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/NCT05985421</url>
    </required_header>
    <id_info>
      <org_study_id>RECHMPL23_0083</org_study_id>
      <nct_id>NCT05985421</nct_id>
    </id_info>
    <brief_title>Gut Microbiota and Bacterial Translocation in Restless Legs Syndrome</brief_title>
    <acronym>RLS-BIOT</acronym>
    <official_title>Study of Gut Microbiota and Bacterial Translocation in Patients With Restless Legs Syndrome and Controls</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>
        Restless Legs Syndrome (RLS) is a common neurological sensorimotor disorder defined by an&#xD;
        urge to move the legs when at rest that increase in the evening and at night. The&#xD;
        pathophysiology of RLS remains poorly understood, but brain iron deficiency plays a major&#xD;
        role. Iron absorption is an active process located in enterocytes of the proximal bowel, and&#xD;
        is inhibited by hepcidin. The gut microbiota plays a central role in intestinal absorption,&#xD;
        and in the maturation of the immune system. An imbalance in the microbiota, known as&#xD;
        dysbiosis, could lead to a decrease in iron absorption, inflammation of the intestinal&#xD;
        epithelium, and an increase in its permeability, thus favoring bacterial translocation and&#xD;
        chronic systemic inflammation. Numerous studies showed an association between RLS and&#xD;
        gastrointestinal diseases: Irritable bowel syndrome, Crohn's disease, ulcerative colitis,&#xD;
        small intestinal bacterial overgrowth. However, no study has examined the gut microbiota in&#xD;
        RLS.&#xD;
  &#xD;
        The investigators hypothesize that there is an imbalance of gut microbiota in patients with&#xD;
        RLS, favoring an increased intestinal permeability and bacterial translocation, leading to&#xD;
        chronic inflammation and reduced iron bioavailability.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Sixty patients with RLS will be included and 60 controls. The patients will be recruited from&#xD;
        the active file of the sleep and wake disorders unit.&#xD;
  &#xD;
        The control subjects will be recruited from :&#xD;
  &#xD;
          -  Patients hospitalized for suspected sleep disorders with normal PSG.&#xD;
  &#xD;
          -  The healthy controls of the RLS cognition protocol, ongoing in the department (ID-RCB:&#xD;
             2012-A00581-42, NCT01823354).&#xD;
  &#xD;
        The patients will be informed of the study during a medical consultation. The consent of&#xD;
        subjects participating in the study will be obtained during the pre-inclusion visit (D-1).&#xD;
        The referring physician of the patients with RLS will propose them to participate in the&#xD;
        study. After being duly informed of the nature, significance, implications of the study and&#xD;
        appropriately documented by one of the investigators, and after sufficient time for&#xD;
        reflection, free, informed and written consent will be obtained from all patients.&#xD;
  &#xD;
        The control subjects will receive information about the study when they are admitted to&#xD;
        hospital for polysomnographic recording, they will sign their consent for. A clinical&#xD;
        examination will also be carried out.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 30, 2023</start_date>
    <completion_date type="Anticipated">September 30, 2025</completion_date>
    <primary_completion_date type="Anticipated">March 29, 2025</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>Cross-Sectional</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Taxonomic composition of gut microbiota</measure>
      <time_frame>24 months</time_frame>
      <description>Diversity (alpha and beta), abundance, nature and relative quantification of bacterial genera and bacterial taxonomic units (OTUs) present in stool samples identified by metagenomics.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Ratio between Firmicutes and Bacteroidetes (majority phyla)</measure>
      <time_frame>24 months</time_frame>
      <description>Richness, diversity and importance of minority phyla in stools, distribution and importance of bacterial genera in patients and controls. The study of the intestinal microbiota will consist of a metabarcoding approach to the V3-V4 regions of the 16S rRNA.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Markers of intestinal inflammation (CD14s, LBP)</measure>
      <time_frame>24 months</time_frame>
      <description>The study of bacterial translocation will be carried out using the ELISA technique for intestinal inflammation markers.</description>
    </other_outcome>
    <other_outcome>
      <measure>Markers of digestive permeability (I-FABP, claudine)</measure>
      <time_frame>24 months</time_frame>
      <description>The study of bacterial translocation will be carried out using the ELISA technique for markers of membrane permeability.</description>
    </other_outcome>
    <other_outcome>
      <measure>Markers of microbial translocation (16S et 18SrDNA)</measure>
      <time_frame>24 months</time_frame>
      <description>The study of bacterial translocation will be carried out using 16S and 18S qPCR for direct translocation markers.</description>
    </other_outcome>
    <other_outcome>
      <measure>Correspondence between bacteria identified by relative quantification of bacterial genera and OTUs present in stools and those detected by qPCR in plasma.</measure>
      <time_frame>24 months</time_frame>
      <description>Identification of the concordance between bacterial genera identified in plasma and bacterial genera and OTUs present in stools will be done using Spearman's correlation coefficient.</description>
    </other_outcome>
    <number_of_groups>2</number_of_groups>
    <enrollment type="Anticipated">120</enrollment>
    <condition>Restless Legs Syndrome</condition>
    <arm_group>
      <arm_group_label>Patients</arm_group_label>
    </arm_group>
    <arm_group>
      <arm_group_label>Control</arm_group_label>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Fecal collection</intervention_name>
      <description>approximate volume of 2 ml</description>
      <arm_group_label>Control</arm_group_label>
      <arm_group_label>Patients</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Blood sampling</intervention_name>
      <description>1 EDTA tube (7 ml) to test for chronic low-grade inflammation + 1 EDTA tube (7 ml) to test for intestinal inflammation, digestive permeability and microbial translocation</description>
      <arm_group_label>Control</arm_group_label>
      <arm_group_label>Patients</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Polysomnography</intervention_name>
      <description>Polysomnography</description>
      <arm_group_label>Control</arm_group_label>
      <arm_group_label>Patients</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Auto questionnaires</intervention_name>
      <description>International RLS Study Group Severity Scale, Epworth Sleepiness Scale, Insomnia Severity Index, Beck Depression Inventory-II, Autonomic symtoms scale (SCOPA-AUT)</description>
      <arm_group_label>Control</arm_group_label>
      <arm_group_label>Patients</arm_group_label>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          60 patients with RLS and 60 controls meeting all criteria, with the aim of having 50&#xD;
          analyzable subjects per group (i.e. with available stool samples).&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          Patient&#xD;
  &#xD;
            -  Idiopathic RLS diagnosed according to the 5 clinical criteria established by the&#xD;
               IRLSSG (International Restless Legs Syndrome Study Group).&#xD;
  &#xD;
            -  Moderate to very severe RLS, IRLSSG questionnaire ≥ 15.&#xD;
  &#xD;
            -  Presence of periodic leg movements (PLM) during sleep (PLM index &gt; 15/hour of sleep).&#xD;
  &#xD;
            -  Patient never treated or weaned at least 15 days prior to evaluation with dopaminergic&#xD;
               agonists, alpha-2delta ligands, opioids or other psychotropic drugs.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          Patient&#xD;
  &#xD;
            -  Presence of digestive, inflammatory, psychiatric or neurological pathologies.&#xD;
  &#xD;
            -  C-reactive protein &gt; 10mg/l (marker of acute inflammation)&#xD;
  &#xD;
            -  Presence of moderate-to-severe sleep apnea syndrome (apnea-hypopnea index &gt;15/h).&#xD;
  &#xD;
            -  History of iron supplementation within 6 months.&#xD;
  &#xD;
            -  Use of treatments known to aggravate or cause RLS, such as antidepressants,&#xD;
               neuroleptics, antihistamines or lithium.&#xD;
  &#xD;
            -  Refusal of consent after information&#xD;
  &#xD;
            -  legally protected adult (guardianship, curatorship)&#xD;
  &#xD;
            -  Pregnant or breast-feeding women&#xD;
  &#xD;
            -  Patient not affiliated to or not benefiting from a social security system.&#xD;
  &#xD;
          Inclusion Criteria:&#xD;
  &#xD;
          Control&#xD;
  &#xD;
            -  Adults without RLS with demographic characteristics similar to patients in terms of&#xD;
               age (+- 5 years) and gender&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          Control&#xD;
  &#xD;
            -  Presence of gastrointestinal, inflammatory, psychiatric or neurological diseases.&#xD;
  &#xD;
            -  C-reactive protein &gt; 10mg/l (marker of acute inflammation).&#xD;
  &#xD;
            -  Presence of PLM in sleep (threshold &gt;15 per hour of sleep).&#xD;
  &#xD;
            -  Treatment with antidepressants, neuroleptics, antihistamines, lithium, antiepileptics,&#xD;
               benzodiazepines, hypnotics, opiates, dopaminergic agonists, levodopa, alpha-2delta&#xD;
               ligands.&#xD;
  &#xD;
            -  Presence of moderate to severe sleep apnea syndrome (apnea-hypopnea index &gt;15/h)&#xD;
  &#xD;
            -  Refusal of consent after information&#xD;
  &#xD;
            -  legally protected adult (guardianship, curatorship)&#xD;
  &#xD;
            -  Pregnant or breast-feeding woman&#xD;
  &#xD;
            -  Participant not affiliated to a social security scheme or not benefiting from such a&#xD;
               system.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>DAUVILLIERS Yves, Pr</last_name>
      <role>Principal Investigator</role>
      <affiliation>Head of Sleep/Wake Unit National reference center for orphan diseases Narcolepsy and hypersomnia</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>CHENINI Sofiene, Dr</last_name>
      <phone>0467332237</phone>
      <phone_ext>33</phone_ext>
      <email>s-chenini@chu-montpellier.fr</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>DAUVILLIERS Yves, Pr</last_name>
      <phone>0467337478</phone>
      <email>y-dauvilliers@chu-montpellier.fr</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Unité des troubles du sommeil et de l'éveil-Centre de référence narcolepsie-Hypersomnie/Département de Neurologie/ Pole neurosciences tête et cou Hôpital Gui De Chauliac</name>
        <address>
          <city>Montpellier</city>
          <zip>34295</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 2, 2023</study_first_submitted>
    <study_first_submitted_qc>August 2, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 9, 2023</last_update_submitted>
    <last_update_submitted_qc>August 9, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Periodic legs movement</keyword>
    <keyword>Gut microbiota</keyword>
    <keyword>Chronic inflammation</keyword>
    <keyword>Iron metabolism</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Psychomotor Agitation</mesh_term>
      <mesh_term>Restless Legs Syndrome</mesh_term>
      <mesh_term>Syndrome</mesh_term>
    </condition_browse>
    <!-- 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/NCT05985421
  org study id: RECHMPL23_0083
  nct id: NCT05985421
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Restless Legs Syndrome (RLS) is a common neurological sensorimotor disorder defined by an
        urge to move the legs when at rest that increase in the evening and at night. The
        pathophysiology of RLS remains poorly understood, but brain iron deficiency plays a major
        role. Iron absorption is an active process located in enterocytes of the proximal bowel, and
        is inhibited by hepcidin. The gut microbiota plays a central role in intestinal absorption,
        and in the maturation of the immune system. An imbalance in the microbiota, known as
        dysbiosis, could lead to a decrease in iron absorption, inflammation of the intestinal
        epithelium, and an increase in its permeability, thus favoring bacterial translocation and
        chronic systemic inflammation. Numerous studies showed an association between RLS and
        gastrointestinal diseases: Irritable bowel syndrome, Crohn's disease, ulcerative colitis,
        small intestinal bacterial overgrowth. However, no study has examined the gut microbiota in
        RLS.
  
        The investigators hypothesize that there is an imbalance of gut microbiota in patients with
        RLS, favoring an increased intestinal permeability and bacterial translocation, leading to
        chronic inflammation and reduced iron bioavailability.
  Sixty patients with RLS will be included and 60 controls. The patients will be recruited from
        the active file of the sleep and wake disorders unit.
  
        The control subjects will be recruited from :
  
          -  Patients hospitalized for suspected sleep disorders with normal PSG.
  
          -  The healthy controls of the RLS cognition protocol, ongoing in the department (ID-RCB:
             2012-A00581-42, NCT01823354).
  
        The patients will be informed of the study during a medical consultation. The consent of
        subjects participating in the study will be obtained during the pre-inclusion visit (D-1).
        The referring physician of the patients with RLS will propose them to participate in the
        study. After being duly informed of the nature, significance, implications of the study and
        appropriately documented by one of the investigators, and after sufficient time for
        reflection, free, informed and written consent will be obtained from all patients.
  
        The control subjects will receive information about the study when they are admitted to
        hospital for polysomnographic recording, they will sign their consent for. A clinical
        examination will also be carried out.
  observational model: Case-Control
  time perspective: Cross-Sectional
  measure: Taxonomic composition of gut microbiota
  time frame: 24 months
  description: Diversity (alpha and beta), abundance, nature and relative quantification of bacterial genera and bacterial taxonomic units (OTUs) present in stool samples identified by metagenomics.
  measure: Ratio between Firmicutes and Bacteroidetes (majority phyla)
  time frame: 24 months
  description: Richness, diversity and importance of minority phyla in stools, distribution and importance of bacterial genera in patients and controls. The study of the intestinal microbiota will consist of a metabarcoding approach to the V3-V4 regions of the 16S rRNA.
  measure: Markers of intestinal inflammation (CD14s, LBP)
  time frame: 24 months
  description: The study of bacterial translocation will be carried out using the ELISA technique for intestinal inflammation markers.
  measure: Markers of digestive permeability (I-FABP, claudine)
  time frame: 24 months
  description: The study of bacterial translocation will be carried out using the ELISA technique for markers of membrane permeability.
  measure: Markers of microbial translocation (16S et 18SrDNA)
  time frame: 24 months
  description: The study of bacterial translocation will be carried out using 16S and 18S qPCR for direct translocation markers.
  measure: Correspondence between bacteria identified by relative quantification of bacterial genera and OTUs present in stools and those detected by qPCR in plasma.
  time frame: 24 months
  description: Identification of the concordance between bacterial genera identified in plasma and bacterial genera and OTUs present in stools will be done using Spearman's correlation coefficient.
  arm group label: Patients
  arm group label: Control
  intervention type: Other
  intervention name: Fecal collection
  description: approximate volume of 2 ml
  arm group label: Control
  arm group label: Patients
  intervention type: Other
  intervention name: Blood sampling
  description: 1 EDTA tube (7 ml) to test for chronic low-grade inflammation + 1 EDTA tube (7 ml) to test for intestinal inflammation, digestive permeability and microbial translocation
  arm group label: Control
  arm group label: Patients
  intervention type: Other
  intervention name: Polysomnography
  description: Polysomnography
  arm group label: Control
  arm group label: Patients
  intervention type: Other
  intervention name: Auto questionnaires
  description: International RLS Study Group Severity Scale, Epworth Sleepiness Scale, Insomnia Severity Index, Beck Depression Inventory-II, Autonomic symtoms scale (SCOPA-AUT)
  arm group label: Control
  arm group label: Patients
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: Accepts Healthy Volunteers
  last name: DAUVILLIERS Yves, Pr
  role: Principal Investigator
  affiliation: Head of Sleep/Wake Unit National reference center for orphan diseases Narcolepsy and hypersomnia
  last name: CHENINI Sofiene, Dr
  phone: 0467332237
  phone ext: 33
  email: s-chenini@chu-montpellier.fr
  last name: DAUVILLIERS Yves, Pr
  phone: 0467337478
  email: y-dauvilliers@chu-montpellier.fr
  facility: 
  country: France
  responsible party type: Sponsor
  mesh term: Psychomotor Agitation
  mesh term: Restless Legs Syndrome
  mesh term: Syndrome