<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/NCT04478409</url>
  </required_header>
  <id_info>
    <org_study_id>69HCL20_0236</org_study_id>
    <nct_id>NCT04478409</nct_id>
  </id_info>
  <brief_title>Characterization of a Functional Test for Mediterranean Family Fever Screening - 2</brief_title>
  <acronym>DEPIST-FMF 2</acronym>
  <official_title>Characterization of a Functional Test for Mediterranean Family Fever Screening - 2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospices Civils de Lyon</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospices Civils de Lyon</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease (prevalence:&#xD;
      1-5 / 10,000 inhabitants). It is caused by mutations in the MEFV gene, which encodes variants&#xD;
      of the Pyrine inflammasome. Inflammasomes are protein complexes of the innate immunity that&#xD;
      produce pro-inflammatory cytokines (interleukin-1β).&#xD;
&#xD;
      In vitro, our preliminary results demonstrated that the activation of the inflammatory pyrine&#xD;
      (measured by the concentration of interleukin-1β) by kinase inhibitors is significantly&#xD;
      increased in FMF patients compared to healthy subjects. Furthermore, a measurement of cell&#xD;
      death gave significant results in differentiating the patients from the controls.&#xD;
&#xD;
      The performance of this functional has been tested, fast and simple diagnostic test on common&#xD;
      mutations and wish to assess its characteristics for MEFV mutations.&#xD;
&#xD;
      The investigators hypothesize that this quick and simple functional test can serve as a&#xD;
      diagnostic tool for FMF and can quantitatively discriminate against patients with different&#xD;
      mutations (genotypes).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 21, 2021</start_date>
  <completion_date type="Anticipated">June 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Quantification of interleukin-1β</measure>
    <time_frame>At inclusion</time_frame>
    <description>quantification of the capacity of the concentration of interleukin-1β measured in the supernatants of primary monocytes in response to kinase inhibitors, to discriminate between FMF subjects among themselves according to genotypes, and among control subjects (healthy subjects).&#xD;
All samples will be analysed in the INSERM Unit 1111 - CIRI Centre International de Recherche en Infectiologie - Lyon - Team Inflammasome, bacterial infections and autoinflammation.</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Familial Mediterranean Fever</condition>
  <condition>MEFV Gene Mutation</condition>
  <arm_group>
    <arm_group_label>Children or adult with Familial Mediterranean fever</arm_group_label>
    <description>Considering 5 clearly pathogenic (homozygous) genotypes, 15 possibly pathogenic genotypes (5 pathogenic mutations in the heterozygous state, 10 possibly pathogenic mutations in the homozygous or heterozygous state), a number of 80 patients will be necessary to cover the correlation analysis genotype / phenotype.&#xD;
The study does not change the usual course of care. Only an additional blood sample (4 ml for children under 12 and 10 ml for children 12 and over and adults) during a planned blood test is specific to research (no risk added). The benefit / risk balance therefore remains unchanged with regard to the usual care of patients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy blood donor</arm_group_label>
    <description>Healthy blood donor</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>one additional blood sample during a planned blood test</intervention_name>
    <description>The study does not change the usual course of care. Only an additional blood sample (4 ml for children under 12 and 10 ml for children 12 and over and adults) during a planned blood test is specific to research (no risk added). The benefit / risk balance therefore remains unchanged with regard to the usual care of patients.</description>
    <arm_group_label>Children or adult with Familial Mediterranean fever</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Sample will be code and sent to the laboratory within 24 hours (Inserm U1111, Lyon). For&#xD;
      healthy subjects, research does not involve drawing additional blood from their blood&#xD;
      donation.&#xD;
&#xD;
      There will be no long-term storage or establishment of biological collections. The monocytes&#xD;
      will be extracted, selected and counted. The pyras inflammasome will then be activated and&#xD;
      the interleukin-1β secretion will be measured by ELISA. Cell death will be quantified in real&#xD;
      time by fluorimetry.&#xD;
&#xD;
      Validation on cellular models in vitro: immortalized monocytes will be invalidated for the&#xD;
      MEFV gene by CrispR-Cas9 and different inducible variants of the MEFV gene will be expressed&#xD;
      in MEFV knot out cells. These genetically modified cells will then undergo the tests for&#xD;
      stimulation of the inflammatory Pyrine according to the same procedures as the monocytes of&#xD;
      the patients.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This study will involve 80 patients with Familial Mediterranean fever, presenting a&#xD;
        previous genetic analysis finding at least one mutation of the MEFV gene, considered&#xD;
        pathogenic or possibly pathogenic (60 heterozygotes or complex mutations and 20&#xD;
        homozygotes). The controls will be 80 healthy subjects (French national medical and&#xD;
        scientific center (INSERM) and French blood bank (EFS) convention).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children 4 years of age or older or adults&#xD;
&#xD;
          -  Having a clinical picture compatible with an FMF and a previous genetic analysis&#xD;
             finding at least one mutation of the MEFV gene pathogenic or possibly pathogenic for&#xD;
             the FMF group;&#xD;
&#xD;
          -  Newly diagnosed or in the process of follow-up (with no time limit or evolutionary&#xD;
             criteria);&#xD;
&#xD;
          -  During specific or non-specific treatment of the disease or without treatment;&#xD;
&#xD;
          -  For whom a blood test is planned as part of routine care;&#xD;
&#xD;
          -  Whose informed non-opposition has been collected (or parental non-opposition in the&#xD;
             case of a minor patient);&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Person under legal protection or under the protection of justice or any other&#xD;
             protective measures;&#xD;
&#xD;
          -  Person out of state to express their consent;&#xD;
&#xD;
          -  Person in emergency situation, vital or not;&#xD;
&#xD;
          -  Known infections with HIV and / or HBV and / or HCV;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Yvan Jamilloux, MD</last_name>
    <phone>26 73 26 36</phone>
    <phone_ext>+33</phone_ext>
    <email>yvan.jamilloux@chu-lyon.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Hôpital Femme-Mère-Enfant</name>
      <address>
        <city>Bron</city>
        <zip>69677</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Alexandre Belot, Pr</last_name>
      <phone>4 27 85 61 28</phone>
      <phone_ext>+33</phone_ext>
      <email>alexandre.belot@chu-lyon.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>CH de Versailles - Hôpital André Mignot</name>
      <address>
        <city>Le Chesnay</city>
        <zip>78157</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Véronique Hentgen, MD</last_name>
      <phone>1 39 63 90 98</phone>
      <phone_ext>+33</phone_ext>
      <email>vhentgen@ch-versailles.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hôpital Edouard Herriot</name>
      <address>
        <city>Lyon</city>
        <zip>69008</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Arnaud Hot, Pr</last_name>
      <phone>4 72 11 75 65</phone>
      <phone_ext>+33</phone_ext>
      <email>arnaud.hot@chu-lyon.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hôpital de la Croix-Rousse</name>
      <address>
        <city>Lyon</city>
        <zip>69317</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yvan Jamilloux, MC/PH</last_name>
      <phone>26 73 26 36</phone>
      <phone_ext>+33</phone_ext>
      <email>yvan.jamilloux@chu-lyon.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Montpellier</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Aurelia Carbasse, MD</last_name>
      <phone>4 67 33 67 33</phone>
      <phone_ext>+33</phone_ext>
      <email>aurelia.carbasse@chu-montpellier.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Service de Pédiatrie - CHU de Nîmes - Hôpital Carémeau</name>
      <address>
        <city>Nîmes</city>
        <zip>30029</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Tu Anh TRAN, MD</last_name>
      <email>tu.anh.TRAN@chu-nimes.fr</email>
    </contact>
    <investigator>
      <last_name>Tu Anh TRAN, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Tenon</name>
      <address>
        <city>Paris</city>
        <zip>75020</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Gilles Grateau, Pr</last_name>
      <phone>1 56 01 66 15</phone>
      <phone_ext>+33</phone_ext>
      <email>gilles.grateau@aphp.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hôpital Lyon Sud</name>
      <address>
        <city>Pierre-Bénite</city>
        <zip>69495</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Isabelle Durieu, Pr</last_name>
      <phone>4 78 86 13 54</phone>
      <phone_ext>+33</phone_ext>
      <email>Isabelle.durieu@chu-lyon.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>July 16, 2020</study_first_submitted>
  <study_first_submitted_qc>July 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>November 15, 2021</last_update_submitted>
  <last_update_submitted_qc>November 15, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 22, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Familial Mediterranean fever</keyword>
  <keyword>Interleukin-1β</keyword>
  <keyword>MEFV gene mutation</keyword>
  <keyword>innate immunity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brucellosis</mesh_term>
    <mesh_term>Familial Mediterranean Fever</mesh_term>
    <mesh_term>Hereditary Autoinflammatory Diseases</mesh_term>
    <mesh_term>Fever</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/NCT04478409
org study id: 69HCL20_0236
nct id: NCT04478409
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease (prevalence:
      1-5 / 10,000 inhabitants). It is caused by mutations in the MEFV gene, which encodes variants
      of the Pyrine inflammasome. Inflammasomes are protein complexes of the innate immunity that
      produce pro-inflammatory cytokines (interleukin-1β).

      In vitro, our preliminary results demonstrated that the activation of the inflammatory pyrine
      (measured by the concentration of interleukin-1β) by kinase inhibitors is significantly
      increased in FMF patients compared to healthy subjects. Furthermore, a measurement of cell
      death gave significant results in differentiating the patients from the controls.

      The performance of this functional has been tested, fast and simple diagnostic test on common
      mutations and wish to assess its characteristics for MEFV mutations.

      The investigators hypothesize that this quick and simple functional test can serve as a
      diagnostic tool for FMF and can quantitatively discriminate against patients with different
      mutations (genotypes).
observational model: Case-Control
time perspective: Prospective
measure: Quantification of interleukin-1β
time frame: At inclusion
description: quantification of the capacity of the concentration of interleukin-1β measured in the supernatants of primary monocytes in response to kinase inhibitors, to discriminate between FMF subjects among themselves according to genotypes, and among control subjects (healthy subjects).
All samples will be analysed in the INSERM Unit 1111 - CIRI Centre International de Recherche en Infectiologie - Lyon - Team Inflammasome, bacterial infections and autoinflammation.
arm group label: Children or adult with Familial Mediterranean fever
description: Considering 5 clearly pathogenic (homozygous) genotypes, 15 possibly pathogenic genotypes (5 pathogenic mutations in the heterozygous state, 10 possibly pathogenic mutations in the homozygous or heterozygous state), a number of 80 patients will be necessary to cover the correlation analysis genotype / phenotype.
The study does not change the usual course of care. Only an additional blood sample (4 ml for children under 12 and 10 ml for children 12 and over and adults) during a planned blood test is specific to research (no risk added). The benefit / risk balance therefore remains unchanged with regard to the usual care of patients.
arm group label: Healthy blood donor
description: Healthy blood donor
intervention type: Biological
intervention name: one additional blood sample during a planned blood test
description: The study does not change the usual course of care. Only an additional blood sample (4 ml for children under 12 and 10 ml for children 12 and over and adults) during a planned blood test is specific to research (no risk added). The benefit / risk balance therefore remains unchanged with regard to the usual care of patients.
arm group label: Children or adult with Familial Mediterranean fever
Sample will be code and sent to the laboratory within 24 hours (Inserm U1111, Lyon). For
      healthy subjects, research does not involve drawing additional blood from their blood
      donation.

      There will be no long-term storage or establishment of biological collections. The monocytes
      will be extracted, selected and counted. The pyras inflammasome will then be activated and
      the interleukin-1β secretion will be measured by ELISA. Cell death will be quantified in real
      time by fluorimetry.

      Validation on cellular models in vitro: immortalized monocytes will be invalidated for the
      MEFV gene by CrispR-Cas9 and different inducible variants of the MEFV gene will be expressed
      in MEFV knot out cells. These genetically modified cells will then undergo the tests for
      stimulation of the inflammatory Pyrine according to the same procedures as the monocytes of
      the patients.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 4 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Yvan Jamilloux, MD
phone: 26 73 26 36
phone ext: +33
email: yvan.jamilloux@chu-lyon.fr
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Brucellosis
mesh term: Familial Mediterranean Fever
mesh term: Hereditary Autoinflammatory Diseases
mesh term: Fever