controlled despite maximal dose of the latter, or&#xD;
      when patients are intolerant to metformin.&#xD;
&#xD;
      A study to evaluate the safety of 'incretinomimetics therapy &quot;showed an increase in&#xD;
      pancreatic weight of 40% (3). Indeed, in a cohort of 34 pancreatic organ donors from brain&#xD;
      death, 20 patients were diabetic and 8 as incretin mimetics for over 1 year. An increase in&#xD;
      pancreatic mass on average 40% was observed compared to diabetic patients without this&#xD;
      treatment.&#xD;
&#xD;
      This study also demonstrated an increase in the mass of beta cells without restoring insulin&#xD;
      function. The advanced for this mass increase without a significant increase of cell size is&#xD;
      a hypothesis decreased apoptosis of beta cells.&#xD;
&#xD;
      Furthermore there is also an increase in the mass of cells producing α intraductulaire cell&#xD;
      proliferation. This would be responsible for the onset of pancreatitis but also the&#xD;
      appearance of endocrine microadenomas. The same study (3) also observed an increase in cell&#xD;
      proliferation in the exocrine compartment of the pancreas (ductal and acinar cells) induced&#xD;
      by incretinomimetic and an increased frequency of lesions potentially pre-cancerous PanIN 1&#xD;
      and 2 with this treatment.&#xD;
&#xD;
      Another study (4) by the same group of researchers showed that GLP-1 induced ductal cell&#xD;
      growth in rats treated with high-dose exenatide for 12 weeks. It could therefore, by ductal&#xD;
      obstruction induce pancreatitis.&#xD;
&#xD;
      All of these studies therefore warns about these new treatments potentially inducers of&#xD;
      different pancreatic lesions.&#xD;
&#xD;
      The aim of our study is to provide a better understanding of the pathophysiological&#xD;
      mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain&#xD;
      treatment of type 2 diabetes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Recruitment too slow&#xD;
  </why_stopped>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">February 13, 2023</completion_date>
  <primary_completion_date type="Actual">February 13, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Volumetric measurement of the pancreas</measure>
    <time_frame>1 year</time_frame>
    <description>A RMN will be done before and 1 year after the treatment. A comparative mesure of pancreatic volume will be performed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quantitative response to secretin</measure>
    <time_frame>1 year</time_frame>
    <description>A RMN with injection of secretin will be done before and after the treatment. A quantitative evaluation of secretin response will be performed.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Fasting glycemia</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 years a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>C-Peptide</measure>
    <time_frame>1 years</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>HbA1c</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cholesterol</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Calcium</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Phosphorus</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Urea</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Creatininemia</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Bilirubinemia</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Alcaline phosphatase</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Gamma GT</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Alanine aminotransferase</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Asparate aminotransferase</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <other_outcome>
    <measure>Lipasemia</measure>
    <time_frame>1 year</time_frame>
    <description>Quarterly during 1 year a blood analysis will be done.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Type 2 Diabetes</condition>
  <condition>Incretinomimetics</condition>
  <condition>Pancreas</condition>
  <arm_group>
    <arm_group_label>Sulfonylurea</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patient will received metformine with sulfonylurea</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Incretinomimectics</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will received metformin with sulfonylurea with GLP-1 analogue</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DPP-4 inhibitors</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will received metformin with DPP-4 inhibitors</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Incretinomimetics</intervention_name>
    <arm_group_label>DPP-4 inhibitors</arm_group_label>
    <arm_group_label>Sulfonylurea</arm_group_label>
    <other_name>- exenatide (Byetta®)</other_name>
    <other_name>- liraglutide (Victoza®)</other_name>
    <other_name>- lixisenatide (Lyxumia®)</other_name>
    <other_name>- exenatide extended-release (Bydureon®).</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DPP-4 inhibitors</intervention_name>
    <arm_group_label>Incretinomimectics</arm_group_label>
    <arm_group_label>Sulfonylurea</arm_group_label>
    <other_name>- sitagliptine (Januvia®)</other_name>
    <other_name>- vildagliptine (Galvus®)</other_name>
    <other_name>- saxagliptine (Onglyza®)</other_name>
    <other_name>- linagliptine (Trajenta®).</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 2 diabetes inadequately controlled or intolerant to metformin&#xD;
&#xD;
          -  Obtaining informed consent&#xD;
&#xD;
          -  Aged between 18 and 70 years&#xD;
&#xD;
          -  BMI between 20 and 45 kg / m²&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to nuclear magnetic resonance (NMR):&#xD;
&#xD;
          -  Carrying a metallic foreign body (pacemaker, valve, intraocular equipment, clips)&#xD;
&#xD;
          -  Allergy to Gadolinium / Secretin&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Contraindication to treatment with incretinomimetic:&#xD;
&#xD;
          -  Hypersensitivity to the active substance or to any of the excipients&#xD;
&#xD;
          -  Severe Gastroparesis&#xD;
&#xD;
          -  Severe renal impairment&#xD;
&#xD;
          -  History of Surgery (gastroduodenal, pancreatic or ileocecal)&#xD;
&#xD;
          -  Presence or history of pancreatic disease&#xD;
&#xD;
          -  Active alcoholism&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vincent Huberty, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gastroenterology Department Erasme Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Gastroenterology Department Erasme Hospital</name>
      <address>
        <city>Brussels</city>
        <zip>1070</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <results_reference>
    <citation>Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006 Nov 11;368(9548):1696-705. doi: 10.1016/S0140-6736(06)69705-5.</citation>
    <PMID>17098089</PMID>
  </results_reference>
  <results_reference>
    <citation>Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007 Jul 11;298(2):194-206. doi: 10.1001/jama.298.2.194.</citation>
    <PMID>17622601</PMID>
  </results_reference>
  <results_reference>
    <citation>Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013 Jul;62(7):2595-604. doi: 10.2337/db12-1686. Epub 2013 Mar 22.</citation>
    <PMID>23524641</PMID>
  </results_reference>
  <results_reference>
    <citation>Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care. 2013 Jul;36(7):2118-25. doi: 10.2337/dc12-2713. Epub 2013 May 3.</citation>
    <PMID>23645885</PMID>
  </results_reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>September 15, 2014</study_first_submitted>
  <study_first_submitted_qc>September 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2014</study_first_posted>
  <last_update_submitted>February 14, 2023</last_update_submitted>
  <last_update_submitted_qc>February 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Type 2 Diabetes</keyword>
  <keyword>Incretinomimetics</keyword>
  <keyword>DPP-4 inhibitors</keyword>
  <keyword>Pancreas</keyword>
  <keyword>PanIN</keyword>
  <keyword>RMN</keyword>
  <keyword>Lipasemia</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>Liraglutide</mesh_term>
    <mesh_term>Exenatide</mesh_term>
    <mesh_term>Lixisenatide</mesh_term>
    <mesh_term>Dipeptidyl-Peptidase IV Inhibitors</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/NCT02244164
org study id: Incretine study
nct id: NCT02244164
lead sponsor: 
has dmc: No
Incretinomimetics and inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments for
      diabetes. Previous retrospective studies have shown that these treatments induced an increase
      in pancreatic mass with potentially a risk for pancreatitis and development of precancerous
      lesions.

      The aim of our study is to provide a better understanding of the pathophysiological
      mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain
      treatment of type 2 diabetes.
The incretinomimetics and the inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments
      for diabetes. The incretinomimetics are analogs of Glucagon Like Peptide 1 (GLP-1), secreted
      from endocrine L-cells of the colon and terminal ileum peptide. Serum GLP-1 increase rapidly
      after a meal. But its degradation is also fast. It acts on the hypothalamus by reducing
      appetite and food intake, on the stomach by delaying gastric emptying and the level of beta
      islet cells by inducing the synthesis and secretion of insulin (1). The incretinomimetics
      currently marketed in Belgium (March 2014) are exenatide (Byetta ®), liraglutide (Victoza ®),
      lixisenatide (Lyxumia ®) and very soon (April 2014) extended-release exenatide (Bydureon ®).
      The DPP-4 prevent the degradation of GLP-1. The DPP-4 currently marketed (March 2014) are
      sitagliptin (Januvia ®), vildagliptin (Galvus ®), saxagliptin (Onglyza ®) and (Trajenta ®)
      linagliptin.

      In diabetic patients, these treatments allow a significant reduction in fasting plasma
      glucose and postprandial, with a low risk of hypoglycemia and no weight gain (and sometimes
      weight loss) (2).

      Their place in the management of type 2 diabetes is considered or in combination with
      metformin, when diabetes is inadequately controlled despite maximal dose of the latter, or
      when patients are intolerant to metformin.

      A study to evaluate the safety of 'incretinomimetics therapy "showed an increase in
      pancreatic weight of 40% (3). Indeed, in a cohort of 34 pancreatic organ donors from brain
      death, 20 patients were diabetic and 8 as incretin mimetics for over 1 year. An increase in
      pancreatic mass on average 40% was observed compared to diabetic patients without this
      treatment.

      This study also demonstrated an increase in the mass of beta cells without restoring insulin
      function. The advanced for this mass increase without a significant increase of cell size is
      a hypothesis decreased apoptosis of beta cells.

      Furthermore there is also an increase in the mass of cells producing α intraductulaire cell
      proliferation. This would be responsible for the onset of pancreatitis but also the
      appearance of endocrine microadenomas. The same study (3) also observed an increase in cell
      proliferation in the exocrine compartment of the pancreas (ductal and acinar cells) induced
      by incretinomimetic and an increased frequency of lesions potentially pre-cancerous PanIN 1
      and 2 with this treatment.

      Another study (4) by the same group of researchers showed that GLP-1 induced ductal cell
      growth in rats treated with high-dose exenatide for 12 weeks. It could therefore, by ductal
      obstruction induce pancreatitis.

      All of these studies therefore warns about these new treatments potentially inducers of
      different pancreatic lesions.

      The aim of our study is to provide a better understanding of the pathophysiological
      mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain
      treatment of type 2 diabetes.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Volumetric measurement of the pancreas
time frame: 1 year
description: A RMN will be done before and 1 year after the treatment. A comparative mesure of pancreatic volume will be performed.
measure: Quantitative response to secretin
time frame: 1 year
description: A RMN with injection of secretin will be done before and after the treatment. A quantitative evaluation of secretin response will be performed.
measure: Fasting glycemia
time frame: 1 year
description: Quarterly during 1 years a blood analysis will be done.
measure: C-Peptide
time frame: 1 years
description: Quarterly during 1 year a blood analysis will be done.
measure: HbA1c
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Cholesterol
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Calcium
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Phosphorus
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Urea
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Creatininemia
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Bilirubinemia
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Alcaline phosphatase
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Gamma GT
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Alanine aminotransferase
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Asparate aminotransferase
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
measure: Lipasemia
time frame: 1 year
description: Quarterly during 1 year a blood analysis will be done.
arm group label: Sulfonylurea
arm group type: Active Comparator
description: Patient will received metformine with sulfonylurea
arm group label: Incretinomimectics
arm group type: Active Comparator
description: Patients will received metformin with sulfonylurea with GLP-1 analogue
arm group label: DPP-4 inhibitors
arm group type: Active Comparator
description: Patients will received metformin with DPP-4 inhibitors
intervention type: Drug
intervention name: Incretinomimetics
arm group label: DPP-4 inhibitors
arm group label: Sulfonylurea
other name: - exenatide (Byetta®)
other name: - liraglutide (Victoza®)
other name: - lixisenatide (Lyxumia®)
other name: - exenatide extended-release (Bydureon®).
intervention type: Drug
intervention name: DPP-4 inhibitors
arm group label: Incretinomimectics
arm group label: Sulfonylurea
other name: - sitagliptine (Januvia®)
other name: - vildagliptine (Galvus®)
other name: - saxagliptine (Onglyza®)
other name: - linagliptine (Trajenta®).
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Vincent Huberty, MD
role: Principal Investigator
affiliation: Gastroenterology Department Erasme Hospital
facility: 
country: Belgium
citation: Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006 Nov 11;368(9548):1696-705. doi: 10.1016/S0140-6736(06)69705-5.
PMID: 17098089
citation: Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007 Jul 11;298(2):194-206. doi: 10.1001/jama.298.2.194.
PMID: 17622601
citation: Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013 Jul;62(7):2595-604. doi: 10.2337/db12-1686. Epub 2013 Mar 22.
PMID: 23524641
citation: Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care. 2013 Jul;36(7):2118-25. doi: 10.2337/dc12-2713. Epub 2013 May 3.
PMID: 23645885
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Liraglutide
mesh term: Exenatide
mesh term: Lixisenatide
mesh term: Dipeptidyl-Peptidase IV Inhibitors