<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/NCT03794739</url>
  </required_header>
  <id_info>
    <org_study_id>2018/ST/080</org_study_id>
    <nct_id>NCT03794739</nct_id>
  </id_info>
  <brief_title>Role of TMEM219 Marker in Type 1 Diabetes</brief_title>
  <acronym>NPOD</acronym>
  <official_title>Ruolo Del Marcatore TMEM219 in Corso di Diabete di Tipo 1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Milan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Milan</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Type 1 diabetes (T1D) is a chronic metabolic disease characterized by autoimmune destruction&#xD;
      of β cells of the insulin producing pancreatic islets. The different immunological approaches&#xD;
      implemented to date to treat T1D have obtained a negligible number of insulin-independent&#xD;
      individuals. The initial stages of diabetic disease are characterized by the massive and&#xD;
      progressive infiltration of T cells and autoantibodies within the tissue with the consequent&#xD;
      development of insulitis and subsequently, the destruction of pancreatic beta cells. The&#xD;
      onset of T1D has been mainly associated to a dysregulation of the immune response. However,&#xD;
      data are emerging on the importance of non-immunological factors responsible for the damage&#xD;
      to pancreatic beta cells. The investigators have recently shown that the expression of the&#xD;
      TMEM219 death factor is an essential factor in controlling the fate of stem cells in&#xD;
      diabetes.&#xD;
&#xD;
      The aim of the study is to identify new markers in the mechanism of damage to pancreatic beta&#xD;
      cells in the onset of type 1 diabetes, with particular reference to apoptotic factors such as&#xD;
      TMEM219.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      METHODS OF RECRUITING THE SUBJECTS Healthy subjects, individuals with type 1 and type 2&#xD;
      diabetes and those who are at risk of developing diabetes will be enrolled. Enrollment was&#xD;
      approved by the University of Florida Ethics Committee within the NPOD project, Network for&#xD;
      the Pancreatic Organ Donors with Diabetes.&#xD;
&#xD;
      Duration of the study: 5 years.&#xD;
&#xD;
      EXPERIMENTAL PROCEDURE:&#xD;
&#xD;
      The following analyses will be performed on the collected and received samples:&#xD;
&#xD;
        -  Study of TMEM219 expression and of other TMEM219-related markers by immunohistochemistry&#xD;
           and immunofluorescence and western blot&#xD;
&#xD;
        -  Study of TMEM219 expression and of other TMEM219-related markers by molecular biology&#xD;
           analysis&#xD;
&#xD;
        -  Analysis of the proteomic profile on collected biological liquids The above analyses&#xD;
           will be performed at the Pediatric Clinical Research Center Romeo ed Enrica Invernizzi&#xD;
           at the Sacco Hospital - University of Milan.&#xD;
&#xD;
      PREVIOUS EXPERIENCES The investigatore expertise in manipulating / studying the signaling&#xD;
      involved in the pathogenesis of type 1 diabetes has been widely recognized in several&#xD;
      publications in recent years (Diabetes 2013, Diabetes 2014, Diabetes 2015, Science&#xD;
      Translational Medicine 2017) as well as the characterization of marker expression including&#xD;
      TMEM219 (Cell Stem Cell 2015).&#xD;
&#xD;
      RELEVANCE OF THE STUDY The study offers the possibility to acquire new information on the&#xD;
      pathogenesis of diabetes and to identify new target mechanisms for designing innovative&#xD;
      therapeutic strategies in the treatment of diabetes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 8, 2020</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">September 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Altered TMEM219 expression in pancreatic islets/beta cells in diabetes.</measure>
    <time_frame>1-24 months</time_frame>
    <description>Change of TMEM219 expression in pancreatic islets/beta cells of healthy subjects as compared to that of individuals with type 1 diabetes (T1D), with type 2 diabetes (T2D) and of those at risk for developing the disease.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Increased beta cell loss due to a dysregulated TMEM219 signaling in diabetes.</measure>
    <time_frame>25 months-48 months</time_frame>
    <description>Change in TMEM219-related factors and signaling in pancreatic islets/beta cells of healthy subjects as compared to individuals with T1D, with T2D and of individuals at risk for developing the disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Altered TMEM219-peripheral regulating factors in diabetes.</measure>
    <time_frame>49 months-60 months</time_frame>
    <description>Change of peripheral factors involved in controlling TMEM219 expression/activation detected in the serum of healthy subjects as compared to individuals with T1D, with T2D and at risk for developing the disease.</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>Healthy subjects</arm_group_label>
    <description>Healthy subjects without diabetes, no recent surgery interventions, no malignancies no pregnancy.&#xD;
No intervention. No age limit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>T1D individuals</arm_group_label>
    <description>Type 1 diabetic individuals with at least 3-year of duration of the disease. No recent surgery interventions, no malignancies no pregnancy.&#xD;
No intervention. No age limit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>T2D individuals</arm_group_label>
    <description>Type 2 diabetic individuals with at least 5-year duration of the disease. No recent surgery interventions, no malignancies no pregnancy.&#xD;
No intervention. No age limit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AutoAb+ individuals</arm_group_label>
    <description>Individuals at risk for type 1 diabetes, with one or more autoantibody detected. No recent surgery interventions, no malignancies no pregnancy.&#xD;
No intervention. No age limit.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum, pancreatic sections, pancreatic islets.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The study already approved at the local Ethical Committee provides for the enrollment of&#xD;
        the following groups of subjects:&#xD;
&#xD;
          -  subjects affected by diabetes (type 1, type 2, MODY)&#xD;
&#xD;
          -  subjects at risk of developing diabetes (positive screening for autoantibodies)&#xD;
&#xD;
          -  subjects not affected by diabetes Enrollment is coordinated by the University of&#xD;
             Florida as part of the NPOD project, Network for the Pancreatic Organ Donors with&#xD;
             Diabetes.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Reported in the NPOD protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Reported in the NPOD protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paolo Fiorina, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Milan</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Francesca D'Addio, MD,PhD</last_name>
    <phone>+390250319820</phone>
    <email>francesca.daddio@unimi.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Francesca D'Addio, MD, PhD</last_name>
    <phone>+390250319820</phone>
    <phone_ext>19820</phone_ext>
    <email>francesca.daddio@unimi.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Pediatric Clinical Research Center</name>
      <address>
        <city>Milan</city>
        <zip>20157</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paolo Fiorina</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>December 31, 2018</study_first_submitted>
  <study_first_submitted_qc>January 2, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 7, 2019</study_first_posted>
  <last_update_submitted>May 9, 2023</last_update_submitted>
  <last_update_submitted_qc>May 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Milan</investigator_affiliation>
    <investigator_full_name>Paolo Fiorina, MD</investigator_full_name>
    <investigator_title>Professor of Endocrinogy University of Milan, Director of Endocrinology and Diabetology Unit ASST Fatebenefratelli-Sacco</investigator_title>
  </responsible_party>
  <keyword>Diabetes mellitus</keyword>
  <keyword>Beta cell loss</keyword>
  <keyword>Beta cell apoptosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
  </condition_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/NCT03794739
org study id: 2018/ST/080
nct id: NCT03794739
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Type 1 diabetes (T1D) is a chronic metabolic disease characterized by autoimmune destruction
      of β cells of the insulin producing pancreatic islets. The different immunological approaches
      implemented to date to treat T1D have obtained a negligible number of insulin-independent
      individuals. The initial stages of diabetic disease are characterized by the massive and
      progressive infiltration of T cells and autoantibodies within the tissue with the consequent
      development of insulitis and subsequently, the destruction of pancreatic beta cells. The
      onset of T1D has been mainly associated to a dysregulation of the immune response. However,
      data are emerging on the importance of non-immunological factors responsible for the damage
      to pancreatic beta cells. The investigators have recently shown that the expression of the
      TMEM219 death factor is an essential factor in controlling the fate of stem cells in
      diabetes.

      The aim of the study is to identify new markers in the mechanism of damage to pancreatic beta
      cells in the onset of type 1 diabetes, with particular reference to apoptotic factors such as
      TMEM219.
METHODS OF RECRUITING THE SUBJECTS Healthy subjects, individuals with type 1 and type 2
      diabetes and those who are at risk of developing diabetes will be enrolled. Enrollment was
      approved by the University of Florida Ethics Committee within the NPOD project, Network for
      the Pancreatic Organ Donors with Diabetes.

      Duration of the study: 5 years.

      EXPERIMENTAL PROCEDURE:

      The following analyses will be performed on the collected and received samples:

        -  Study of TMEM219 expression and of other TMEM219-related markers by immunohistochemistry
           and immunofluorescence and western blot

        -  Study of TMEM219 expression and of other TMEM219-related markers by molecular biology
           analysis

        -  Analysis of the proteomic profile on collected biological liquids The above analyses
           will be performed at the Pediatric Clinical Research Center Romeo ed Enrica Invernizzi
           at the Sacco Hospital - University of Milan.

      PREVIOUS EXPERIENCES The investigatore expertise in manipulating / studying the signaling
      involved in the pathogenesis of type 1 diabetes has been widely recognized in several
      publications in recent years (Diabetes 2013, Diabetes 2014, Diabetes 2015, Science
      Translational Medicine 2017) as well as the characterization of marker expression including
      TMEM219 (Cell Stem Cell 2015).

      RELEVANCE OF THE STUDY The study offers the possibility to acquire new information on the
      pathogenesis of diabetes and to identify new target mechanisms for designing innovative
      therapeutic strategies in the treatment of diabetes.
observational model: Cohort
time perspective: Retrospective
measure: Altered TMEM219 expression in pancreatic islets/beta cells in diabetes.
time frame: 1-24 months
description: Change of TMEM219 expression in pancreatic islets/beta cells of healthy subjects as compared to that of individuals with type 1 diabetes (T1D), with type 2 diabetes (T2D) and of those at risk for developing the disease.
measure: Increased beta cell loss due to a dysregulated TMEM219 signaling in diabetes.
time frame: 25 months-48 months
description: Change in TMEM219-related factors and signaling in pancreatic islets/beta cells of healthy subjects as compared to individuals with T1D, with T2D and of individuals at risk for developing the disease.
measure: Altered TMEM219-peripheral regulating factors in diabetes.
time frame: 49 months-60 months
description: Change of peripheral factors involved in controlling TMEM219 expression/activation detected in the serum of healthy subjects as compared to individuals with T1D, with T2D and at risk for developing the disease.
arm group label: Healthy subjects
description: Healthy subjects without diabetes, no recent surgery interventions, no malignancies no pregnancy.
No intervention. No age limit.
arm group label: T1D individuals
description: Type 1 diabetic individuals with at least 3-year of duration of the disease. No recent surgery interventions, no malignancies no pregnancy.
No intervention. No age limit.
arm group label: T2D individuals
description: Type 2 diabetic individuals with at least 5-year duration of the disease. No recent surgery interventions, no malignancies no pregnancy.
No intervention. No age limit.
arm group label: AutoAb+ individuals
description: Individuals at risk for type 1 diabetes, with one or more autoantibody detected. No recent surgery interventions, no malignancies no pregnancy.
No intervention. No age limit.
Serum, pancreatic sections, pancreatic islets.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Paolo Fiorina, MD, PhD
role: Principal Investigator
affiliation: University of Milan
last name: Francesca D'Addio, MD,PhD
phone: +390250319820
email: francesca.daddio@unimi.it
last name: Francesca D'Addio, MD, PhD
phone: +390250319820
phone ext: 19820
email: francesca.daddio@unimi.it
facility: 
status: Recruiting
contact: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: University of Milan
investigator full name: Paolo Fiorina, MD
investigator title: Professor of Endocrinogy University of Milan, Director of Endocrinology and Diabetology Unit ASST Fatebenefratelli-Sacco
mesh term: Diabetes Mellitus