<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/NCT04453917</url>
  </required_header>
  <id_info>
    <org_study_id>RC31/19/0506</org_study_id>
    <nct_id>NCT04453917</nct_id>
  </id_info>
  <brief_title>Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy</brief_title>
  <acronym>ICIP</acronym>
  <official_title>Dynamics of T Cell Expression of Immune Checkpoint Molecules in Progressive Multifocal Leukoencephalopathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Toulouse</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Toulouse</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>
      Progressive multifocal leukoencephalopathy (PML) is a rare viral infection of the central&#xD;
      nervous system (CNS) occurring in immunocompromised patients. Recovery of JC virus (JCV)&#xD;
      specific T cell immune responses is the only available therapeutic option. JCV may use immune&#xD;
      checkpoint inhibitory pathways to evade immune responses. The aim of this project is to&#xD;
      determine whether T cell expression of immune checkpoint molecules is correlated to antiviral&#xD;
      T cell responses, control of JCV replication and PML outcome. Immune checkpoint blockade by&#xD;
      reversing T cell exhaustion may represent a therapeutic perspective for PML.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PML is a devastating orphan disease of the CNS due to the reactivation of JCV in&#xD;
      immunocompromised patients. Given the lack of drugs controlling JCV replication, initiation&#xD;
      of antiretroviral therapy in HIV-infected patients or cessation of immunosuppressive&#xD;
      therapies in others, and subsequent recovery of JCV-specific T cell immune responses remains&#xD;
      to date the only available therapeutic option. Promoting antiviral immune responses may&#xD;
      improve the control of viral replication and the outcome of this severe disease. Immune&#xD;
      checkpoint molecules such as PD-1 are inhibitory receptors expressed on T cells that trigger&#xD;
      inhibitory signaling pathways, limiting effector immune responses in cancer and chronic&#xD;
      infections. Immune checkpoint inhibitory pathways implicated in evading immune responses may&#xD;
      be at play in PML. Immune checkpoint blockade using monoclonal antibodies targeting PD-1, by&#xD;
      reversing T cell exhaustion, has been suggested as a therapeutic perspective for PML. More&#xD;
      insights in the dynamics of immune checkpoint molecules expressed by T cells in PML patients&#xD;
      are needed to pave the way for a therapeutic study.&#xD;
&#xD;
      The aim here is to determine whether T cell expression of a broad range of immune checkpoint&#xD;
      molecules, and its dynamics, correlates with the generation of antiviral of immune responses,&#xD;
      the control of JCV replication and PML outcome.&#xD;
&#xD;
      To this end the investigators will recruit 15 PML patients from 4 teaching hospitals in the&#xD;
      South West of France and assess at PML diagnosis and 1, 3 and 6 months after, the expression&#xD;
      of immune checkpoint molecules on circulating T cells, ex vivo specific immune responses&#xD;
      against a JCV peptide library, JC viral load in cerebrospinal fluid, blood and urine, and&#xD;
      clinical and neuroradiological outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 23, 2021</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</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>Patients with neurological symptoms (&lt; 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Immune checkpoint molecules</measure>
    <time_frame>1 month</time_frame>
    <description>Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Immune checkpoint molecules</measure>
    <time_frame>3 months</time_frame>
    <description>Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Immune checkpoint molecules</measure>
    <time_frame>6 months</time_frame>
    <description>Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry</description>
  </primary_outcome>
  <primary_outcome>
    <measure>JC viral load</measure>
    <time_frame>1 month</time_frame>
    <description>JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>JC viral load</measure>
    <time_frame>3 months</time_frame>
    <description>JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>JC viral load</measure>
    <time_frame>6 months</time_frame>
    <description>JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Detection of immune responses against a JCV peptide library</measure>
    <time_frame>1 month</time_frame>
    <description>Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Detection of immune responses against a JCV peptide library</measure>
    <time_frame>3 months</time_frame>
    <description>Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Detection of immune responses against a JCV peptide library</measure>
    <time_frame>6 months</time_frame>
    <description>Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Differential impact of immune checkpoint inhibition</measure>
    <time_frame>1 month, 3 months and 6 months</time_frame>
    <description>Differential impact of immune checkpoint inhibition in vitro on detection of specific immune responses at PML diagnosis by flow cytometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical outcome with Performance status</measure>
    <time_frame>1 month, 3 months and 6 months</time_frame>
    <description>Clinical outcome using validated scales such as Performance status at PML diagnosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical outcome with NIHSS</measure>
    <time_frame>1 month, 3 months and 6 months</time_frame>
    <description>Clinical outcome using validated scales such as NIHSS (National Institute of Health Stroke Score) at PML diagnosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical outcome with Rankin</measure>
    <time_frame>1 month, 3 months and 6 months</time_frame>
    <description>Clinical outcome using validated scales such as Rankin at PML diagnosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuroradiological monitoring</measure>
    <time_frame>3 months and 6 months</time_frame>
    <description>Neuroradiological monitoring by brain MRI at PML diagnosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>JC virus genotyping</measure>
    <time_frame>1 month, 3 months and 6 months</time_frame>
    <description>JC virus genotyping in blood, cerebrospinal fluid (CSF) and urine by ultra-sensitive PCR at PML diagnosis</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Progressive Multifocal Leukoencephalopathy</condition>
  <arm_group>
    <arm_group_label>Patients with active PML</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with neurological symptoms (&lt; 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Collection of blood and urine</intervention_name>
    <description>Collection of blood (47 mL) and urine (5 mL) at PML diagnosis and 1, 3 and 6 months after, for analysis of immune checkpoint molecules expression, detection of antiviral immune responses and virological analyses.</description>
    <arm_group_label>Patients with active PML</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Spinal tap</intervention_name>
    <description>Spinal tap for monitoring of JC viral load at PML diagnosis and 1, 3 and 6 months after, and collection of CSF (2 mL) for virological analyses.</description>
    <arm_group_label>Patients with active PML</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Brain MRI</intervention_name>
    <description>Brain MRI at at PML diagnosis and 3 and 6 months after</description>
    <arm_group_label>Patients with active PML</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Neurological evaluation</intervention_name>
    <description>Neurological evaluation at PML diagnosis and 1, 3 and 6 months after</description>
    <arm_group_label>Patients with active PML</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults ≥18 years old&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
          -  Active virological PML : Recent neurological symptoms (&lt; 3 months) with brain MRI&#xD;
             lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV&#xD;
&#xD;
          -  Affiliated or benefiting from public health insurance.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non active PML&#xD;
&#xD;
          -  Possible PML with negative JCV PCR&#xD;
&#xD;
          -  Adults under guardianship or other legal protection, deprived of their liberty by&#xD;
             judicial or administrative decision&#xD;
&#xD;
          -  Pregnant and/or breastfeeding women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Guillaume MARTIN-BLONDEL</last_name>
    <role>Principal Investigator</role>
    <affiliation>CHU Toulouse</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Guillaume MARTIN-BLONDEL</last_name>
    <phone>5 61 77 96 99</phone>
    <phone_ext>33</phone_ext>
    <email>martin-blondel.g@chu-toulouse.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>CHU Bordeaux</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Charles CAZANAVE</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU Montpellier</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Vincent LE MOING</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU Nimes</name>
      <address>
        <city>Nîmes</city>
        <zip>30029</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Albert SOTTO</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de TOULOUSE</name>
      <address>
        <city>Toulouse</city>
        <zip>31000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Charline Daguzan, PhD</last_name>
      <phone>561778490</phone>
      <phone_ext>33</phone_ext>
      <email>daguzan.c@chu-toulouse.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>July 27, 2023</last_update_submitted>
  <last_update_submitted_qc>July 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Progressive multifocal leukoencephalopathy</keyword>
  <keyword>Pathophysiology</keyword>
  <keyword>Immune checkpoint molecules</keyword>
  <keyword>Immune Checkpoint Inhibitors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukoencephalopathy, Progressive Multifocal</mesh_term>
    <mesh_term>Leukoencephalopathies</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04453917
org study id: RC31/19/0506
nct id: NCT04453917
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Progressive multifocal leukoencephalopathy (PML) is a rare viral infection of the central
      nervous system (CNS) occurring in immunocompromised patients. Recovery of JC virus (JCV)
      specific T cell immune responses is the only available therapeutic option. JCV may use immune
      checkpoint inhibitory pathways to evade immune responses. The aim of this project is to
      determine whether T cell expression of immune checkpoint molecules is correlated to antiviral
      T cell responses, control of JCV replication and PML outcome. Immune checkpoint blockade by
      reversing T cell exhaustion may represent a therapeutic perspective for PML.
PML is a devastating orphan disease of the CNS due to the reactivation of JCV in
      immunocompromised patients. Given the lack of drugs controlling JCV replication, initiation
      of antiretroviral therapy in HIV-infected patients or cessation of immunosuppressive
      therapies in others, and subsequent recovery of JCV-specific T cell immune responses remains
      to date the only available therapeutic option. Promoting antiviral immune responses may
      improve the control of viral replication and the outcome of this severe disease. Immune
      checkpoint molecules such as PD-1 are inhibitory receptors expressed on T cells that trigger
      inhibitory signaling pathways, limiting effector immune responses in cancer and chronic
      infections. Immune checkpoint inhibitory pathways implicated in evading immune responses may
      be at play in PML. Immune checkpoint blockade using monoclonal antibodies targeting PD-1, by
      reversing T cell exhaustion, has been suggested as a therapeutic perspective for PML. More
      insights in the dynamics of immune checkpoint molecules expressed by T cells in PML patients
      are needed to pave the way for a therapeutic study.

      The aim here is to determine whether T cell expression of a broad range of immune checkpoint
      molecules, and its dynamics, correlates with the generation of antiviral of immune responses,
      the control of JCV replication and PML outcome.

      To this end the investigators will recruit 15 PML patients from 4 teaching hospitals in the
      South West of France and assess at PML diagnosis and 1, 3 and 6 months after, the expression
      of immune checkpoint molecules on circulating T cells, ex vivo specific immune responses
      against a JCV peptide library, JC viral load in cerebrospinal fluid, blood and urine, and
      clinical and neuroradiological outcomes.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Patients with neurological symptoms (< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
primary purpose: Basic Science
masking: None (Open Label)
measure: Immune checkpoint molecules
time frame: 1 month
description: Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
measure: Immune checkpoint molecules
time frame: 3 months
description: Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
measure: Immune checkpoint molecules
time frame: 6 months
description: Expression level of a broad panel of immune checkpoint molecules by T cells at PML diagnosis bu flow cytometry
measure: JC viral load
time frame: 1 month
description: JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
measure: JC viral load
time frame: 3 months
description: JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
measure: JC viral load
time frame: 6 months
description: JC viral load in cerebrospinal fluid, blood and urine by ultra-sensitive PCR at PML diagnosis
measure: Detection of immune responses against a JCV peptide library
time frame: 1 month
description: Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
measure: Detection of immune responses against a JCV peptide library
time frame: 3 months
description: Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
measure: Detection of immune responses against a JCV peptide library
time frame: 6 months
description: Detection of specific immune responses against a JCV peptide library at PML diagnosis by flow cytometry
measure: Differential impact of immune checkpoint inhibition
time frame: 1 month, 3 months and 6 months
description: Differential impact of immune checkpoint inhibition in vitro on detection of specific immune responses at PML diagnosis by flow cytometry
measure: Clinical outcome with Performance status
time frame: 1 month, 3 months and 6 months
description: Clinical outcome using validated scales such as Performance status at PML diagnosis
measure: Clinical outcome with NIHSS
time frame: 1 month, 3 months and 6 months
description: Clinical outcome using validated scales such as NIHSS (National Institute of Health Stroke Score) at PML diagnosis
measure: Clinical outcome with Rankin
time frame: 1 month, 3 months and 6 months
description: Clinical outcome using validated scales such as Rankin at PML diagnosis
measure: Neuroradiological monitoring
time frame: 3 months and 6 months
description: Neuroradiological monitoring by brain MRI at PML diagnosis
measure: JC virus genotyping
time frame: 1 month, 3 months and 6 months
description: JC virus genotyping in blood, cerebrospinal fluid (CSF) and urine by ultra-sensitive PCR at PML diagnosis
arm group label: Patients with active PML
arm group type: Experimental
description: Patients with neurological symptoms (< 3 months) with brain MRI lesions suggestive of PML and positive PCR in cerebrospinal fluid for JCV
intervention type: Biological
intervention name: Collection of blood and urine
description: Collection of blood (47 mL) and urine (5 mL) at PML diagnosis and 1, 3 and 6 months after, for analysis of immune checkpoint molecules expression, detection of antiviral immune responses and virological analyses.
arm group label: Patients with active PML
intervention type: Biological
intervention name: Spinal tap
description: Spinal tap for monitoring of JC viral load at PML diagnosis and 1, 3 and 6 months after, and collection of CSF (2 mL) for virological analyses.
arm group label: Patients with active PML
intervention type: Diagnostic Test
intervention name: Brain MRI
description: Brain MRI at at PML diagnosis and 3 and 6 months after
arm group label: Patients with active PML
intervention type: Biological
intervention name: Neurological evaluation
description: Neurological evaluation at PML diagnosis and 1, 3 and 6 months after
arm group label: Patients with active PML
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Guillaume MARTIN-BLONDEL
role: Principal Investigator
affiliation: CHU Toulouse
last name: Guillaume MARTIN-BLONDEL
phone: 5 61 77 96 99
phone ext: 33
email: martin-blondel.g@chu-toulouse.fr
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Leukoencephalopathy, Progressive Multifocal
mesh term: Leukoencephalopathies
sharing ipd: No