<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/NCT03304717</url>
  </required_header>
  <id_info>
    <org_study_id>17-013715</org_study_id>
    <secondary_id>U01HD082806-03</secondary_id>
    <nct_id>NCT03304717</nct_id>
  </id_info>
  <brief_title>Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome</brief_title>
  <acronym>RTI in AGS</acronym>
  <official_title>Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital of Philadelphia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Human Genome Research Institute (NHGRI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Gilead Sciences</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Emerson Resources</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital of Philadelphia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall objectives are to explore the safety and efficacy of Reverse Transcriptase&#xD;
      Inhibitors Tenofovir (TDF)/ Emtricitabine (FTC) administered in AGS affected children 2 to 18&#xD;
      years of age.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators propose that a trial to assess the proof of principle that antiretroviral&#xD;
      therapy through a drug combination of Tenofovir (TDF) and Emtricitabine (FTC) can decrease&#xD;
      endogenous retroelement accumulation, and alter interferon signaling in Aicardi Goutières&#xD;
      Syndrome (AGS) patients is reasonable and warranted at this time, based on existing in vitro&#xD;
      and animal data. Additionally, this trial will further the investigators understanding of&#xD;
      this disorder, measuring for the first time retroelements in human participants, exploring&#xD;
      the retroviral burden in cerebrospinal fluid (CSF), the Interferon (IFN) signaling response,&#xD;
      as well as evaluating antigen targets of autoimmunity and cytokines. If successful, this&#xD;
      approach will clearly demonstrate the need for a larger trial of antiretrovirals in AGS with&#xD;
      more clinically relevant outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">December 2023</start_date>
  <completion_date type="Anticipated">December 2028</completion_date>
  <primary_completion_date type="Anticipated">December 2028</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in interferon activation as measured by interferon response genes</measure>
    <time_frame>From Baseline to 13 months</time_frame>
    <description>The investigators propose to measure genes in the IFN stimulatory pathway in AGS patients, as a measure of disease activity and as a possible biomarker of therapeutic activity. Current data suggests that IFN related genes remain elevated in the late teens in AGS affected subjects, making it a more reliable measure of disease activity than IFN alpha. Validation of this preliminary data includes serial measurements in blood across several time points, to assess for variability.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Determination of immune cell composition in CSF</measure>
    <time_frame>From Baseline to 13 months</time_frame>
    <description>The investigators will pursue immunophenotyping of CSF cells in AGS subjects. Immunophenotyping and target antigens will further understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination of immune cell composition in blood</measure>
    <time_frame>From Baseline to 13 months</time_frame>
    <description>The investigators will pursue immunophenotyping of peripheral blood monocytes in AGS participants. Immunophenotyping and target antigens will further our understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation of endogenous retroelements as measured in circulating immune cells</measure>
    <time_frame>From Baseline to 13 months</time_frame>
    <description>Performed by assays from previously collected samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation of endogenous retroelements as measured in circulating CSF</measure>
    <time_frame>From Baseline to 13 months</time_frame>
    <description>Performed by assays from previously collected samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in presence of non-specific and specific autoantibodies in blood</measure>
    <time_frame>From Baseline to 13 months</time_frame>
    <description>Performed by assays from previously collected samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Adverse Events - Safety monitoring laboratory tests</measure>
    <time_frame>From Baseline to 13 months and as clinically warranted</time_frame>
    <description>Patient monitoring for adverse effects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in total days hospitalized for disease-related illnesses.</measure>
    <time_frame>Baseline - 13 months</time_frame>
    <description>Assess the effects of the treatment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">34</enrollment>
  <condition>Aicardi Goutières Syndrome</condition>
  <arm_group>
    <arm_group_label>TDF/FTC then Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a double-blind, placebo-controlled, 2 arm, cross-over trial involving 34 children with clinical findings and molecular confirmation of Aicardi Goutieres Syndrome, who also have an abnormal interferon signature. For arm 1, half of the patients will receive TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for the first 6 months of the study. There will be a one month washout period before starting on placebo for 6 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo then TDF/FTC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>For arm 2, half of the patients will receive placebo for the first 6 months of the study. There will be a one month washout period before starting on TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for 6 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tenofovir (TDF) and Emtricitabine (FTC)</intervention_name>
    <description>Tenofovir (TDF): a nucleotide reverse transcriptase inhibitor (NtRTI) an acyclic nucleotide analog of adenosine 5'-monophosphate. This is used in children as young as age 2.&#xD;
Emtricitabine (FTC): a nucleoside reverse transcriptase inhibitor (NRTI), a synthetic analog of cytidine which binds at the active site of the reverse transcriptase.</description>
    <arm_group_label>Placebo then TDF/FTC</arm_group_label>
    <arm_group_label>TDF/FTC then Placebo</arm_group_label>
    <other_name>Truvada (Tenofovir Disoproxil Fumarate and Emtricitabine)</other_name>
    <other_name>Viread (Brand for tenofovir disoproxil fumarate)</other_name>
    <other_name>Emtriva (Brand for emtricitabine)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo for Tenofovir and Placebo for Emtricitabine</description>
    <arm_group_label>Placebo then TDF/FTC</arm_group_label>
    <arm_group_label>TDF/FTC then Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Molecular, neuroimaging, and clinical findings consistent with a diagnosis of AGS,&#xD;
             with the exception of Double-stranded RNA-specific adenosine deaminase (ADAR1) and&#xD;
             IFIH1, which are not postulated to result in nucleic acid accumulation&#xD;
&#xD;
          -  Evidence of interferon activation such as elevation of CSF&#xD;
             neopterin/tetrahydrobiopterin measured on the first evaluation.&#xD;
&#xD;
          -  Ages 2-18 years (the age of 2 years is used because the drugs are FDA approved in&#xD;
             children greater than 2 years)&#xD;
&#xD;
          -  Weight of at least 10 kg&#xD;
&#xD;
          -  Willingness to undergo serial lumbar punctures and blow draws for evaluation of&#xD;
             laboratory based outcome measures&#xD;
&#xD;
          -  Willingness to abstain from initiating the use of immune modulating therapies&#xD;
             including corticosteroids&#xD;
&#xD;
          -  Able to receive medications orally, by nasogastric (NG) tube or by Gastric (G)-tube&#xD;
&#xD;
          -  No concomitant illness which would preclude safe participation as judged by the&#xD;
             investigator&#xD;
&#xD;
          -  Signed informed consent by the subject's legally acceptable representative&#xD;
&#xD;
          -  Negative testing for HIV&#xD;
&#xD;
          -  Negative testing for Hepatitis B&#xD;
&#xD;
          -  Concurrent enrollment in the Myelin Disorders Biorepository Project (MDBP,&#xD;
             ClinicalTrials.gov NCT03047369) and willingness to undergo associated procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 2 years or &gt;18 years&#xD;
&#xD;
          -  Hepatic insufficiency with liver function tests greater than 3-times the upper limit&#xD;
             of normal&#xD;
&#xD;
          -  Renal insufficiency with creatinine clearance &lt;60&#xD;
&#xD;
          -  Significant malabsorption&#xD;
&#xD;
          -  Any clinical or laboratory abnormality or medical condition that, at the discretion of&#xD;
             the investigator, may put the subject at an additional risk by participating in this&#xD;
             study&#xD;
&#xD;
          -  HIV infection&#xD;
&#xD;
          -  Hepatitis B infection&#xD;
&#xD;
          -  Mutations in ADAR1 or IFIH1&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adeline Vanderver, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital of Philadelphia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>William Gahl, MD. PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Health Genome Research Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Constance Besnier</last_name>
    <phone>215-590-0373</phone>
    <email>besnierc@chop.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <contact>
      <last_name>Adeline Vanderver, MD</last_name>
      <phone>215-590-1719</phone>
      <email>vandervera@chop.edu</email>
    </contact>
    <investigator>
      <last_name>Adeline Vanderver, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>August 4, 2017</study_first_submitted>
  <study_first_submitted_qc>October 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 9, 2017</study_first_posted>
  <last_update_submitted>January 17, 2023</last_update_submitted>
  <last_update_submitted_qc>January 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Leukodystrophy</keyword>
  <keyword>Antiretroviral Drugs</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nervous System Malformations</mesh_term>
    <mesh_term>Autoimmune Diseases of the Nervous System</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
    <mesh_term>Emtricitabine</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/NCT03304717
org study id: 17-013715
secondary id: U01HD082806-03
nct id: NCT03304717
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The overall objectives are to explore the safety and efficacy of Reverse Transcriptase
      Inhibitors Tenofovir (TDF)/ Emtricitabine (FTC) administered in AGS affected children 2 to 18
      years of age.
The investigators propose that a trial to assess the proof of principle that antiretroviral
      therapy through a drug combination of Tenofovir (TDF) and Emtricitabine (FTC) can decrease
      endogenous retroelement accumulation, and alter interferon signaling in Aicardi Goutières
      Syndrome (AGS) patients is reasonable and warranted at this time, based on existing in vitro
      and animal data. Additionally, this trial will further the investigators understanding of
      this disorder, measuring for the first time retroelements in human participants, exploring
      the retroviral burden in cerebrospinal fluid (CSF), the Interferon (IFN) signaling response,
      as well as evaluating antigen targets of autoimmunity and cytokines. If successful, this
      approach will clearly demonstrate the need for a larger trial of antiretrovirals in AGS with
      more clinically relevant outcomes.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Change in interferon activation as measured by interferon response genes
time frame: From Baseline to 13 months
description: The investigators propose to measure genes in the IFN stimulatory pathway in AGS patients, as a measure of disease activity and as a possible biomarker of therapeutic activity. Current data suggests that IFN related genes remain elevated in the late teens in AGS affected subjects, making it a more reliable measure of disease activity than IFN alpha. Validation of this preliminary data includes serial measurements in blood across several time points, to assess for variability.
measure: Determination of immune cell composition in CSF
time frame: From Baseline to 13 months
description: The investigators will pursue immunophenotyping of CSF cells in AGS subjects. Immunophenotyping and target antigens will further understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity.
measure: Determination of immune cell composition in blood
time frame: From Baseline to 13 months
description: The investigators will pursue immunophenotyping of peripheral blood monocytes in AGS participants. Immunophenotyping and target antigens will further our understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity.
measure: Accumulation of endogenous retroelements as measured in circulating immune cells
time frame: From Baseline to 13 months
description: Performed by assays from previously collected samples
measure: Accumulation of endogenous retroelements as measured in circulating CSF
time frame: From Baseline to 13 months
description: Performed by assays from previously collected samples
measure: Change in presence of non-specific and specific autoantibodies in blood
time frame: From Baseline to 13 months
description: Performed by assays from previously collected samples
measure: Changes in Adverse Events - Safety monitoring laboratory tests
time frame: From Baseline to 13 months and as clinically warranted
description: Patient monitoring for adverse effects
measure: Changes in total days hospitalized for disease-related illnesses.
time frame: Baseline - 13 months
description: Assess the effects of the treatment
arm group label: TDF/FTC then Placebo
arm group type: Experimental
description: This is a double-blind, placebo-controlled, 2 arm, cross-over trial involving 34 children with clinical findings and molecular confirmation of Aicardi Goutieres Syndrome, who also have an abnormal interferon signature. For arm 1, half of the patients will receive TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for the first 6 months of the study. There will be a one month washout period before starting on placebo for 6 months.
arm group label: Placebo then TDF/FTC
arm group type: Experimental
description: For arm 2, half of the patients will receive placebo for the first 6 months of the study. There will be a one month washout period before starting on TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for 6 months.
intervention type: Drug
intervention name: Tenofovir (TDF) and Emtricitabine (FTC)
description: Tenofovir (TDF): a nucleotide reverse transcriptase inhibitor (NtRTI) an acyclic nucleotide analog of adenosine 5'-monophosphate. This is used in children as young as age 2.
Emtricitabine (FTC): a nucleoside reverse transcriptase inhibitor (NRTI), a synthetic analog of cytidine which binds at the active site of the reverse transcriptase.
arm group label: Placebo then TDF/FTC
arm group label: TDF/FTC then Placebo
other name: Truvada (Tenofovir Disoproxil Fumarate and Emtricitabine)
other name: Viread (Brand for tenofovir disoproxil fumarate)
other name: Emtriva (Brand for emtricitabine)
intervention type: Other
intervention name: Placebo
description: Placebo for Tenofovir and Placebo for Emtricitabine
arm group label: Placebo then TDF/FTC
arm group label: TDF/FTC then Placebo
criteria: 
gender: All
minimum age: 2 Years
maximum age: 18 Years
healthy volunteers: No
last name: Adeline Vanderver, MD
role: Principal Investigator
affiliation: Children's Hospital of Philadelphia
last name: William Gahl, MD. PhD
role: Principal Investigator
affiliation: National Institute of Health Genome Research Institute
last name: Constance Besnier
phone: 215-590-0373
email: besnierc@chop.edu
facility: 
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Nervous System Malformations
mesh term: Autoimmune Diseases of the Nervous System
mesh term: Syndrome
mesh term: Tenofovir
mesh term: Emtricitabine