<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/NCT03754348</url>
  </required_header>
  <id_info>
    <org_study_id>RECHMPL18_0067</org_study_id>
    <nct_id>NCT03754348</nct_id>
  </id_info>
  <brief_title>Microglial Activation in Narcolepsy Type 1 and Kleine-Levin Syndrome: Positron Emission Tomography (PET) Study in [18F] DPA-714</brief_title>
  <acronym>NARCOGLIE</acronym>
  <official_title>Microglial Activation in Narcolepsy Type 1 and Kleine-Levin Syndrome: Positron Emission Tomography (PET) Study in [18F] DPA-714</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Montpellier</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centre Hospitalier Universitaire de Nīmes</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Montpellier</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>
      Type 1 narcolepsy (NT1) is a chronic sleep disorder caused by the selective and irreversible&#xD;
      loss of neurons from the hypothalamus, which synthesizes a neurotransmitter: hypocretin&#xD;
      (Hcrt) / orexin. The exact cause of this destruction is still unknown, but the autoimmune&#xD;
      hypothesis is strongly favored, involving the interaction of genetic and environmental&#xD;
      factors. The treatment of NT1 is currently only symptomatic, targeting hypersomnolence and&#xD;
      cataplexy. To prevent the destruction of Hcrt neurons, immunomodulatory agents have been&#xD;
      tested, with varying efficacy, probably due to varying degrees of hypothalamic impairment and&#xD;
      stages of disease progression. During microglial activation, a condition associated with&#xD;
      neuroinflammation in the brain, there is an increase in the mitochondrial translocation&#xD;
      protein (TSPO), which can be quantified in vivo by specific tracers, such as the [18F] DPA-&#xD;
      714, in positron emission tomography (PET), a very sensitive nuclear imaging technique. The&#xD;
      aim here is to study microglial activation in PET [18F] DPA-714 in NT1 patients with recent&#xD;
      evolution in comparison with controls; then analyze the effect of age, and the severity of&#xD;
      symptoms on this PET imaging biomarker. The hypothesis is that microglial activation,&#xD;
      especially of the hypothalamic region, is greater in NT1 than controls.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Formerly known as narcolepsy with cataplexy, narcolepsy type 1 (NT1) is a rare and disabling&#xD;
      sleep pathology that affects 0.02% of the population. It occurs mainly in young adults and&#xD;
      children, with repercussions throughout their existence. It is characterized by excessive&#xD;
      daytime sleepiness (EDS), which is often the most disabling symptom. Diurnal sleep access is&#xD;
      irrepressible, typically short-lived, and refreshing. Cataplexies are the most specific,&#xD;
      almost pathognomonic sign of this condition. It is a loss of muscle tone in full&#xD;
      consciousness, sudden, triggered by an often positive emotion (laugh, excitement, joke).&#xD;
      Nighttime sleep is also disturbed and there may be other signs of paradoxical sleep&#xD;
      dysregulation such as hypnagogic hallucinations (at sleep) or hypnopompic (waking)&#xD;
      hallucinations, and sleep paralysis.&#xD;
&#xD;
      The diagnosis is confirmed by a polysomnographic recording (PSG) followed by iterative sleep&#xD;
      latency tests (TILE) the next day. According to the new international criteria (ICSD-3),&#xD;
      patients have a sleep latency of less than or equal to 8 minutes to TILE, and at least 2&#xD;
      sleep in paradoxical sleep (ESP) . An ESP during the previous night PSG can replace a TILE&#xD;
      ESP. Typical cataplexies must also be found during the interrogation, but a level of&#xD;
      hypocretin-1 collapsed in cerebrospinal fluid (CSF) (&lt;110 ng / L) can now be sufficient for&#xD;
      diagnosis, given its very high specificity ( 99%) and sensitivity (&gt; 87%) for NT1.&#xD;
&#xD;
      NT1 is due to the selective and irreversible loss of Hcrt neurons. The exact cause of this&#xD;
      destruction is still unknown, but the autoimmune hypothesis is strongly favored. The etiology&#xD;
      is probably multifactorial, involving genetic and environmental factors. In fact, 97% of&#xD;
      patients with NT1 are carriers of the HLA (Human Leukocyte Antigen) allele DQB1 * 06: 02, a&#xD;
      class II major histocompatibility complex (MHC) allele.&#xD;
&#xD;
      Treatments of NT1 are currently only symptomatic, targeting the different symptoms:&#xD;
      drowsiness, poor sleep at night, cataplexy, and other symptoms related to dysregulation of&#xD;
      sleep Microglial activation is involved in the neuroinflammation process of certain central&#xD;
      nervous system pathologies.&#xD;
&#xD;
      When microglia are activated, following aggression or cellular inflammation, the expression&#xD;
      of TSPO increases. Positron Emission Tomography (PET) is a nuclear imaging technique that can&#xD;
      be used to create anatomical and molecular images with high sensitivity. New TSPO-specific&#xD;
      tracers have been recently developed, such as [18F] DPA-714, to quantify in vivo microglial&#xD;
      activation in brain PET.&#xD;
&#xD;
      The goal here is to study the cerebral microglial activation in PET in NT1 patients with&#xD;
      recent evolution (appearance of the first symptoms - somnolence and cataplexy - less than 2&#xD;
      years ago) in comparison with controls; then analyze the effect of age, and the severity of&#xD;
      symptoms on this PET imaging biomarker. Thus, we hypothesize microglial activation,&#xD;
      particularly of the hypothalamic region, in NT1 patients at an early stage of disease&#xD;
      progression, possibly correlated with the severity of symptoms. To test this hypothesis, we&#xD;
      will compare the in vivo microglial activation with PET [18F] DPA-714 in NT1 subjects, versus&#xD;
      control subjects followed for another age-and-sex-matched non-narcolepsy and hypersomnia-free&#xD;
      sleep pathology. The images will be analyzed semi-quantitatively by determining SuVr (or&#xD;
      normalized binding value), a method validated in international studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 15, 2019</start_date>
  <completion_date type="Anticipated">April 2022</completion_date>
  <primary_completion_date type="Anticipated">March 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Quantification of microglial activation in the hypothalamus (SuVr) of adult NT1 patients compared to controls</measure>
    <time_frame>1 day</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in adult and child patients and severity of the disease</measure>
    <time_frame>1 day</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in adult and child patients and electrophysiological biomarkers</measure>
    <time_frame>1 day</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in adult and child patients and inflammatory biomarkers</measure>
    <time_frame>1 day</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microglial activation in the hypothalamus, thalamus, and other regions of interest in KLS patients vs NT1 patients</measure>
    <time_frame>1 day</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in KLS patients and time and severity of the disease (clinical, polysomnographic and biologic parameters)</measure>
    <time_frame>1 day</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">78</enrollment>
  <condition>Narcolepsy 1</condition>
  <condition>Kleine-Levin Syndrome</condition>
  <arm_group>
    <arm_group_label>NT1 group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>hypothalamus neuroinflammation evaluation in Narcoleptic patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>hypothalamus neuroinflammation evaluation in control patients (patients without hypersomnia or inflammatory pathology)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>KLS group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>hypothalamus neuroinflammation evaluation in Kleine-Levin syndrome patients</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>PET scan with tracer injection [18F] DPA-714</intervention_name>
    <description>the subject will receive a dose of 3.5MBq / kg intravenous (in bolus) more or less 20%, knowing that the minimum dose injected is unchanged at 150MBq and the maximum dose at 370 MBq. Irradiation will remain below 10 mSv</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>KLS group</arm_group_label>
    <arm_group_label>NT1 group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. For all groups :&#xD;
&#xD;
               -  Written agreement for participation&#xD;
&#xD;
               -  Able to understand instructions and information data&#xD;
&#xD;
               -  Without any immunomodulatory, immunosuppressant, or anti-inflamatory medication&#xD;
&#xD;
          2. For NT1 patients:&#xD;
&#xD;
               -  10 years-old or more&#xD;
&#xD;
               -  Responding to NT1 criteria (ICSD-3)&#xD;
&#xD;
               -  Under psychostimulant or not for narcolepsy&#xD;
&#xD;
          3. For KLS patients:&#xD;
&#xD;
               -  10 years-old or more&#xD;
&#xD;
               -  KLS diagnosis&#xD;
&#xD;
          4. For controls&#xD;
&#xD;
               -  18 years-old or more&#xD;
&#xD;
               -  Absence of narcolepsy&#xD;
&#xD;
               -  Absence of acute or chronic inflammatory disease&#xD;
&#xD;
        Exclusion criteria (for all groups):&#xD;
&#xD;
          -  People without public insurance regime&#xD;
&#xD;
          -  Specific contraindication to the use of PET (specific allergy related to the ligand).&#xD;
&#xD;
          -  Pregnant and breastfeeding women&#xD;
&#xD;
          -  Persons deprived of liberty by judicial or administrative decision&#xD;
&#xD;
          -  People hospitalized without consent, or subject to legal protection&#xD;
&#xD;
          -  Persons unable to consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Yves YD DAUVILLIERS, PU-PH</last_name>
    <phone>04 67 33 74 78</phone>
    <email>y-dauvilliers@chu-montpellier.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Beatriz BA ABRIL, PH</last_name>
    <phone>04 66 68 39 00</phone>
    <email>beatriz.abril@chu-nimes.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Hospital of Montpellier</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yves Dauvilliers</last_name>
    </contact>
    <contact_backup>
      <last_name>Lucie Barateau</last_name>
    </contact_backup>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>November 5, 2018</study_first_submitted>
  <study_first_submitted_qc>November 22, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 27, 2018</study_first_posted>
  <last_update_submitted>July 27, 2020</last_update_submitted>
  <last_update_submitted_qc>July 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>narcolepsy type 1</keyword>
  <keyword>orexin</keyword>
  <keyword>hypocretin</keyword>
  <keyword>[18F] DPA-714</keyword>
  <keyword>biomarker</keyword>
  <keyword>auto immunity</keyword>
  <keyword>kleine-levin syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Narcolepsy</mesh_term>
    <mesh_term>Kleine-Levin Syndrome</mesh_term>
    <mesh_term>Syndrome</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/NCT03754348
org study id: RECHMPL18_0067
nct id: NCT03754348
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Type 1 narcolepsy (NT1) is a chronic sleep disorder caused by the selective and irreversible
      loss of neurons from the hypothalamus, which synthesizes a neurotransmitter: hypocretin
      (Hcrt) / orexin. The exact cause of this destruction is still unknown, but the autoimmune
      hypothesis is strongly favored, involving the interaction of genetic and environmental
      factors. The treatment of NT1 is currently only symptomatic, targeting hypersomnolence and
      cataplexy. To prevent the destruction of Hcrt neurons, immunomodulatory agents have been
      tested, with varying efficacy, probably due to varying degrees of hypothalamic impairment and
      stages of disease progression. During microglial activation, a condition associated with
      neuroinflammation in the brain, there is an increase in the mitochondrial translocation
      protein (TSPO), which can be quantified in vivo by specific tracers, such as the [18F] DPA-
      714, in positron emission tomography (PET), a very sensitive nuclear imaging technique. The
      aim here is to study microglial activation in PET [18F] DPA-714 in NT1 patients with recent
      evolution in comparison with controls; then analyze the effect of age, and the severity of
      symptoms on this PET imaging biomarker. The hypothesis is that microglial activation,
      especially of the hypothalamic region, is greater in NT1 than controls.
Formerly known as narcolepsy with cataplexy, narcolepsy type 1 (NT1) is a rare and disabling
      sleep pathology that affects 0.02% of the population. It occurs mainly in young adults and
      children, with repercussions throughout their existence. It is characterized by excessive
      daytime sleepiness (EDS), which is often the most disabling symptom. Diurnal sleep access is
      irrepressible, typically short-lived, and refreshing. Cataplexies are the most specific,
      almost pathognomonic sign of this condition. It is a loss of muscle tone in full
      consciousness, sudden, triggered by an often positive emotion (laugh, excitement, joke).
      Nighttime sleep is also disturbed and there may be other signs of paradoxical sleep
      dysregulation such as hypnagogic hallucinations (at sleep) or hypnopompic (waking)
      hallucinations, and sleep paralysis.

      The diagnosis is confirmed by a polysomnographic recording (PSG) followed by iterative sleep
      latency tests (TILE) the next day. According to the new international criteria (ICSD-3),
      patients have a sleep latency of less than or equal to 8 minutes to TILE, and at least 2
      sleep in paradoxical sleep (ESP) . An ESP during the previous night PSG can replace a TILE
      ESP. Typical cataplexies must also be found during the interrogation, but a level of
      hypocretin-1 collapsed in cerebrospinal fluid (CSF) (<110 ng / L) can now be sufficient for
      diagnosis, given its very high specificity ( 99%) and sensitivity (> 87%) for NT1.

      NT1 is due to the selective and irreversible loss of Hcrt neurons. The exact cause of this
      destruction is still unknown, but the autoimmune hypothesis is strongly favored. The etiology
      is probably multifactorial, involving genetic and environmental factors. In fact, 97% of
      patients with NT1 are carriers of the HLA (Human Leukocyte Antigen) allele DQB1 * 06: 02, a
      class II major histocompatibility complex (MHC) allele.

      Treatments of NT1 are currently only symptomatic, targeting the different symptoms:
      drowsiness, poor sleep at night, cataplexy, and other symptoms related to dysregulation of
      sleep Microglial activation is involved in the neuroinflammation process of certain central
      nervous system pathologies.

      When microglia are activated, following aggression or cellular inflammation, the expression
      of TSPO increases. Positron Emission Tomography (PET) is a nuclear imaging technique that can
      be used to create anatomical and molecular images with high sensitivity. New TSPO-specific
      tracers have been recently developed, such as [18F] DPA-714, to quantify in vivo microglial
      activation in brain PET.

      The goal here is to study the cerebral microglial activation in PET in NT1 patients with
      recent evolution (appearance of the first symptoms - somnolence and cataplexy - less than 2
      years ago) in comparison with controls; then analyze the effect of age, and the severity of
      symptoms on this PET imaging biomarker. Thus, we hypothesize microglial activation,
      particularly of the hypothalamic region, in NT1 patients at an early stage of disease
      progression, possibly correlated with the severity of symptoms. To test this hypothesis, we
      will compare the in vivo microglial activation with PET [18F] DPA-714 in NT1 subjects, versus
      control subjects followed for another age-and-sex-matched non-narcolepsy and hypersomnia-free
      sleep pathology. The images will be analyzed semi-quantitatively by determining SuVr (or
      normalized binding value), a method validated in international studies.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Single (Outcomes Assessor)
measure: Quantification of microglial activation in the hypothalamus (SuVr) of adult NT1 patients compared to controls
time frame: 1 day
measure: Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in adult and child patients and severity of the disease
time frame: 1 day
measure: Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in adult and child patients and electrophysiological biomarkers
time frame: 1 day
measure: Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in adult and child patients and inflammatory biomarkers
time frame: 1 day
measure: Microglial activation in the hypothalamus, thalamus, and other regions of interest in KLS patients vs NT1 patients
time frame: 1 day
measure: Correlation between microglial activation in the hypothalamus, thalamus, and other regions of interest in KLS patients and time and severity of the disease (clinical, polysomnographic and biologic parameters)
time frame: 1 day
arm group label: NT1 group
arm group type: Experimental
description: hypothalamus neuroinflammation evaluation in Narcoleptic patients
arm group label: Control group
arm group type: Other
description: hypothalamus neuroinflammation evaluation in control patients (patients without hypersomnia or inflammatory pathology)
arm group label: KLS group
arm group type: Experimental
description: hypothalamus neuroinflammation evaluation in Kleine-Levin syndrome patients
intervention type: Radiation
intervention name: PET scan with tracer injection [18F] DPA-714
description: the subject will receive a dose of 3.5MBq / kg intravenous (in bolus) more or less 20%, knowing that the minimum dose injected is unchanged at 150MBq and the maximum dose at 370 MBq. Irradiation will remain below 10 mSv
arm group label: Control group
arm group label: KLS group
arm group label: NT1 group
criteria: 
gender: All
minimum age: 10 Years
maximum age: N/A
healthy volunteers: No
last name: Yves YD DAUVILLIERS, PU-PH
phone: 04 67 33 74 78
email: y-dauvilliers@chu-montpellier.fr
last name: Beatriz BA ABRIL, PH
phone: 04 66 68 39 00
email: beatriz.abril@chu-nimes.fr
facility: 
status: Recruiting
contact: 
contact backup: 
country: France
responsible party type: Sponsor
mesh term: Narcolepsy
mesh term: Kleine-Levin Syndrome
mesh term: Syndrome