<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/NCT03825601</url>
  </required_header>
  <id_info>
    <org_study_id>C16-31</org_study_id>
    <nct_id>NCT03825601</nct_id>
  </id_info>
  <brief_title>PET With [18F]Flumazenil as an Index of Neurodegeneration in MS</brief_title>
  <acronym>FLUMA-SEP-T</acronym>
  <official_title>PET With [18F]Flumazenil as an Index of Neurodegeneration in MS: Sensitivity at an Early Disease Stage and Pathophysiological Meaning</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut National de la Santé Et de la Recherche Médicale, France</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>
      Beyond white matter pathology, grey matter damage is considered as a key player in disability&#xD;
      onset and progression in Multiple Sclerosis (MS). The underlying substratum of grey matter&#xD;
      damage is complex and pluriform, ranging from cortical demyelinating lesions, synapse and&#xD;
      dendrite disappearance to neuronal cell death. Current Magnetic Resonance Imaging MRI&#xD;
      techniques fail to fully assess and quantify grey matter pathology in this disease. The&#xD;
      development of a quantitative marker of neurodegeneration for MS patients would allow: (i) to&#xD;
      better understand the pathophysiological mechanisms underlying the distinct forms of MS; (ii)&#xD;
      to stratify patients according to their prognosis; and (iii) to evaluate new therapies aimed&#xD;
      at promoting neuroprotection. would allow to better understand the mechanisms underlying the&#xD;
      distinct forms of MS, to stratify patients according to their prognosis, and to evaluate new&#xD;
      therapies aimed at promoting neuroprotection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators have recently shown that PET (Tomographie par Émission de Positrons) with&#xD;
      [11C]Flumazenil ([11C]FMZ), that binds to the benzodiazepine site of GABA-A receptors,&#xD;
      allowed to quantify and map neuronal damage in MS patients.&#xD;
&#xD;
      In the present project, the investigators will assess neuronal damage in MS using PET with&#xD;
      [18F]Flumazenil ([18F]FMZ), at the early phase of either relapsing or primary progressive MS,&#xD;
      and investigate the pathophysiological meaning of this neuronal damage by combining PET with&#xD;
      Flumazenil with MRI at 7T and 3T.&#xD;
&#xD;
      The main objective will be to quantify and map [18F]FMZ binding changes in the grey matter of&#xD;
      MS patients compared to controls, both at the group and the individual level. Secondary and&#xD;
      exploratory objectives will be to investigate the relationship between Flumazenil binding&#xD;
      changes and: i) cortical demyelinating lesions identified by several 7T MRI sequences ; ii)&#xD;
      dendritic arborisation assessed by 3T DWI; ii) available MRI metrics obtained on a clinical&#xD;
      3T scan (grey matter atrophy MTR modifications, resting state connectivity); iv) clinical&#xD;
      metrics.&#xD;
&#xD;
      This study will develop and assess a new imaging biomarker that has the potential to be used&#xD;
      as an index of neurodegeneration in MS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 1, 2019</start_date>
  <completion_date type="Anticipated">April 1, 2021</completion_date>
  <primary_completion_date type="Anticipated">April 1, 2021</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding in different groups</measure>
    <time_frame>[0-2] MONTHS</time_frame>
    <description>11C -Flumazenil binding in the grey matter : Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding kinetic analysis, and expressed as a Bmax estimation, in the cortex and deep grey matter of subjects.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>individual maps of neurodegeneration: changes in individual mapping of Flumazenil binding in different groups</measure>
    <time_frame>[0-2] MONTHS</time_frame>
    <description>Individual mapping of Flumazenil binding changes in the grey matter of patients with MS compared to healthy controls at the voxel level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume</measure>
    <time_frame>[0-2] MONTHS</time_frame>
    <description>volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load</measure>
    <time_frame>[0-2] MONTHS</time_frame>
    <description>volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of gadolinium-enhanced white matter lesions on T1 sequence</measure>
    <time_frame>[0-2] MONTHS</time_frame>
    <description>Volume of gadolinium-enhanced white matter lesions assessed on T1 sequence</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups</measure>
    <time_frame>[0-2] MONTHS</time_frame>
    <description>Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>functional connectivity changes in patients</measure>
    <time_frame>[0-2] MONTHS</time_frame>
    <description>functional connectivity assessed on resting state fMRI</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">45</enrollment>
  <condition>Multiple Sclerosis</condition>
  <condition>Relapsing-Remitting Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Patients with multiple sclerosis</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>The multiple sclerosis group (n=30) will be subdivided in two subgroups: 15 patients with a relapsing remmitting MS (RRMS), and 15 patients with a primary progressive MS (PPMS).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>healthy subjects</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>15 healthy subjects will be included. Among them 7 to 8 subjects will be matched for age and gender with the RRMS subgroup, and 7 to 8 will be matched for age and gender with the PPMS subgroup.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>PET with [11C]Flumazenil</intervention_name>
    <description>7T MRI sequences : TSE, T2w FLAIR GRE-T2* and DIR 3T MRI sequences: T1, T2, T1 with gadolinium, magnetization transfer, diffusion weighted, resting state fMRI.</description>
    <arm_group_label>Patients with multiple sclerosis</arm_group_label>
    <arm_group_label>healthy subjects</arm_group_label>
    <other_name>7T and 3T MRI</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient group:&#xD;
&#xD;
               -  Aged 18-55 years old&#xD;
&#xD;
               -  Diagnosis of RRMS or PPMS according to the 2010 Mc Donald criteria&#xD;
&#xD;
               -  Disease duration &lt; 10 years&#xD;
&#xD;
               -  Able to understand the study objective and procedure&#xD;
&#xD;
               -  Efficient contraception for women of potential child-bearing&#xD;
&#xD;
               -  Inscription to the national health care system&#xD;
&#xD;
               -  Having signed the written consent form&#xD;
&#xD;
               -  No current benzodiazepine or other GABAA-interacting drug (that have to be&#xD;
                  stopped 15 days before inclusion)&#xD;
&#xD;
               -  Accept to be informed of any incidental finding on imaging acquisitions&#xD;
&#xD;
          -  Healthy subjects&#xD;
&#xD;
               -  Aged 18-55 years old&#xD;
&#xD;
               -  No evolutive pathology&#xD;
&#xD;
               -  Able to understand the study objective and procedure&#xD;
&#xD;
               -  Efficient contraception for women of potential child-bearing&#xD;
&#xD;
               -  Inscription to the national health care system&#xD;
&#xD;
               -  Having signed the written consent form&#xD;
&#xD;
               -  No concurrent benzodiazepine or other GABAA-interacting drug treatment (that have&#xD;
                  to be stopped 15 days before inclusion)&#xD;
&#xD;
               -  Accept to be informed of any incidental finding on imaging acquisitions&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any reason, which does not allow to perform MRI, including claustrophobia, the implant&#xD;
             of a pace-maker or the presence of an intra-ocular foreign body.&#xD;
&#xD;
          -  For women: pregnancy, lactation, lack of efficient contraception. A positive pregnancy&#xD;
             test conducted at visit 2 will lead to the immediate exclusion of the subject.&#xD;
&#xD;
          -  Current symptoms of severe or uncontrolled renal, hepatic, hematological,&#xD;
             gastrointestinal pulmonary or cardiac disease.&#xD;
&#xD;
          -  Radiation exposure during the last year before inclusion due to prior participations&#xD;
             to other research protocols&#xD;
&#xD;
          -  Other chronic neurological diseases.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>January 30, 2019</last_update_submitted>
  <last_update_submitted_qc>January 30, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 31, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Patients,</keyword>
  <keyword>Multiple Sclerosis,</keyword>
  <keyword>Relapsing-Remitting</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Multiple Sclerosis, Relapsing-Remitting</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Nerve Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Flumazenil</mesh_term>
  </intervention_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/NCT03825601
org study id: C16-31
nct id: NCT03825601
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Beyond white matter pathology, grey matter damage is considered as a key player in disability
      onset and progression in Multiple Sclerosis (MS). The underlying substratum of grey matter
      damage is complex and pluriform, ranging from cortical demyelinating lesions, synapse and
      dendrite disappearance to neuronal cell death. Current Magnetic Resonance Imaging MRI
      techniques fail to fully assess and quantify grey matter pathology in this disease. The
      development of a quantitative marker of neurodegeneration for MS patients would allow: (i) to
      better understand the pathophysiological mechanisms underlying the distinct forms of MS; (ii)
      to stratify patients according to their prognosis; and (iii) to evaluate new therapies aimed
      at promoting neuroprotection. would allow to better understand the mechanisms underlying the
      distinct forms of MS, to stratify patients according to their prognosis, and to evaluate new
      therapies aimed at promoting neuroprotection.
The investigators have recently shown that PET (Tomographie par Émission de Positrons) with
      [11C]Flumazenil ([11C]FMZ), that binds to the benzodiazepine site of GABA-A receptors,
      allowed to quantify and map neuronal damage in MS patients.

      In the present project, the investigators will assess neuronal damage in MS using PET with
      [18F]Flumazenil ([18F]FMZ), at the early phase of either relapsing or primary progressive MS,
      and investigate the pathophysiological meaning of this neuronal damage by combining PET with
      Flumazenil with MRI at 7T and 3T.

      The main objective will be to quantify and map [18F]FMZ binding changes in the grey matter of
      MS patients compared to controls, both at the group and the individual level. Secondary and
      exploratory objectives will be to investigate the relationship between Flumazenil binding
      changes and: i) cortical demyelinating lesions identified by several 7T MRI sequences ; ii)
      dendritic arborisation assessed by 3T DWI; ii) available MRI metrics obtained on a clinical
      3T scan (grey matter atrophy MTR modifications, resting state connectivity); iv) clinical
      metrics.

      This study will develop and assess a new imaging biomarker that has the potential to be used
      as an index of neurodegeneration in MS.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding in different groups
time frame: [0-2] MONTHS
description: 11C -Flumazenil binding in the grey matter : Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding kinetic analysis, and expressed as a Bmax estimation, in the cortex and deep grey matter of subjects.
measure: individual maps of neurodegeneration: changes in individual mapping of Flumazenil binding in different groups
time frame: [0-2] MONTHS
description: Individual mapping of Flumazenil binding changes in the grey matter of patients with MS compared to healthy controls at the voxel level
measure: volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume
time frame: [0-2] MONTHS
description: volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume
measure: volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load
time frame: [0-2] MONTHS
description: volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load
measure: Volume of gadolinium-enhanced white matter lesions on T1 sequence
time frame: [0-2] MONTHS
description: Volume of gadolinium-enhanced white matter lesions assessed on T1 sequence
measure: Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups
time frame: [0-2] MONTHS
description: Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups
measure: functional connectivity changes in patients
time frame: [0-2] MONTHS
description: functional connectivity assessed on resting state fMRI
arm group label: Patients with multiple sclerosis
arm group type: Other
description: The multiple sclerosis group (n=30) will be subdivided in two subgroups: 15 patients with a relapsing remmitting MS (RRMS), and 15 patients with a primary progressive MS (PPMS).
arm group label: healthy subjects
arm group type: Other
description: 15 healthy subjects will be included. Among them 7 to 8 subjects will be matched for age and gender with the RRMS subgroup, and 7 to 8 will be matched for age and gender with the PPMS subgroup.
intervention type: Diagnostic Test
intervention name: PET with [11C]Flumazenil
description: 7T MRI sequences : TSE, T2w FLAIR GRE-T2* and DIR 3T MRI sequences: T1, T2, T1 with gadolinium, magnetization transfer, diffusion weighted, resting state fMRI.
arm group label: Patients with multiple sclerosis
arm group label: healthy subjects
other name: 7T and 3T MRI
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Relapsing-Remitting
mesh term: Sclerosis
mesh term: Nerve Degeneration
mesh term: Flumazenil