<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/NCT02264860</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00062730a</org_study_id>
    <secondary_id>1R01HL125042-01</secondary_id>
    <nct_id>NCT02264860</nct_id>
  </id_info>
  <brief_title>Researching Alveolar Macrophage Improvements With Supplements in HIV</brief_title>
  <acronym>RAISe</acronym>
  <official_title>Cohort 2: Researching Alveolar Macrophage Improvements With Supplements in HIV</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Emory University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Emory University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      HIV infection causes systemic zinc deficiency and oxidative stress that impairs host immunity&#xD;
      in the alveolar space.The purpose of this study is to see if taking two nutritional&#xD;
      supplements, zinc and SAMe (S-adenosylmethionine), can improve lung health and immune&#xD;
      function in persons with HIV.&#xD;
&#xD;
      The investigators hypothesize that long-term dietary supplementation with zinc and the&#xD;
      glutathione precursor SAMe will enhance pulmonary host immune function in HIV-infected&#xD;
      individuals who do not respond adequately to ART alone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This new proposal entitled &quot;The alveolar macrophage pool is a reservoir of HIV&quot; addresses a&#xD;
      fundamental question; specifically, does the alveolar macrophage pool serve as a reservoir of&#xD;
      HIV even when peripheral viral suppression is achieved by anti-retroviral therapy (ART) and&#xD;
      if so, how does this reservoir alter the environment within the alveolar space and impair&#xD;
      alveolar macrophage immune function? This is a critical question to address as lung&#xD;
      infections remain the leading cause of death in persons living with HIV even when they are&#xD;
      adherent to ART. There is compelling experimental evidence that HIV infection inhibits&#xD;
      anti-oxidant defenses within the alveolar space and causes severe redox stress. Based on&#xD;
      preliminary data presented in this proposal, the investigators hypothesize that HIV inhibits&#xD;
      the expression and actions of Nrf2, the master transcription factor that activates the&#xD;
      anti-oxidant response element (ARE), in part by inducing zinc deficiency in this vulnerable&#xD;
      microenvironment, and thereby prevents the alveolar epithelium and the alveolar macrophage&#xD;
      from generating glutathione and other anti-oxidants that are critically required to maintain&#xD;
      a healthy redox potential within the alveolar space. The investigators further hypothesize&#xD;
      that as a result of this targeted inhibition of the Nrf2-ARE signaling pathway, HIV promotes&#xD;
      its own ability to infect alveolar macrophages and accumulate a large pool of intracellular&#xD;
      pro-virus that produces a large HIV reservoir within the alveolar space. In parallel,&#xD;
      HIV-induced oxidative stress shifts the alveolar macrophage toward alternative activation (so&#xD;
      called 'M2 phenotype'). As a consequence, the innate immune capacity of the alveolar&#xD;
      macrophage is impaired and this not only confers further resistance to clearing the viral&#xD;
      reservoir but also renders the infected individual susceptible to serious lung infections.&#xD;
      The investigators will leverage ongoing collaborative clinical studies in HIV-infected&#xD;
      individuals. As a result, investigators not only have ongoing access to alveolar epithelial&#xD;
      lining fluid and macrophages from well-defined subsets of HIV-infected individuals, they also&#xD;
      have the expertise to apply state-of-the-art basic techniques in HIV pathogenesis,&#xD;
      metabolomics, and redox signaling to test hypotheses. In parallel, the investigators are&#xD;
      already conducting a prospective clinical trial of dietary zinc and S-adenosylmethionine (a&#xD;
      thiol anti-oxidant that among its many actions increases the glutathione pool in the alveolar&#xD;
      space) in HIV-infected individuals with inadequate immunological responses to ART&#xD;
      (NCT01806870). This unique cohort will form the foundation for a greatly expanded clinical&#xD;
      trial that will allow the investigators to test the corollary hypothesis that therapeutic&#xD;
      strategies designed to improve zinc bioavailability and the redox potential within the&#xD;
      alveolar space can enhance alveolar macrophage innate immune function and significantly&#xD;
      decrease the HIV reservoir in the lung. This project will produce novel insights into how we&#xD;
      can target the alveolar macrophage pool to decrease HIV burden as well as improve lung health&#xD;
      in these vulnerable individuals.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2014</start_date>
  <completion_date type="Actual">December 15, 2018</completion_date>
  <primary_completion_date type="Actual">December 15, 2018</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>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dosage Efficacy</measure>
    <time_frame>Three months</time_frame>
    <description>Incidence of treatment-related adverse events, particularly gastrointestinal problems such as nausea, gastritis or diarrhea</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in exhaled breath condensate (EBC) levels of glutathione (GSH)</measure>
    <time_frame>Baseline, 12 months</time_frame>
    <description>Collection of exhaled breath condensate (EBC) is a non-invasive technique obtained by freezing and collecting exhaled breath that contains glutathione (GSH) from the lower airways. EBC GSH is measured is nmoles/µg urea.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in exhaled breath condensate (EBC) levels of glutathione (GSH)</measure>
    <time_frame>Baseline, 24 months</time_frame>
    <description>Collection of exhaled breath condensate (EBC) is a non-invasive technique obtained by freezing and collecting exhaled breath that contains glutathione (GSH) from the lower airways. EBC GSH is measured is nmoles/µg urea.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">67</enrollment>
  <condition>HIV-1 Infection</condition>
  <arm_group>
    <arm_group_label>Nutritional Supplements Zinc and SAMe</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>All men subjects will be started on 30 mg/day and women will be started on 25mg of elemental zinc plus 1600 mg/day of SAMe.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Zinc and SAMe</intervention_name>
    <description>The subjects will have the supplements dispensed at visit 2. They will be contacted weekly for the next three weeks to ensure that they are tolerating the supplements without significant side-effects. If these side-effects are significant then the dose of zinc will be decreased for all subjects to 15 mg of elemental zinc/day; if symptoms persist the SAMe dose will then be decreased by 25% (to 1200 mg/day) and then by 50% (to 800 mg/day) if necessary until the supplements are tolerated. 12 mg of zinc and 800 mg of SAMe is the lowest dose possible.</description>
    <arm_group_label>Nutritional Supplements Zinc and SAMe</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects living with HIV-1 infection who have been on anti-retroviral therapy (ART)&#xD;
             for a minimum of 18 months and are followed longitudinally for their HIV healthcare in&#xD;
             one of the study sites in Atlanta.&#xD;
&#xD;
          -  Ability to give informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Documented history of cirrhosis or a direct bilirubin ≥ 2.0 mg/ld.&#xD;
&#xD;
          -  Documentation of left ventricular ejection fraction &lt; 40% or myocardial infarction&#xD;
             within the past 6 months.&#xD;
&#xD;
          -  End-stage renal disease requiring dialysis or a serum creatinine ≥ 2 mg/dL.&#xD;
&#xD;
          -  Spirometry with Forced vital capacity (FVC) or Forced expiratory volume in 1 second&#xD;
             (FEV1) &lt; 70% of predicted value.&#xD;
&#xD;
          -  Diabetes&#xD;
&#xD;
          -  Known or possible pregnancy or attempting to become pregnant or breastfeeding&#xD;
&#xD;
          -  BMI &lt; 17&#xD;
&#xD;
          -  Age &lt; 21&#xD;
&#xD;
          -  Parkinson's disease: these are all b/c the SAMe risks sections states that these pts&#xD;
             will not qualify&#xD;
&#xD;
          -  Bipolar disorder&#xD;
&#xD;
          -  Bleeding disorders such as thrombocytopenia or significant gastrointestinal bleeding&#xD;
             within the past year&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David M Guidot, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ponce De Leon Center</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>October 9, 2014</study_first_submitted>
  <study_first_submitted_qc>October 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 15, 2014</study_first_posted>
  <last_update_submitted>April 29, 2019</last_update_submitted>
  <last_update_submitted_qc>April 29, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Emory University</investigator_affiliation>
    <investigator_full_name>David M. Guidot, MD</investigator_full_name>
    <investigator_title>Director, Division of Pulmonary, Allergy, &amp; Critical Care Medicine</investigator_title>
  </responsible_party>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 22, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT02264860/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT02264860
org study id: IRB00062730a
secondary id: 1R01HL125042-01
nct id: NCT02264860
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
HIV infection causes systemic zinc deficiency and oxidative stress that impairs host immunity
      in the alveolar space.The purpose of this study is to see if taking two nutritional
      supplements, zinc and SAMe (S-adenosylmethionine), can improve lung health and immune
      function in persons with HIV.

      The investigators hypothesize that long-term dietary supplementation with zinc and the
      glutathione precursor SAMe will enhance pulmonary host immune function in HIV-infected
      individuals who do not respond adequately to ART alone.
This new proposal entitled "The alveolar macrophage pool is a reservoir of HIV" addresses a
      fundamental question; specifically, does the alveolar macrophage pool serve as a reservoir of
      HIV even when peripheral viral suppression is achieved by anti-retroviral therapy (ART) and
      if so, how does this reservoir alter the environment within the alveolar space and impair
      alveolar macrophage immune function? This is a critical question to address as lung
      infections remain the leading cause of death in persons living with HIV even when they are
      adherent to ART. There is compelling experimental evidence that HIV infection inhibits
      anti-oxidant defenses within the alveolar space and causes severe redox stress. Based on
      preliminary data presented in this proposal, the investigators hypothesize that HIV inhibits
      the expression and actions of Nrf2, the master transcription factor that activates the
      anti-oxidant response element (ARE), in part by inducing zinc deficiency in this vulnerable
      microenvironment, and thereby prevents the alveolar epithelium and the alveolar macrophage
      from generating glutathione and other anti-oxidants that are critically required to maintain
      a healthy redox potential within the alveolar space. The investigators further hypothesize
      that as a result of this targeted inhibition of the Nrf2-ARE signaling pathway, HIV promotes
      its own ability to infect alveolar macrophages and accumulate a large pool of intracellular
      pro-virus that produces a large HIV reservoir within the alveolar space. In parallel,
      HIV-induced oxidative stress shifts the alveolar macrophage toward alternative activation (so
      called 'M2 phenotype'). As a consequence, the innate immune capacity of the alveolar
      macrophage is impaired and this not only confers further resistance to clearing the viral
      reservoir but also renders the infected individual susceptible to serious lung infections.
      The investigators will leverage ongoing collaborative clinical studies in HIV-infected
      individuals. As a result, investigators not only have ongoing access to alveolar epithelial
      lining fluid and macrophages from well-defined subsets of HIV-infected individuals, they also
      have the expertise to apply state-of-the-art basic techniques in HIV pathogenesis,
      metabolomics, and redox signaling to test hypotheses. In parallel, the investigators are
      already conducting a prospective clinical trial of dietary zinc and S-adenosylmethionine (a
      thiol anti-oxidant that among its many actions increases the glutathione pool in the alveolar
      space) in HIV-infected individuals with inadequate immunological responses to ART
      (NCT01806870). This unique cohort will form the foundation for a greatly expanded clinical
      trial that will allow the investigators to test the corollary hypothesis that therapeutic
      strategies designed to improve zinc bioavailability and the redox potential within the
      alveolar space can enhance alveolar macrophage innate immune function and significantly
      decrease the HIV reservoir in the lung. This project will produce novel insights into how we
      can target the alveolar macrophage pool to decrease HIV burden as well as improve lung health
      in these vulnerable individuals.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Dosage Efficacy
time frame: Three months
description: Incidence of treatment-related adverse events, particularly gastrointestinal problems such as nausea, gastritis or diarrhea
measure: Change in exhaled breath condensate (EBC) levels of glutathione (GSH)
time frame: Baseline, 12 months
description: Collection of exhaled breath condensate (EBC) is a non-invasive technique obtained by freezing and collecting exhaled breath that contains glutathione (GSH) from the lower airways. EBC GSH is measured is nmoles/µg urea.
measure: Change in exhaled breath condensate (EBC) levels of glutathione (GSH)
time frame: Baseline, 24 months
description: Collection of exhaled breath condensate (EBC) is a non-invasive technique obtained by freezing and collecting exhaled breath that contains glutathione (GSH) from the lower airways. EBC GSH is measured is nmoles/µg urea.
arm group label: Nutritional Supplements Zinc and SAMe
arm group type: Other
description: All men subjects will be started on 30 mg/day and women will be started on 25mg of elemental zinc plus 1600 mg/day of SAMe.
intervention type: Dietary Supplement
intervention name: Zinc and SAMe
description: The subjects will have the supplements dispensed at visit 2. They will be contacted weekly for the next three weeks to ensure that they are tolerating the supplements without significant side-effects. If these side-effects are significant then the dose of zinc will be decreased for all subjects to 15 mg of elemental zinc/day; if symptoms persist the SAMe dose will then be decreased by 25% (to 1200 mg/day) and then by 50% (to 800 mg/day) if necessary until the supplements are tolerated. 12 mg of zinc and 800 mg of SAMe is the lowest dose possible.
arm group label: Nutritional Supplements Zinc and SAMe
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: No
last name: David M Guidot, MD
role: Principal Investigator
affiliation: Emory University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Emory University
investigator full name: David M. Guidot, MD
investigator title: Director, Division of Pulmonary, Allergy, & Critical Care Medicine
provided document: 