<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/NCT01676363</url>
  </required_header>
  <id_info>
    <org_study_id>H11-03547</org_study_id>
    <secondary_id>H11-03547</secondary_id>
    <nct_id>NCT01676363</nct_id>
  </id_info>
  <brief_title>Pilot Study of Diflunisal in HIV-infected Adults</brief_title>
  <official_title>Pilot Study of Diflunisal in HIV-infected Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of British Columbia</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Diflunisal is an anti-inflammatory drug (like ASA or ibuprofen) that has been used as a&#xD;
      painkiller for 20 years. Recent research shows that it may have an anti-HIV effect in the&#xD;
      laboratory. Approximately 20 HIV-infected adults who are not receiving antiretroviral therapy&#xD;
      will be given diflunisal by mouth twice daily for 4 weeks, at a dose that has been shown to&#xD;
      be safe when used to treat pain. Subjects will be monitored closely for safety and will have&#xD;
      frequent blood tests during the study to see if the drug has any effect on the level of HIV&#xD;
      in their blood.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Following informed consent, potential subjects will undergo a screening visit to determine&#xD;
      study eligibility. Within 2 weeks of screening, they will undergo a Day 1 visit for blood&#xD;
      testing. At the Day 8 visit on the following Monday, after study visit procedures have been&#xD;
      completed, they will commence taking diflunisal 500 mg twice daily by mouth for 4 weeks (Days&#xD;
      8-36, study treatment period), during which they will be seen once a week for blood tests.&#xD;
      Following the last dose of diflunisal which will be taken on the morning of Day 36, they will&#xD;
      be seen for blood tests after 1 week off the study drug (Days 43, washout phase), and again&#xD;
      for a final visit after 2 weeks off study drug, on Day 50.&#xD;
&#xD;
      Subjects will be instructed to take diflunisal 500 mg by mouth in two doses approximately 12&#xD;
      hours apart (+ or - 1 hour), with or without food. A 2-week supply will be dispensed on Days&#xD;
      8 and 22. Study medication bottles (empty or not) will be returned to the clinic on Days 22&#xD;
      and 36. Pill counts will be performed to assess adherence. Adherence will further be&#xD;
      evaluated by measuring diflunisal drug levels in plasma samples collected weekly starting at&#xD;
      the baseline visit, and assayed at the end of the study.&#xD;
&#xD;
      After the subject has provided informed consent, a screening visit will be performed&#xD;
      including a complete medical history and record of concomitant medications to determine study&#xD;
      eligibility. Complete physical exam, CBC, platelet count, serum creatinine and estimated GFR,&#xD;
      serum potassium, AST, ALT, total bilirubin, CD4 cell count, and pregnancy test for women of&#xD;
      child-bearing potential will be performed at the screening visit and repeated at the final&#xD;
      study visit. At each study visit, blood will be drawn for HIV RNA, and a serum sample will be&#xD;
      collected and stored for measurement of C-reactive protein (CRP), d-dimer, and possibly other&#xD;
      inflammatory biomarkers. Plasma (for diflunisal drug level measurement) and peripheral blood&#xD;
      mononuclear cells (PBMC's) will be collected and stored weekly from the baseline visit to Day&#xD;
      50. PBMC's will be frozen and shipped in batches to Eric Verdin, MD at the Gladstone&#xD;
      Institute of Virology and Immunology (1650 Owens St San Francisco, CA 94158, USA) for&#xD;
      analysis of T cell subsets (naïve, memory CD4 and CD8 T cells) and levels of protein&#xD;
      acetylation (histone or other) as a surrogate marker of drug activity. Adverse events and&#xD;
      concomitant medications will be recorded at the baseline visit and updated weekly.&#xD;
&#xD;
      After completion of the final study visit, subjects will be compensated for their time in the&#xD;
      amount of $500. Subjects who need to discontinue the study early, e.g. due to significant&#xD;
      clinical or laboratory adverse events related to the study drug, will receive the full&#xD;
      stipend at the end of their participation in the study. Subjects who choose to withdraw from&#xD;
      the study early or who are withdrawn for study noncompliance will not be eligible to receive&#xD;
      the stipend. Subjects who require ongoing reimbursement for travel expenses to enable them to&#xD;
      attend study visits will receive advances on their stipend upon providing receipts for&#xD;
      parking, etc.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Insufficient enrollment.&#xD;
  </why_stopped>
  <start_date>March 2013</start_date>
  <completion_date type="Actual">October 12, 2016</completion_date>
  <primary_completion_date type="Actual">October 12, 2016</primary_completion_date>
  <phase>Phase 4</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in plasma HIV RNA level</measure>
    <time_frame>between baseline and end of 4-week treatment, and between end of treatment and end of 2-week washout</time_frame>
    <description>Plasma HIV RNA changes between baseline and end of 4-week treatment, and between end of treatment and end of 2-week washout</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical adverse events including serious adverse events</measure>
    <time_frame>from screening until final study visit on Day 50</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinically significant changes in laboratory parameters</measure>
    <time_frame>between screening and Day 50</time_frame>
    <description>changes in complete blood count (CBC), platelets; serum creatinine, estimated glomerular filtration rate (GFR); AST, ALT, total bilirubin; serum potassium; CD4 cell count</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Slope of HIV RNA change</measure>
    <time_frame>during 4-week treatment and 2-week washout phases</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in inflammatory biomarkers</measure>
    <time_frame>during 4-week treatment and 2-week washout phases</time_frame>
    <description>Changes in C-reactive protein (CRP), d-dimer, possibly other biomarkers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in T cell subsets</measure>
    <time_frame>during 4-week treatment and 2-week washout phases</time_frame>
    <description>Changes in naïve and memory CD4 and CD8 cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in protein acetylation (histone or other) in peripheral blood mononuclear cells (PBMCs)</measure>
    <time_frame>during 4-week treatment and 2-week washout phases</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>HIV Infection</condition>
  <arm_group>
    <arm_group_label>Diflunisal</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Diflunisal</intervention_name>
    <description>Open-label diflunisal 500 mg twice daily for 4 weeks</description>
    <arm_group_label>Diflunisal</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult men and women aged 19 years or over&#xD;
&#xD;
          2. HIV positive by ELISA and Western blot, at least 3 months prior to screening&#xD;
&#xD;
          3. No antiretroviral therapy within 3 months prior to screening&#xD;
&#xD;
          4. Plasma HIV RNA (viral load) &gt; 2,500 copies/mL at screening&#xD;
&#xD;
          5. Current CD4 cell count &gt;350 cells/mm3 at screening&#xD;
&#xD;
          6. Adequate renal function as demonstrated by eGFR &gt;60 mL/min. at screening&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or breast-feeding&#xD;
&#xD;
          2. Any HIV-associated symptom or condition (e.g. nephropathy) for which standard&#xD;
             antiretroviral therapy is indicated immediately&#xD;
&#xD;
          3. History of peptic ulcer and/or gastrointestinal bleeding&#xD;
&#xD;
          4. Allergy to ASA, other salicylates, or NSAIDs&#xD;
&#xD;
          5. Currently receiving treatment with an ACE inhibitor, ASA, anticoagulants, antacids&#xD;
             containing aluminum hydroxide, cyclosporine, diuretics, systemic glucocorticoids,&#xD;
             lithium, methotrexate, or other NSAIDs&#xD;
&#xD;
          6. Significant hepatic impairment or active liver disease - screening AST, ALT, or&#xD;
             bilirubin &gt;2.5x upper limit of normal (ULN)&#xD;
&#xD;
          7. Hyperkalemia - screening serum potassium &gt;5.5 mmol/L&#xD;
&#xD;
          8. Anemia - screening hemoglobin &lt;85 g/L&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Julio Montaner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Providence Health Care/ University of British Columbia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Immunodeficiency Clinic, St. Paul's Hospital</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>August 28, 2012</study_first_submitted>
  <study_first_submitted_qc>August 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <last_update_submitted>October 25, 2017</last_update_submitted>
  <last_update_submitted_qc>October 25, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 27, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of British Columbia</investigator_affiliation>
    <investigator_full_name>Julio Montaner</investigator_full_name>
    <investigator_title>Dr. Julio Montaner</investigator_title>
  </responsible_party>
  <keyword>diflunisal</keyword>
  <keyword>anti-inflammatory agents, non-steroidal</keyword>
  <keyword>antiviral agents</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diflunisal</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/NCT01676363
org study id: H11-03547
secondary id: H11-03547
nct id: NCT01676363
lead sponsor: 
has dmc: No
Diflunisal is an anti-inflammatory drug (like ASA or ibuprofen) that has been used as a
      painkiller for 20 years. Recent research shows that it may have an anti-HIV effect in the
      laboratory. Approximately 20 HIV-infected adults who are not receiving antiretroviral therapy
      will be given diflunisal by mouth twice daily for 4 weeks, at a dose that has been shown to
      be safe when used to treat pain. Subjects will be monitored closely for safety and will have
      frequent blood tests during the study to see if the drug has any effect on the level of HIV
      in their blood.
Following informed consent, potential subjects will undergo a screening visit to determine
      study eligibility. Within 2 weeks of screening, they will undergo a Day 1 visit for blood
      testing. At the Day 8 visit on the following Monday, after study visit procedures have been
      completed, they will commence taking diflunisal 500 mg twice daily by mouth for 4 weeks (Days
      8-36, study treatment period), during which they will be seen once a week for blood tests.
      Following the last dose of diflunisal which will be taken on the morning of Day 36, they will
      be seen for blood tests after 1 week off the study drug (Days 43, washout phase), and again
      for a final visit after 2 weeks off study drug, on Day 50.

      Subjects will be instructed to take diflunisal 500 mg by mouth in two doses approximately 12
      hours apart (+ or - 1 hour), with or without food. A 2-week supply will be dispensed on Days
      8 and 22. Study medication bottles (empty or not) will be returned to the clinic on Days 22
      and 36. Pill counts will be performed to assess adherence. Adherence will further be
      evaluated by measuring diflunisal drug levels in plasma samples collected weekly starting at
      the baseline visit, and assayed at the end of the study.

      After the subject has provided informed consent, a screening visit will be performed
      including a complete medical history and record of concomitant medications to determine study
      eligibility. Complete physical exam, CBC, platelet count, serum creatinine and estimated GFR,
      serum potassium, AST, ALT, total bilirubin, CD4 cell count, and pregnancy test for women of
      child-bearing potential will be performed at the screening visit and repeated at the final
      study visit. At each study visit, blood will be drawn for HIV RNA, and a serum sample will be
      collected and stored for measurement of C-reactive protein (CRP), d-dimer, and possibly other
      inflammatory biomarkers. Plasma (for diflunisal drug level measurement) and peripheral blood
      mononuclear cells (PBMC's) will be collected and stored weekly from the baseline visit to Day
      50. PBMC's will be frozen and shipped in batches to Eric Verdin, MD at the Gladstone
      Institute of Virology and Immunology (1650 Owens St San Francisco, CA 94158, USA) for
      analysis of T cell subsets (naïve, memory CD4 and CD8 T cells) and levels of protein
      acetylation (histone or other) as a surrogate marker of drug activity. Adverse events and
      concomitant medications will be recorded at the baseline visit and updated weekly.

      After completion of the final study visit, subjects will be compensated for their time in the
      amount of $500. Subjects who need to discontinue the study early, e.g. due to significant
      clinical or laboratory adverse events related to the study drug, will receive the full
      stipend at the end of their participation in the study. Subjects who choose to withdraw from
      the study early or who are withdrawn for study noncompliance will not be eligible to receive
      the stipend. Subjects who require ongoing reimbursement for travel expenses to enable them to
      attend study visits will receive advances on their stipend upon providing receipts for
      parking, etc.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in plasma HIV RNA level
time frame: between baseline and end of 4-week treatment, and between end of treatment and end of 2-week washout
description: Plasma HIV RNA changes between baseline and end of 4-week treatment, and between end of treatment and end of 2-week washout
measure: Clinical adverse events including serious adverse events
time frame: from screening until final study visit on Day 50
measure: Clinically significant changes in laboratory parameters
time frame: between screening and Day 50
description: changes in complete blood count (CBC), platelets; serum creatinine, estimated glomerular filtration rate (GFR); AST, ALT, total bilirubin; serum potassium; CD4 cell count
measure: Slope of HIV RNA change
time frame: during 4-week treatment and 2-week washout phases
measure: Changes in inflammatory biomarkers
time frame: during 4-week treatment and 2-week washout phases
description: Changes in C-reactive protein (CRP), d-dimer, possibly other biomarkers
measure: Changes in T cell subsets
time frame: during 4-week treatment and 2-week washout phases
description: Changes in naïve and memory CD4 and CD8 cells
measure: Changes in protein acetylation (histone or other) in peripheral blood mononuclear cells (PBMCs)
time frame: during 4-week treatment and 2-week washout phases
arm group label: Diflunisal
arm group type: Experimental
intervention type: Drug
intervention name: Diflunisal
description: Open-label diflunisal 500 mg twice daily for 4 weeks
arm group label: Diflunisal
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Julio Montaner, MD
role: Principal Investigator
affiliation: Providence Health Care/ University of British Columbia
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University of British Columbia
investigator full name: Julio Montaner
investigator title: Dr. Julio Montaner
mesh term: HIV Infections
mesh term: Diflunisal