<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/NCT02212522</url>
  </required_header>
  <id_info>
    <org_study_id>AOM 08049</org_study_id>
    <nct_id>NCT02212522</nct_id>
  </id_info>
  <brief_title>Genetic and Environmental Risk Factors of Type 1 Autoimmune Diabetes and Its Early Complications</brief_title>
  <acronym>ISIS-DIAB</acronym>
  <official_title>Genetic and Environmental Risk Factors of Type 1 Autoimmune Diabetes and Its Early Complications. French Multicentric Cohort of Diabetic Patients.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centre National de Génotypage</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study is to complete the identification of genetic factors (G) and to&#xD;
      undertake the search of environmental factors (E) predisposing to type 1 diabetes (T1D) by&#xD;
      constituting a cohort of 3500 T1D patients and a control cohort. We will use the base of G&#xD;
      analysis (whole genome genotyping done once a patient using methods conually updated at&#xD;
      Centre National de Genotype) and innovative E analysis to develop the following long term&#xD;
      objectives :&#xD;
&#xD;
        -  Identify G and E factors influencing the process of remaining beta cells' destruction&#xD;
           during the first 3 years after diagnosis (subgroup of T1D patients with a 0-3 years&#xD;
           diabetes duration);&#xD;
&#xD;
        -  Identify G factors (pharmacogenomics) of the individual response to insulin using the&#xD;
           effective insulin dose as a phenotype over a period of 2 years (subgroup of T1D patients&#xD;
           with negative C-peptide and well managed diabetes);&#xD;
&#xD;
        -  Undertake a prospective research of G and E risk factors of &quot;death in bed&quot; syndrome in&#xD;
           diabetic adolescents;&#xD;
&#xD;
        -  Undertake a prospective research of G and E risk factors of incipient glomerular&#xD;
           microangiopathy (regule measurement of microalbuminuria).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Still recognized in youth only at a stage of complete beta-cell mass destruction and insulin&#xD;
      deficiency, autoimmune T1D remains a source of major morbidity through daily life and chronic&#xD;
      angiopathic complications despite a better glycemic control. T1D onset is now predominantly&#xD;
      pediatric, since its incidence shows a rapid and continuous increase in young European&#xD;
      children, due to unknown emerging environmental changes, creating a major need for&#xD;
      discoveries in the environmental field. Finding avoidable E factors can allow T1D prevention&#xD;
      in the whole children population. Lack of infectious exposures (&quot;the hygiene hypothesis&quot;),&#xD;
      viruses, early nutrition, or other factors have been suspected, but E causes of T1D remain a&#xD;
      black box, as for most human diseases, that should now be approached more systematically and&#xD;
      with respect to gene-environment interactions.&#xD;
&#xD;
      The aim of our study is to complete the identification of genetic factors (G) and to&#xD;
      undertake the search of environmental factors (E) predisposing to type 1 diabetes (T1D) by&#xD;
      constituting a cohort of 3500 T1D patients and a control cohort. We will use the base of G&#xD;
      analysis (whole genome genotyping done once a patient using methods conually updated at&#xD;
      Centre National de Genotype) and innovative E analysis to develop the following long term&#xD;
      objectives :&#xD;
&#xD;
        -  Identify G and E factors influencing the process of remaining beta cells' destruction&#xD;
           during the first 3 years after diagnosis (subgroup of T1D patients with a 0-3 years&#xD;
           diabetes duration);&#xD;
&#xD;
        -  Identify G factors (pharmacogenomics) of the individual response to insulin using the&#xD;
           effective insulin dose as a phenotype over a period of 2 years (subgroup of T1D patients&#xD;
           with negative C-peptide and well managed diabetes);&#xD;
&#xD;
        -  Undertake a prospective research of G and E risk factors of &quot;death in bed&quot; syndrome in&#xD;
           diabetic adolescents;&#xD;
&#xD;
        -  Undertake a prospective research of G and E risk factors of incipient glomerular&#xD;
           microangiopathy (regule measurement of microalbuminuria).&#xD;
&#xD;
      We propose to constitute a French multicentric cohort of T1D patients, well phenotyped by 3&#xD;
      data types : genetic, environmental and clinical data. The data collection scheme includes at&#xD;
      entry a comprehensive 850 items environmental questionnaire for all subjects and a full&#xD;
      genotyping with at least 500,000 SNPs until whole-genome sequencing can be deployed by&#xD;
      CNG-CEA. Every 6 months, a standardized clinical assessment is made in patients (a WEB&#xD;
      application ensuring this standardization has already been developed). Personal address(es)&#xD;
      will be collected and geocoded, then mapped with environmental geographic information systems&#xD;
      (GIS).&#xD;
&#xD;
      With environmental modelling, the high dimensionality analyses (HDA) constitutes one of the&#xD;
      main originality of ISIS-DIAB approaches of translational research. HDA will face not only a&#xD;
      massive mass of data, but data of a remarkable diversity (genomic variants, environmental&#xD;
      items from questionnaires, environmental data bases mapped to patient address, space-time&#xD;
      items, characteristics of social environment, clinical phenotypes etc). A given genotype&#xD;
      (defined by many genomic variants) will predispose to T1D only in a given environmental&#xD;
      context (defined possibly by a number of factors) and induce a given type of autoimmune&#xD;
      process (age of onset, rate of destruction, biomarkers). Since T1D is both multifactorial and&#xD;
      heterogeneous, causal factors may interact in a considerable number of scenarii, thus&#xD;
      platforms which study these factors should obviously interact. Without HDA, each platform&#xD;
      would be left faced with its own data. The chef d'orchestre has to be HDA, to integrate the&#xD;
      massive amounts of data and draw networks of causality. Technological advances in HDA&#xD;
      developed in other fields of sciences, business and economics (forecasting technology) will&#xD;
      be transferred to biomedical research through ISIS-DIAB. French have a strong tradition of&#xD;
      high-level maths in this area. We designed the ISIS-DIAB cohort and collection of data to&#xD;
      feed HDA with multidisciplinary data. In ISIS-DIAB program, HDA will identify the variables&#xD;
      that have the most predictive value on several outcomes (not confined to T1D causality).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>November 2004</start_date>
  <completion_date type="Anticipated">June 2018</completion_date>
  <primary_completion_date type="Anticipated">December 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
  </study_design_info>
  <primary_outcome>
    <measure>Genetic and environmental risk factors of T1D predisposition</measure>
    <time_frame>10 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Genetic and environmental risk factors of T1D complications</measure>
    <time_frame>10 years</time_frame>
    <description>Regular measurement of microalbuminuria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify G and E factors influencing the process of remaining beta cells' destruction during the first 3 years after diagnosis</measure>
    <time_frame>5 years</time_frame>
    <description>Subgroup of T1D patients with a 0-3 years diabetes duration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify G factors (pharmacogenomics) of the individual response to insulin using the effective insulin dose as a phenotype over a period of 2 years</measure>
    <time_frame>4 years</time_frame>
    <description>Subgroup of T1D patients with negative C-peptide and well managed diabetes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Undertake a prospective research of G and E risk factors of &quot;death in bed&quot; syndrome in diabetic adolescents</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">20000</enrollment>
  <condition>Diabetes Mellitus</condition>
  <condition>Insulin-Dependent</condition>
  <arm_group>
    <arm_group_label>Isis-Diab patients</arm_group_label>
    <description>French T1D patients with genetic data (GWAS), and environmental data (questionnaire and environmental databases), clinical data</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Isis-Diab controls</arm_group_label>
    <description>French control population with genetic data (GWAS) and environmental data (questionnaire and environmental databases</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Collect of environmental data on T1D patients before diagnosis</intervention_name>
    <description>Questionnaires on large environment during mother's pregnancy and patient's childhood, health book copies, addresses' geolocation, quantification of viral exposures using Sentinel Network data</description>
    <arm_group_label>Isis-Diab patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Collect of blood samples for DNA extraction and genetic characterization (GWAS)</intervention_name>
    <description>Collect of blood samples for DNA extraction and genetic characterization (GWAS) on Illumina platform (Centre National de Genotype)</description>
    <arm_group_label>Isis-Diab patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Collect of clinical data on the disease and its evolution</intervention_name>
    <description>Collect of clinical data on the disease and its evolution every 6 months after enrollment</description>
    <arm_group_label>Isis-Diab patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Collect of environmental data on French controls (age-matched for T1D patients)</intervention_name>
    <description>Questionnaires on large environment during mother's pregnancy and patient's childhood, health book copies, addresses' geolocation, quantification of viral exposures using Sentinel Network data</description>
    <arm_group_label>Isis-Diab controls</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Collect of blood samples for DNA extraction and genetic characterization (GWAS)</intervention_name>
    <description>Collect of blood samples for DNA extraction and genetic characterization (GWAS) on Illumina platform (Centre National de Genotype)</description>
    <arm_group_label>Isis-Diab controls</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      whole blood&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients: T1D patients are enrolled into the Isis-Diab cohort, continuously, from 110&#xD;
        clinical diabetes centers distributed over the whole France territory. Inclusion in the&#xD;
        cohort occurs most often soon after the initial diagnosis of T1D. This diagnosis is made&#xD;
        according to classical criteria of autoimmune T1D.&#xD;
&#xD;
        Controls: we will recruit age-matched controls among friend patients' families and among&#xD;
        cases admitted in the participating centers for benign transient intercurrent events.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Insulin-dependent diabetes&#xD;
&#xD;
          -  Patients older than 6 months at inclusion&#xD;
&#xD;
          -  European or North African geographical origin (defined by the birthplaces of the 4&#xD;
             grandparents), for the purpose of genetic homogeneity of the cohort&#xD;
&#xD;
          -  Anti-GAD, IA2, and insulin autoantibodies, that are present only in the first year of&#xD;
             the disease evolution, are not a criterion of absolute inclusion (low risk of error)&#xD;
             but will be noted if they were searched at diagnosis&#xD;
&#xD;
          -  Informed consent dated and voluntarily signed (patient and/or parents)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non-insulin dependent diabetes&#xD;
&#xD;
          -  MODY&#xD;
&#xD;
          -  Severe psychological problems, co-morbidities that could possibly invalidate informed&#xD;
             consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pierre BOUGNERES, MD-PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Inserm U986/ Pediatric endocrinology department of the Bicêtre hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Sophie Le Fur, PhD</last_name>
    <phone>+33 1 49 59 53 43</phone>
    <email>sophie.le-fur@inserm.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Laurence LECOMTE, PhD</last_name>
    <phone>+33 1 71 19 64 94</phone>
    <email>laurence.lecomte@nck.aphp.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Inserm U986</name>
      <address>
        <city>Le Kremlin Bicêtre</city>
        <zip>94276</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sophie Le Fur, PhD</last_name>
      <phone>+ 33 1 49 59 53 43</phone>
      <email>sophie.le-fur@inserm.fr</email>
    </contact>
    <contact_backup>
      <last_name>Laurence Lecomte, PhD</last_name>
      <phone>+33 1 71 19 64 94</phone>
      <email>laurence.lecomte@nck.aphp.fr</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <link>
    <url>http://www.isis-diab.org</url>
    <description>public web-site of the Isis-Diab cohort</description>
  </link>
  <verification_date>June 2016</verification_date>
  <study_first_submitted>August 6, 2014</study_first_submitted>
  <study_first_submitted_qc>August 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 8, 2014</study_first_posted>
  <last_update_submitted>June 27, 2016</last_update_submitted>
  <last_update_submitted_qc>June 27, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">June 28, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes Mellitus</keyword>
  <keyword>Insulin-Dependent</keyword>
  <keyword>Genome-Wide Association Study</keyword>
  <keyword>Environment-Wide Association Study</keyword>
  <keyword>Predisposition</keyword>
  <keyword>Complications</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 1</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT02212522
org study id: AOM 08049
nct id: NCT02212522
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
The aim of this study is to complete the identification of genetic factors (G) and to
      undertake the search of environmental factors (E) predisposing to type 1 diabetes (T1D) by
      constituting a cohort of 3500 T1D patients and a control cohort. We will use the base of G
      analysis (whole genome genotyping done once a patient using methods conually updated at
      Centre National de Genotype) and innovative E analysis to develop the following long term
      objectives :

        -  Identify G and E factors influencing the process of remaining beta cells' destruction
           during the first 3 years after diagnosis (subgroup of T1D patients with a 0-3 years
           diabetes duration);

        -  Identify G factors (pharmacogenomics) of the individual response to insulin using the
           effective insulin dose as a phenotype over a period of 2 years (subgroup of T1D patients
           with negative C-peptide and well managed diabetes);

        -  Undertake a prospective research of G and E risk factors of "death in bed" syndrome in
           diabetic adolescents;

        -  Undertake a prospective research of G and E risk factors of incipient glomerular
           microangiopathy (regule measurement of microalbuminuria).
Still recognized in youth only at a stage of complete beta-cell mass destruction and insulin
      deficiency, autoimmune T1D remains a source of major morbidity through daily life and chronic
      angiopathic complications despite a better glycemic control. T1D onset is now predominantly
      pediatric, since its incidence shows a rapid and continuous increase in young European
      children, due to unknown emerging environmental changes, creating a major need for
      discoveries in the environmental field. Finding avoidable E factors can allow T1D prevention
      in the whole children population. Lack of infectious exposures ("the hygiene hypothesis"),
      viruses, early nutrition, or other factors have been suspected, but E causes of T1D remain a
      black box, as for most human diseases, that should now be approached more systematically and
      with respect to gene-environment interactions.

      The aim of our study is to complete the identification of genetic factors (G) and to
      undertake the search of environmental factors (E) predisposing to type 1 diabetes (T1D) by
      constituting a cohort of 3500 T1D patients and a control cohort. We will use the base of G
      analysis (whole genome genotyping done once a patient using methods conually updated at
      Centre National de Genotype) and innovative E analysis to develop the following long term
      objectives :

        -  Identify G and E factors influencing the process of remaining beta cells' destruction
           during the first 3 years after diagnosis (subgroup of T1D patients with a 0-3 years
           diabetes duration);

        -  Identify G factors (pharmacogenomics) of the individual response to insulin using the
           effective insulin dose as a phenotype over a period of 2 years (subgroup of T1D patients
           with negative C-peptide and well managed diabetes);

        -  Undertake a prospective research of G and E risk factors of "death in bed" syndrome in
           diabetic adolescents;

        -  Undertake a prospective research of G and E risk factors of incipient glomerular
           microangiopathy (regule measurement of microalbuminuria).

      We propose to constitute a French multicentric cohort of T1D patients, well phenotyped by 3
      data types : genetic, environmental and clinical data. The data collection scheme includes at
      entry a comprehensive 850 items environmental questionnaire for all subjects and a full
      genotyping with at least 500,000 SNPs until whole-genome sequencing can be deployed by
      CNG-CEA. Every 6 months, a standardized clinical assessment is made in patients (a WEB
      application ensuring this standardization has already been developed). Personal address(es)
      will be collected and geocoded, then mapped with environmental geographic information systems
      (GIS).

      With environmental modelling, the high dimensionality analyses (HDA) constitutes one of the
      main originality of ISIS-DIAB approaches of translational research. HDA will face not only a
      massive mass of data, but data of a remarkable diversity (genomic variants, environmental
      items from questionnaires, environmental data bases mapped to patient address, space-time
      items, characteristics of social environment, clinical phenotypes etc). A given genotype
      (defined by many genomic variants) will predispose to T1D only in a given environmental
      context (defined possibly by a number of factors) and induce a given type of autoimmune
      process (age of onset, rate of destruction, biomarkers). Since T1D is both multifactorial and
      heterogeneous, causal factors may interact in a considerable number of scenarii, thus
      platforms which study these factors should obviously interact. Without HDA, each platform
      would be left faced with its own data. The chef d'orchestre has to be HDA, to integrate the
      massive amounts of data and draw networks of causality. Technological advances in HDA
      developed in other fields of sciences, business and economics (forecasting technology) will
      be transferred to biomedical research through ISIS-DIAB. French have a strong tradition of
      high-level maths in this area. We designed the ISIS-DIAB cohort and collection of data to
      feed HDA with multidisciplinary data. In ISIS-DIAB program, HDA will identify the variables
      that have the most predictive value on several outcomes (not confined to T1D causality).
observational model: Case-Control
measure: Genetic and environmental risk factors of T1D predisposition
time frame: 10 years
measure: Genetic and environmental risk factors of T1D complications
time frame: 10 years
description: Regular measurement of microalbuminuria
measure: Identify G and E factors influencing the process of remaining beta cells' destruction during the first 3 years after diagnosis
time frame: 5 years
description: Subgroup of T1D patients with a 0-3 years diabetes duration
measure: Identify G factors (pharmacogenomics) of the individual response to insulin using the effective insulin dose as a phenotype over a period of 2 years
time frame: 4 years
description: Subgroup of T1D patients with negative C-peptide and well managed diabetes
measure: Undertake a prospective research of G and E risk factors of "death in bed" syndrome in diabetic adolescents
time frame: 5 years
arm group label: Isis-Diab patients
description: French T1D patients with genetic data (GWAS), and environmental data (questionnaire and environmental databases), clinical data
arm group label: Isis-Diab controls
description: French control population with genetic data (GWAS) and environmental data (questionnaire and environmental databases
intervention type: Other
intervention name: Collect of environmental data on T1D patients before diagnosis
description: Questionnaires on large environment during mother's pregnancy and patient's childhood, health book copies, addresses' geolocation, quantification of viral exposures using Sentinel Network data
arm group label: Isis-Diab patients
intervention type: Genetic
intervention name: Collect of blood samples for DNA extraction and genetic characterization (GWAS)
description: Collect of blood samples for DNA extraction and genetic characterization (GWAS) on Illumina platform (Centre National de Genotype)
arm group label: Isis-Diab patients
intervention type: Other
intervention name: Collect of clinical data on the disease and its evolution
description: Collect of clinical data on the disease and its evolution every 6 months after enrollment
arm group label: Isis-Diab patients
intervention type: Other
intervention name: Collect of environmental data on French controls (age-matched for T1D patients)
description: Questionnaires on large environment during mother's pregnancy and patient's childhood, health book copies, addresses' geolocation, quantification of viral exposures using Sentinel Network data
arm group label: Isis-Diab controls
intervention type: Genetic
intervention name: Collect of blood samples for DNA extraction and genetic characterization (GWAS)
description: Collect of blood samples for DNA extraction and genetic characterization (GWAS) on Illumina platform (Centre National de Genotype)
arm group label: Isis-Diab controls
whole blood
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 6 Months
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Pierre BOUGNERES, MD-PhD
role: Principal Investigator
affiliation: Inserm U986/ Pediatric endocrinology department of the Bicêtre hospital
last name: Sophie Le Fur, PhD
phone: +33 1 49 59 53 43
email: sophie.le-fur@inserm.fr
last name: Laurence LECOMTE, PhD
phone: +33 1 71 19 64 94
email: laurence.lecomte@nck.aphp.fr
facility: 
status: Recruiting
contact: 
contact backup: 
country: France
url: http://www.isis-diab.org
description: public web-site of the Isis-Diab cohort
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
sharing ipd: No