<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/NCT01730131</url>
  </required_header>
  <id_info>
    <org_study_id>130017</org_study_id>
    <secondary_id>13-N-0017</secondary_id>
    <nct_id>NCT01730131</nct_id>
  </id_info>
  <brief_title>Natural History Study of Progressive Multifocal Leukoencephalopathy (PML)</brief_title>
  <official_title>Natural History Study of Progressive Multifocal Leukoencephalopathy (PML)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</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>
      Background:&#xD;
&#xD;
      - Progressive multifocal leukoencephalopathy (PML) is a severe viral infection of the brain.&#xD;
      It is caused by JC virus. Many people have this virus in their bodies all their life, but it&#xD;
      is usually kept in check by their immune system. If the immune system does not work right&#xD;
      because of a disease or medication, the virus becomes active and can damage cells in the&#xD;
      brain. Not much is known about PML or how it affects the immune system. Researchers want to&#xD;
      study people with PML to better understand the natural history of the disease.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To study the natural history of PML.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Individuals at least 2 years of age who have PML.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with a physical exam, medical history, and imaging&#xD;
           studies.&#xD;
&#xD;
        -  Participants will have several visits to the National Institutes of Health Clinical&#xD;
           Center. There will be an initial visit, monthly visits for the next 6 months, a 12-month&#xD;
           visit, and possible visits afterward.&#xD;
&#xD;
        -  At the initial visit, participants will give blood, urine, and spinal fluid samples.&#xD;
           They will also have neurological tests and imaging studies of the brain.&#xD;
&#xD;
        -  For the next five visits, participants will give blood and urine samples. They will also&#xD;
           have neurological tests and imaging studies of the brain.&#xD;
&#xD;
        -  The 6-month and 12-month visits will repeat the tests from the initial visit.&#xD;
&#xD;
        -  Other optional procedures include bone marrow samples and skin biopsies. Additional&#xD;
           blood tests and imaging studies may be performed.&#xD;
&#xD;
        -  Treatment will not be provided as part of this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The objective of this study is to examine the risk factors and natural course of JCV&#xD;
      infection and progressive multifocal leukoencephalopathy (PML). PML is a devastating,&#xD;
      demyelinating neurological disease affecting the brain of patients with a compromised immune&#xD;
      system. It is caused by reactivation of JC virus (JCV), a small DNA virus that infects the&#xD;
      majority of the population without clinical significance. There are currently no treatments&#xD;
      available for PML.&#xD;
&#xD;
      We plan to study patients with suspected or confirmed PML with different underlying&#xD;
      conditions including patients on immune-modulatory therapies for multiple sclerosis (MS),&#xD;
      rheumatologic diseases or other autoimmune diseases, as well as patients with HIV infection&#xD;
      or other conditions leading to a compromised immune system. Patients will be seen at defined&#xD;
      time points during their disease course and detailed assessments will be performed to collect&#xD;
      clinical and imaging data. Blood, cerebrospinal fluid (CSF) and urine will also be collected&#xD;
      at these time points to evaluate the behavior and biology of the JCV and the patients immune&#xD;
      responses to the infection. These tests will lead to a better understanding of the&#xD;
      pathophysiology of PML and the course of this disease in different patient groups.&#xD;
      Additionally, we will recruit a patient control cohort represented by patients with impaired&#xD;
      immune function for any cause and considered at risk for development of PML, and a healthy&#xD;
      volunteer cohort. The purpose of these additional cohorts is to explore and validate&#xD;
      biomarkers for risk of development of PML and early diagnosis. Additionally, the healthy&#xD;
      volunteer cohort may be screened and evaluated as possible donors of peripheral blood&#xD;
      mononuclear cells (PBMC) for manufacture of virus-specific T cells.&#xD;
&#xD;
      The detailed characterization described above will be used to help identify:&#xD;
&#xD;
        1. Clinical imaging and/or laboratory features pathognomonic of JCV infection and disease&#xD;
           course that may aid in earlier diagnosis and appropriate intervention&#xD;
&#xD;
        2. Clinical imaging and/or laboratory features of the disease course that is predictive of&#xD;
           clinical outcomes&#xD;
&#xD;
      This information will be integrated to develop a clinically relevant, disease-specific&#xD;
      assessment scale of PML, which is currently not available. Such a scale would be a useful&#xD;
      tool for the clinical management of patients (i.e., for development of standards of care), as&#xD;
      well as for clinical trial design and interpretation.&#xD;
&#xD;
      The long-term objectives of this study are to improve the understanding of the disease course&#xD;
      and underlying pathophysiology, to identify subgroups with different prognosis and/or&#xD;
      susceptibility to interventions, and to help identify therapeutic targets and/or intervention&#xD;
      strategies. Equally important, these efforts will allow development of a repository of&#xD;
      cryopreserved biological samples that will be used for validation of candidate biomarkers in&#xD;
      future studies; this data and biological bank will be made available to outside laboratories.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 8, 2012</start_date>
  <primary_completion_date type="Anticipated">January 1, 2027</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>To characterize the baseline features, of patients with PML with regards to clinical features imaging studies, immunological markers, and viral studies.</measure>
    <time_frame>one year following last enrollment</time_frame>
    <description>1. Characterization of distinctive imaging features to differentiate between actively progressing PML, and PML-IRIS and inactive PML 2. Characterization of distinctive clinical features to differentiate between actively progressing PML, PML- and IRIS, and inactive PML 3. Characterization of immune and virological features to differentiate between actively progressing PML, and PML- IRIS, and inactive PML 4. Characterization of immune and virological differences across PML patient populations with different underlying disease, subjects at risk for developing PML, and healthy individuals 5. Characterization of genetic susceptibility for development of PML</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To longitudinally follow patients with PML with thorough characterization of their clinical course, imaging correlates, immunological markers, and viral studies</measure>
    <time_frame>one year following last enrollment</time_frame>
    <description>1. Temporal correlation between clinical course and imaging and/or laboratory measures 2. To identify biomarkers that can predict long-term outcome and response to treatment interventions 3. To develop a clinically relevant assessment scale for PML that identifies milestones of disease progression 4. To develop a repository of cryopreserved biological samples that will be used for validation of candidate biomarkers in future studies 5. To characterize the immune profile in blood and CSF of patients with PML 6. To determine the eligibility of PML patients for participation in other studies 7. To screen and evaluate healthy subjects as donors for manufacture of virus-specific T cells (to be administered to patients under separate, dedicated protocol)</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">700</enrollment>
  <condition>Progressive Multifocal Leukoencephalopathy</condition>
  <arm_group>
    <arm_group_label>Control Patients at Risk for PML</arm_group_label>
    <description>Participants with impaired immune function from any cause and considered at risk for PML</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Volunteers</arm_group_label>
    <description>Healthy volunteers without impaired immune function</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PML Patients</arm_group_label>
    <description>Participants with PML</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Primary clinical for participants that have PML or at risk for PML and community&#xD;
        sample/healthy relatives for healthy volunteers.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
               1. Suspected or confirmed PML&#xD;
&#xD;
               2. MRI compatible with PML&#xD;
&#xD;
               3. Able to participate in the studies and follow-up required by the protocol&#xD;
&#xD;
               4. At least 2 years old&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Significant condition, which in the judgment of the principal investigator, would make&#xD;
             participation in the diagnostic and research parts of evaluation impossible or risky.&#xD;
&#xD;
          2. Medical contraindication to MRI (i.e., devices such as a cardiac pacemaker or infusion&#xD;
             pump, other metallic implants, metallic foreign objects, body piercings that cannot be&#xD;
             removed)&#xD;
&#xD;
          3. Pregnancy&#xD;
&#xD;
          4. Inability to provide informed consent, either directly or via appointed power of&#xD;
             attorney&#xD;
&#xD;
          5. Unwillingness to consent for collection of biological samples or their&#xD;
             cryopreservation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>120 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Irene CM Cortese, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Neurological Disorders and Stroke (NINDS)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mauricio Campillay</last_name>
    <phone>(301) 496-3825</phone>
    <email>mauricio.campillay@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Irene CM Cortese, M.D.</last_name>
    <phone>(301) 496-9175</phone>
    <email>corteseir@ninds.nih.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)</last_name>
      <phone>800-411-1222</phone>
      <phone_ext>TTY dial 711</phone_ext>
      <email>ccopr@nih.gov</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2013-N-0017.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Cinque P, Koralnik IJ, Gerevini S, Miro JM, Price RW. Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet Infect Dis. 2009 Oct;9(10):625-36. doi: 10.1016/S1473-3099(09)70226-9.</citation>
    <PMID>19778765</PMID>
  </reference>
  <reference>
    <citation>Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet. 1971 Jun 19;1(7712):1257-60. doi: 10.1016/s0140-6736(71)91777-6. No abstract available.</citation>
    <PMID>4104715</PMID>
  </reference>
  <reference>
    <citation>Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry. 2010 Mar;81(3):247-54. doi: 10.1136/jnnp.2009.187666. Epub 2009 Oct 14.</citation>
    <PMID>19828476</PMID>
  </reference>
  <verification_date>June 15, 2023</verification_date>
  <study_first_submitted>November 17, 2012</study_first_submitted>
  <study_first_submitted_qc>November 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2012</study_first_posted>
  <last_update_submitted>September 8, 2023</last_update_submitted>
  <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Encephalitis</keyword>
  <keyword>Immune Reconstitution Syndrome</keyword>
  <keyword>Human Immunodeficiency Virus</keyword>
  <keyword>Multiple Sclerosis</keyword>
  <keyword>Natural History</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>
  <!-- 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/NCT01730131
org study id: 130017
secondary id: 13-N-0017
nct id: NCT01730131
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Background:

      - Progressive multifocal leukoencephalopathy (PML) is a severe viral infection of the brain.
      It is caused by JC virus. Many people have this virus in their bodies all their life, but it
      is usually kept in check by their immune system. If the immune system does not work right
      because of a disease or medication, the virus becomes active and can damage cells in the
      brain. Not much is known about PML or how it affects the immune system. Researchers want to
      study people with PML to better understand the natural history of the disease.

      Objectives:

      - To study the natural history of PML.

      Eligibility:

      - Individuals at least 2 years of age who have PML.

      Design:

        -  Participants will be screened with a physical exam, medical history, and imaging
           studies.

        -  Participants will have several visits to the National Institutes of Health Clinical
           Center. There will be an initial visit, monthly visits for the next 6 months, a 12-month
           visit, and possible visits afterward.

        -  At the initial visit, participants will give blood, urine, and spinal fluid samples.
           They will also have neurological tests and imaging studies of the brain.

        -  For the next five visits, participants will give blood and urine samples. They will also
           have neurological tests and imaging studies of the brain.

        -  The 6-month and 12-month visits will repeat the tests from the initial visit.

        -  Other optional procedures include bone marrow samples and skin biopsies. Additional
           blood tests and imaging studies may be performed.

        -  Treatment will not be provided as part of this study.
The objective of this study is to examine the risk factors and natural course of JCV
      infection and progressive multifocal leukoencephalopathy (PML). PML is a devastating,
      demyelinating neurological disease affecting the brain of patients with a compromised immune
      system. It is caused by reactivation of JC virus (JCV), a small DNA virus that infects the
      majority of the population without clinical significance. There are currently no treatments
      available for PML.

      We plan to study patients with suspected or confirmed PML with different underlying
      conditions including patients on immune-modulatory therapies for multiple sclerosis (MS),
      rheumatologic diseases or other autoimmune diseases, as well as patients with HIV infection
      or other conditions leading to a compromised immune system. Patients will be seen at defined
      time points during their disease course and detailed assessments will be performed to collect
      clinical and imaging data. Blood, cerebrospinal fluid (CSF) and urine will also be collected
      at these time points to evaluate the behavior and biology of the JCV and the patients immune
      responses to the infection. These tests will lead to a better understanding of the
      pathophysiology of PML and the course of this disease in different patient groups.
      Additionally, we will recruit a patient control cohort represented by patients with impaired
      immune function for any cause and considered at risk for development of PML, and a healthy
      volunteer cohort. The purpose of these additional cohorts is to explore and validate
      biomarkers for risk of development of PML and early diagnosis. Additionally, the healthy
      volunteer cohort may be screened and evaluated as possible donors of peripheral blood
      mononuclear cells (PBMC) for manufacture of virus-specific T cells.

      The detailed characterization described above will be used to help identify:

        1. Clinical imaging and/or laboratory features pathognomonic of JCV infection and disease
           course that may aid in earlier diagnosis and appropriate intervention

        2. Clinical imaging and/or laboratory features of the disease course that is predictive of
           clinical outcomes

      This information will be integrated to develop a clinically relevant, disease-specific
      assessment scale of PML, which is currently not available. Such a scale would be a useful
      tool for the clinical management of patients (i.e., for development of standards of care), as
      well as for clinical trial design and interpretation.

      The long-term objectives of this study are to improve the understanding of the disease course
      and underlying pathophysiology, to identify subgroups with different prognosis and/or
      susceptibility to interventions, and to help identify therapeutic targets and/or intervention
      strategies. Equally important, these efforts will allow development of a repository of
      cryopreserved biological samples that will be used for validation of candidate biomarkers in
      future studies; this data and biological bank will be made available to outside laboratories.
observational model: Cohort
time perspective: Prospective
measure: To characterize the baseline features, of patients with PML with regards to clinical features imaging studies, immunological markers, and viral studies.
time frame: one year following last enrollment
description: 1. Characterization of distinctive imaging features to differentiate between actively progressing PML, and PML-IRIS and inactive PML 2. Characterization of distinctive clinical features to differentiate between actively progressing PML, PML- and IRIS, and inactive PML 3. Characterization of immune and virological features to differentiate between actively progressing PML, and PML- IRIS, and inactive PML 4. Characterization of immune and virological differences across PML patient populations with different underlying disease, subjects at risk for developing PML, and healthy individuals 5. Characterization of genetic susceptibility for development of PML
measure: To longitudinally follow patients with PML with thorough characterization of their clinical course, imaging correlates, immunological markers, and viral studies
time frame: one year following last enrollment
description: 1. Temporal correlation between clinical course and imaging and/or laboratory measures 2. To identify biomarkers that can predict long-term outcome and response to treatment interventions 3. To develop a clinically relevant assessment scale for PML that identifies milestones of disease progression 4. To develop a repository of cryopreserved biological samples that will be used for validation of candidate biomarkers in future studies 5. To characterize the immune profile in blood and CSF of patients with PML 6. To determine the eligibility of PML patients for participation in other studies 7. To screen and evaluate healthy subjects as donors for manufacture of virus-specific T cells (to be administered to patients under separate, dedicated protocol)
arm group label: Control Patients at Risk for PML
description: Participants with impaired immune function from any cause and considered at risk for PML
arm group label: Healthy Volunteers
description: Healthy volunteers without impaired immune function
arm group label: PML Patients
description: Participants with PML
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 2 Years
maximum age: 120 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Irene CM Cortese, M.D.
role: Principal Investigator
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
last name: Mauricio Campillay
phone: (301) 496-3825
email: mauricio.campillay@nih.gov
last name: Irene CM Cortese, M.D.
phone: (301) 496-9175
email: corteseir@ninds.nih.gov
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2013-N-0017.html
description: NIH Clinical Center Detailed Web Page
citation: Cinque P, Koralnik IJ, Gerevini S, Miro JM, Price RW. Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet Infect Dis. 2009 Oct;9(10):625-36. doi: 10.1016/S1473-3099(09)70226-9.
PMID: 19778765
citation: Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet. 1971 Jun 19;1(7712):1257-60. doi: 10.1016/s0140-6736(71)91777-6. No abstract available.
PMID: 4104715
citation: Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry. 2010 Mar;81(3):247-54. doi: 10.1136/jnnp.2009.187666. Epub 2009 Oct 14.
PMID: 19828476
responsible party type: Sponsor
mesh term: Leukoencephalopathy, Progressive Multifocal
mesh term: Leukoencephalopathies