xml: <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/NCT06033339</url>
    </required_header>
    <id_info>
      <org_study_id>RECHMPL22_0296 - UF 8310</org_study_id>
      <nct_id>NCT06033339</nct_id>
    </id_info>
    <brief_title>Assessment of microRNAs Role in Familial Mediterranean Fever FMF Pathophysiology</brief_title>
    <acronym>miRinFMF</acronym>
    <official_title>Etude du rôle Des microARNs Dans la Physiopathologie de la fièvre méditerranéenne Familiale</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University Hospital, Montpellier</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University Hospital, Montpellier</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>
        Familial Mediterranean Fever (FMF) genetic diagnosis is well established for homozygous&#xD;
        patients. On the other hand, although heterozygous individuals are theoretically healthy&#xD;
        carriers, 1/3 of them will develop clinical symptoms of FMF and could benefit from&#xD;
        prophylactic treatment. This suggests that the disorder expression mechanisms are not fully&#xD;
        elucidated to date. The preliminary results obtained at the Institute for Regenerative&#xD;
        Medicine and Biotherapy (IRMB) suggest the involvement of an epigenetic mechanism in FMF&#xD;
        pathogenesis, and our laboratory has strong arguments as to the involvement of microRNAs (in&#xD;
        particular miR-326) which are negative regulators of gene expression.&#xD;
  &#xD;
        This study is exploratory and aims to validate the role of miRNAs in the clinical expression&#xD;
        of FMF in patients, thus to explore the epigenetic mechanisms that may explain the&#xD;
        variability of expression of this disorder.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder due to mutations in&#xD;
        the MEFV (MEditerranean FeVer) gene, that causes recurrent episodes of fever and acute&#xD;
        serositis (peritoneum, pleura, synovium) beginning in early childhood.&#xD;
  &#xD;
        MEFV gene identification allowed the development of a genomic sequencing test to confirm the&#xD;
        diagnosis. The most frequent mutations are M680I, M694V, V726A and M694I, located in exon 10.&#xD;
        This gene encodes the protein pyrin, which, following a pro-inflammatory stimulus, is capable&#xD;
        of assembling a multi-protein complex to form the pyrin inflammasome. MEFV gene mutations&#xD;
        lead to an alteration of its expression in innate immune system cells in FMF patients,&#xD;
        causing a dysregulation of the immune response, which results in the abnormal secretion of&#xD;
        certain proinflammatory cytokines such as IL-1β and IL-18.&#xD;
  &#xD;
        FMF is an autosomal recessive disorder. Thus, heterozygous individuals are theoretically&#xD;
        healthy carriers. Nevertheless, in nearly 1/3 of patients with clinical symptoms of FMF, a&#xD;
        single heterozygous mutation is found. To date, there is no biological marker to distinguish&#xD;
        heterozygous individuals who will develop the disease from those who remain healthy carriers,&#xD;
        hence diagnostic errors and delays in treatment. Several hypotheses have been put forward to&#xD;
        explain this variation in mutation expression, whether it is the environment, the involvement&#xD;
        of other genes, or the involvement of epigenetic modifiers.&#xD;
  &#xD;
        Among the mechanisms that regulate gene expression, microRNAs (miRNAs),which are small&#xD;
        non-coding RNAs, negatively regulate gene expression at the post-transcriptional level by&#xD;
        binding to sequences located mainly in the region 3'UTR of gene mRNA. Many publications&#xD;
        report that they are abnormally expressed in various pathologies. Very recently, this has&#xD;
        been reported for FMF. Several studies have focused on miRNAs as biomarkers of FMF, without&#xD;
        evaluating their role in FMF pathogenesis.&#xD;
  &#xD;
        Assessing the role of miRNAs specifically targeting the MEFV gene in myeloid cells&#xD;
        (especially monocytes), and the functional impact of their modulation in these cells, would&#xD;
        deepen our understanding of FMF physiopathology. If a miRNA specifically targeting MEFV has a&#xD;
        proven role in FMF pathophysiology, it could ultimately prove to be a prognostic biomarker of&#xD;
        the disorder for heterozygous patients, or even a future therapeutic target.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 2, 2023</start_date>
    <completion_date type="Anticipated">October 2, 2025</completion_date>
    <primary_completion_date type="Anticipated">October 2, 2025</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <intervention_model_description>Among the 40 subjects to be enrolled: 10 are MEFV homozygous patients, 10 are symptomatic MEFV heterozygous patients, 10 are asymptomatic MEFV heterozygous patients and 10 are control subjects. All enrolled patients receive the same intervention (biological sample collection).</intervention_model_description>
      <primary_purpose>Other</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>miR-326 expression level quantification</measure>
      <time_frame>1 day (at enrollment)</time_frame>
      <description>Analyze the expression levels (quantification) of miRNA miR-326 in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects, in order to determine whether or not miR-326 influences the inflammatory response of monocytes.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>MEFV expression level quantification</measure>
      <time_frame>1 day (at enrollment)</time_frame>
      <description>Analyze the expression levels (quantification) of MEFV gene in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>miR-326 expression level comparison</measure>
      <time_frame>1 day (at enrollment)</time_frame>
      <description>Compare the expression levels of miR-326 between symptomatic and asymptomatic heterozygous groups.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>MEFV expression level comparison</measure>
      <time_frame>1 day (at enrollment)</time_frame>
      <description>Compare the expression levels of MEFV between symptomatic and asymptomatic heterozygous groups.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Blood samples collection</measure>
      <time_frame>1 day (at enrollment)</time_frame>
      <description>Create a biobank (freezing monocytes extracted from patient samples) in order to subsequently study other miRNAs</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expression levels of other candidate miRNAs targeting MEFV</measure>
      <time_frame>1 day (at enrollment)</time_frame>
      <description>Quantification of the the expression levels of other candidate miRNAs targetting MEFV within the 4 groups of participants. 5 miRNAs will be selected using a methylome study currently being carried out.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Familial Mediterranean Fever</condition>
    <arm_group>
      <arm_group_label>Blood Sampling</arm_group_label>
      <arm_group_type>Other</arm_group_type>
      <description>Collection of 10 ml of blood on EDTA tube during:&#xD;
  Standard check-up visit as a part of the standard monitoring of the disorder for homozygous and symptomatic heterozygous patients&#xD;
  Specific study visit for asymptomatic heterozygous patients&#xD;
  Presurgery blood test for control subjects</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Blood sampling</intervention_name>
      <description>Collection of 10 ml of blood on EDTA tubes per patient. Once collected, the blood tubes will be transported within 24 hours to the IRB (Biotherapy Research Institute) of Montpellier University Hospital, where the monocytes will be isolated by magnetic sorting on the basis of expression of surface marker CD14+, after a preliminary step of Ficoll. Monocytes will then be frozen in nitrogen at -196°C until use (biobank).Gain-of-function experiments will then be performed on monocytes by transfecting them with the microRNA of interest or control. The expression of the pyrin protein and its phosphorylation rate will be evaluated after induction by immunoprecipitation experiments followed by western blot. The activity of the pyrin inflammasome will also be studied by looking at pyroptosis and toxicity rate using LDH test. All these experiments will be carried out in the absence and in the presence of the microRNA in order to study its role in the pathophysiology of FMF.</description>
      <arm_group_label>Blood Sampling</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patient aged ≥1 year&#xD;
  &#xD;
            -  Body weight ≥ 10kg&#xD;
  &#xD;
            -  Homozygous patients group: patients homozygous for MEFV (M694V, M694I, M680I, V726A)&#xD;
  &#xD;
            -  Symptomatic heterozygous patients group: patients heterozygous for the MEFV gene&#xD;
               (M694V, M694I, M680I, V726A) meeting the Yalcinkaya criteria for FMF diagnosis (Fever&#xD;
               lasting 6 to 72 hours with at least 3 attacks - Abdominal pain of 6 to 72 hours&#xD;
               duration with at least 3 attacks - Chest pain of 6 to 72 hours duration with at least&#xD;
               3 attacks - Arthritis of 6 to 72 hours duration with at least 3 attacks- FMF Family&#xD;
               History of FMF)&#xD;
  &#xD;
            -  Asymptomatic heterozygous patients group: patients heterozygous for the MEFV gene&#xD;
               (M694V, M694I, M680I, V726A) who do not meet the Yalcinkaya criteria for FMF diagnosis&#xD;
  &#xD;
            -  Control subjects group: absence of identified auto-inflammatory disorder&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Absence of collection of informed consent of participant or absence of informed&#xD;
               consent of the legal representatives/guardians of pediatric participant&#xD;
  &#xD;
            -  Subjects not registered in Social Security system&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>1 Year</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Eric JEZIORSKI, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University Hospital, Montpellier</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Anna DEGUET, MD</last_name>
      <phone>0033669107224</phone>
      <email>a-deguet@chu-montpellier.fr</email>
    </overall_contact>
    <location>
      <facility>
        <name>University Hospital of Nîmes</name>
        <address>
          <city>Nîmes</city>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Tu Anh TRAN, MD</last_name>
      </contact>
      <investigator>
        <last_name>Tu Anh TRAN, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Robert Debré University Hospital of Paris</name>
        <address>
          <city>Paris</city>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Ulrich MEINZER, MD</last_name>
      </contact>
      <investigator>
        <last_name>Ulrich MEINZER, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>University Hospital of Paris Kremlin Bicêtre</name>
        <address>
          <city>Paris</city>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Isabelle KONE-PAUT, MD</last_name>
      </contact>
      <investigator>
        <last_name>Isabelle KONE-PAUT, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>University Hospital of Toulouse</name>
        <address>
          <city>Toulouse</city>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Karine BROCHARD-PAYET, MD</last_name>
      </contact>
      <investigator>
        <last_name>Karine BROCHARD-PAYET, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 5, 2023</study_first_submitted>
    <study_first_submitted_qc>September 5, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 12, 2023</last_update_submitted>
    <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>MEditerranean FeVer MEFV gene</keyword>
    <keyword>micro ribonucleic acid miRNA</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>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06033339
  org study id: RECHMPL22_0296 - UF 8310
  nct id: NCT06033339
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Familial Mediterranean Fever (FMF) genetic diagnosis is well established for homozygous
        patients. On the other hand, although heterozygous individuals are theoretically healthy
        carriers, 1/3 of them will develop clinical symptoms of FMF and could benefit from
        prophylactic treatment. This suggests that the disorder expression mechanisms are not fully
        elucidated to date. The preliminary results obtained at the Institute for Regenerative
        Medicine and Biotherapy (IRMB) suggest the involvement of an epigenetic mechanism in FMF
        pathogenesis, and our laboratory has strong arguments as to the involvement of microRNAs (in
        particular miR-326) which are negative regulators of gene expression.
  
        This study is exploratory and aims to validate the role of miRNAs in the clinical expression
        of FMF in patients, thus to explore the epigenetic mechanisms that may explain the
        variability of expression of this disorder.
  Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder due to mutations in
        the MEFV (MEditerranean FeVer) gene, that causes recurrent episodes of fever and acute
        serositis (peritoneum, pleura, synovium) beginning in early childhood.
  
        MEFV gene identification allowed the development of a genomic sequencing test to confirm the
        diagnosis. The most frequent mutations are M680I, M694V, V726A and M694I, located in exon 10.
        This gene encodes the protein pyrin, which, following a pro-inflammatory stimulus, is capable
        of assembling a multi-protein complex to form the pyrin inflammasome. MEFV gene mutations
        lead to an alteration of its expression in innate immune system cells in FMF patients,
        causing a dysregulation of the immune response, which results in the abnormal secretion of
        certain proinflammatory cytokines such as IL-1β and IL-18.
  
        FMF is an autosomal recessive disorder. Thus, heterozygous individuals are theoretically
        healthy carriers. Nevertheless, in nearly 1/3 of patients with clinical symptoms of FMF, a
        single heterozygous mutation is found. To date, there is no biological marker to distinguish
        heterozygous individuals who will develop the disease from those who remain healthy carriers,
        hence diagnostic errors and delays in treatment. Several hypotheses have been put forward to
        explain this variation in mutation expression, whether it is the environment, the involvement
        of other genes, or the involvement of epigenetic modifiers.
  
        Among the mechanisms that regulate gene expression, microRNAs (miRNAs),which are small
        non-coding RNAs, negatively regulate gene expression at the post-transcriptional level by
        binding to sequences located mainly in the region 3'UTR of gene mRNA. Many publications
        report that they are abnormally expressed in various pathologies. Very recently, this has
        been reported for FMF. Several studies have focused on miRNAs as biomarkers of FMF, without
        evaluating their role in FMF pathogenesis.
  
        Assessing the role of miRNAs specifically targeting the MEFV gene in myeloid cells
        (especially monocytes), and the functional impact of their modulation in these cells, would
        deepen our understanding of FMF physiopathology. If a miRNA specifically targeting MEFV has a
        proven role in FMF pathophysiology, it could ultimately prove to be a prognostic biomarker of
        the disorder for heterozygous patients, or even a future therapeutic target.
  allocation: N/A
  intervention model: Single Group Assignment
  intervention model description: Among the 40 subjects to be enrolled: 10 are MEFV homozygous patients, 10 are symptomatic MEFV heterozygous patients, 10 are asymptomatic MEFV heterozygous patients and 10 are control subjects. All enrolled patients receive the same intervention (biological sample collection).
  primary purpose: Other
  masking: None (Open Label)
  measure: miR-326 expression level quantification
  time frame: 1 day (at enrollment)
  description: Analyze the expression levels (quantification) of miRNA miR-326 in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects, in order to determine whether or not miR-326 influences the inflammatory response of monocytes.
  measure: MEFV expression level quantification
  time frame: 1 day (at enrollment)
  description: Analyze the expression levels (quantification) of MEFV gene in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects
  measure: miR-326 expression level comparison
  time frame: 1 day (at enrollment)
  description: Compare the expression levels of miR-326 between symptomatic and asymptomatic heterozygous groups.
  measure: MEFV expression level comparison
  time frame: 1 day (at enrollment)
  description: Compare the expression levels of MEFV between symptomatic and asymptomatic heterozygous groups.
  measure: Blood samples collection
  time frame: 1 day (at enrollment)
  description: Create a biobank (freezing monocytes extracted from patient samples) in order to subsequently study other miRNAs
  measure: Expression levels of other candidate miRNAs targeting MEFV
  time frame: 1 day (at enrollment)
  description: Quantification of the the expression levels of other candidate miRNAs targetting MEFV within the 4 groups of participants. 5 miRNAs will be selected using a methylome study currently being carried out.
  arm group label: Blood Sampling
  arm group type: Other
  description: Collection of 10 ml of blood on EDTA tube during:
  Standard check-up visit as a part of the standard monitoring of the disorder for homozygous and symptomatic heterozygous patients
  Specific study visit for asymptomatic heterozygous patients
  Presurgery blood test for control subjects
  intervention type: Other
  intervention name: Blood sampling
  description: Collection of 10 ml of blood on EDTA tubes per patient. Once collected, the blood tubes will be transported within 24 hours to the IRB (Biotherapy Research Institute) of Montpellier University Hospital, where the monocytes will be isolated by magnetic sorting on the basis of expression of surface marker CD14+, after a preliminary step of Ficoll. Monocytes will then be frozen in nitrogen at -196°C until use (biobank).Gain-of-function experiments will then be performed on monocytes by transfecting them with the microRNA of interest or control. The expression of the pyrin protein and its phosphorylation rate will be evaluated after induction by immunoprecipitation experiments followed by western blot. The activity of the pyrin inflammasome will also be studied by looking at pyroptosis and toxicity rate using LDH test. All these experiments will be carried out in the absence and in the presence of the microRNA in order to study its role in the pathophysiology of FMF.
  arm group label: Blood Sampling
  criteria: 
  gender: All
  minimum age: 1 Year
  maximum age: N/A
  healthy volunteers: Accepts Healthy Volunteers
  last name: Eric JEZIORSKI, MD
  role: Principal Investigator
  affiliation: University Hospital, Montpellier
  last name: Anna DEGUET, MD
  phone: 0033669107224
  email: a-deguet@chu-montpellier.fr
  facility: 
  contact: 
  investigator: 
  facility: 
  contact: 
  investigator: 
  facility: 
  contact: 
  investigator: 
  facility: 
  contact: 
  investigator: 
  country: France
  responsible party type: Sponsor
  mesh term: Brucellosis
  mesh term: Familial Mediterranean Fever
  mesh term: Hereditary Autoinflammatory Diseases
  mesh term: Fever
  sharing ipd: No