<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/NCT03262441</url>
  </required_header>
  <id_info>
    <org_study_id>8589</org_study_id>
    <secondary_id>STUDY00002182</secondary_id>
    <secondary_id>109614-62-RGRL</secondary_id>
    <secondary_id>ACTU-2100</secondary_id>
    <nct_id>NCT03262441</nct_id>
  </id_info>
  <brief_title>MMF for HIV Reservoir Reduction</brief_title>
  <official_title>Mycophenolate Mofetil Therapy for Reduction of the HIV Reservoir</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fred Hutchinson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Fred Hutchinson Cancer Center</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>
      This is an open label, randomized Phase II study to determine whether Mycophenolate mofetil&#xD;
      (MMF) given over 22 months meaningfully decreases the size of participants' HIV reservoir.&#xD;
&#xD;
      In addition to primary safety endpoints, the following hypotheses regarding drug efficacy&#xD;
      will be tested:&#xD;
&#xD;
        1. MMF will be well tolerated and will not decrease adherence to or antiviral efficacy of&#xD;
           ART.&#xD;
&#xD;
        2. Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during&#xD;
           treatment with MMF and ART.&#xD;
&#xD;
        3. There will be no excess risk of opportunistic infections in MMF-treated study&#xD;
           participants.&#xD;
&#xD;
        4. MMF therapy will lead to a progressive decrease in reservoir size over 22 months of&#xD;
           treatment.&#xD;
&#xD;
        5. MMF therapy will lead to a continual shift in HIV reservoir composition from primarily&#xD;
           effector memory CD4+ T cells (TEM) and central memory CD4+ T cells (TCM), to primarily&#xD;
           stem cell like memory (TSCM) and naïve (TN) CD4+ T cells.&#xD;
&#xD;
        6. MMF will eliminate detectable measures of the HIV reservoir, including by&#xD;
           cell-associated DNA/mRNA and quantitative viral outgrowth.&#xD;
&#xD;
        7. MMF will not decrease the humoral immune response to routine annual influenza&#xD;
           vaccination.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, randomized pilot trial to determine whether MMF given over 22 months&#xD;
      meaningfully decreases the size of the HIV reservoir.&#xD;
&#xD;
      At the University of Washington in Seattle, investigators will enroll 5 study participants&#xD;
      who have been on ≥2 years of suppressive ART. Study participants will be followed closely for&#xD;
      at least 22 months with safety labs and serial measurements of the HIV reservoir&#xD;
      (specifically, cell-associated HIV DNA and mRNA (ca-DNA &amp; ca-RNA), quantitative viral&#xD;
      outgrowth assay (QVOA), and single copy plasma viral load (scVL)). A &quot;go/no-go&quot; decision will&#xD;
      occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir&#xD;
      measured with ca-DNA.&#xD;
&#xD;
      All participants will be offered enrollment in a sub-study in which an anoscopy with rectum&#xD;
      biopsies is performed on 3 occasions to assess the reservoir in the gastrointestinal&#xD;
      lymphatic tissue (GALT).&#xD;
&#xD;
      Investigators will vaccinate study participants with the annual influenza vaccine and analyze&#xD;
      their humoral response to this vaccine approximately one month later with a routine blood&#xD;
      draw done in conjunction with a safety labs blood draw.&#xD;
&#xD;
      Investigators hypothesize that low doses of MMF will be well tolerated among healthy&#xD;
      HIV-infected study participants who have fully ART-suppressed HIV. Investigators hypothesize&#xD;
      that the incidence of opportunistic infections will not exceed that of comparable larger&#xD;
      cohorts of HIV-treated patients. Of note, certain opportunistic infections such as herpes&#xD;
      zoster or HSV-2 recurrence continue to occur despite suppressive ART, while pneumocystis&#xD;
      pneumonia, CMV end organ disease, cryptococcus and many other opportunistic infections are&#xD;
      much less common in this context. Therefore, in the event of an infection, Investigators will&#xD;
      confer with the data safety management (DSM) panel to discuss whether this event is directly&#xD;
      attributable to MMF. Finally, investigators hypothesize that peripheral blood CD4+ and CD8+ T&#xD;
      cell counts will remain unchanged throughout MMF therapy, and that HIV replication will&#xD;
      remain controlled on ART with addition of MMF.&#xD;
&#xD;
      Investigators hypothesize at least a 0.25-log reduction in cell-associated HIV DNA at&#xD;
      one-year intervals in study participants who have a demonstrated anti-proliferative response&#xD;
      to MMF treatment. Investigators hypothesize that cell-associated HIV DNA will undergo a shift&#xD;
      from predominant residence in TCM and TEM to predominant residence in TN and TSCM. In regards&#xD;
      to our sub-study, investigators predict that reservoir depletion will occur with equivalent&#xD;
      rates in blood and GALT.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 12, 2018</start_date>
  <completion_date type="Actual">August 31, 2019</completion_date>
  <primary_completion_date type="Actual">August 31, 2019</primary_completion_date>
  <phase>Phase 2</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>This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA &amp; ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). &quot;Go/no-go&quot; decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 T Cells Over 12 Months</measure>
    <time_frame>12 months</time_frame>
    <description>Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 &amp; 12 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 Effector Memory CD4+ T Cells Over 12 Months</measure>
    <time_frame>12 months</time_frame>
    <description>Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 3 time points between 0 &amp; 12 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Cell-associated Intact HIV DNA (Ca-iDNA) Levels Per 10^6 T Cells Over 12 Months</measure>
    <time_frame>12 months</time_frame>
    <description>Regression slope of change in cell-associated intact HIV DNA (ca-iDNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 &amp; 12 months</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood CD4+ T Cells Per mm^3 Blood</measure>
    <time_frame>12 months</time_frame>
    <description>Frequency of participants with any time point with &lt;200 CD4+ T cells per mm^3 from 4 sampled time points between 0 &amp; 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Opportunistic Infection</measure>
    <time_frame>12 months</time_frame>
    <description>Number of participants experiencing opportunistic infection</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Human Immunodeficiency Virus I Infection</condition>
  <arm_group>
    <arm_group_label>Mycophenolate mofetil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mycophenolate Mofetil 500Mg Tab</intervention_name>
    <description>500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
    <arm_group_label>Mycophenolate mofetil</arm_group_label>
    <other_name>Mycophenolate Mofetil Tablets USP Roxane Laboratories</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Confirmed HIV infection, by two different positive antibody tests and/or detectable&#xD;
             plasma HIV RNA on two different dates&#xD;
&#xD;
          2. ≥18 and ≤65 years of age&#xD;
&#xD;
          3. Continuous ART during the last two years, with current ART preferably including an&#xD;
             integrase inhibitor&#xD;
&#xD;
          4. HIV RNA &lt;40 copies / mL on four occasions during continuous ART of ≥ 2 years with no&#xD;
             more than one blip of &lt;1000 HIV RNA copies / mL&#xD;
&#xD;
          5. CD4+ T cell count &gt; 350/mm3 within the past 365 days&#xD;
&#xD;
          6. Karnofsky score ≥80&#xD;
&#xD;
          7. Plan to reside in area 2 years&#xD;
&#xD;
          8. Consents to study&#xD;
&#xD;
          9. Tolerability of MMF during one week dose escalation lead-in phase of 500 mg once daily&#xD;
&#xD;
         10. Demonstrated anti-proliferative effect of MMF 500 mg twice daily&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Active malignancy including skin cancer, myelodysplastic syndrome, or&#xD;
             myeloproliferative disease within 24 weeks prior to study entry&#xD;
&#xD;
          2. Prior organ or bone marrow transplantation&#xD;
&#xD;
          3. Diagnosed autoimmune disease&#xD;
&#xD;
          4. Medical need for ongoing treatment with an immunosuppressive drug&#xD;
&#xD;
          5. Diagnosis of AIDS (defined as any AIDS-defining opportunistic infection or cancer, or&#xD;
             a history of blood CD4+ T cell count &lt; 200/µL)&#xD;
&#xD;
          6. Active opportunistic infection&#xD;
&#xD;
          7. Using disallowed medications (see 4.3)&#xD;
&#xD;
          8. Vomiting or diarrhea which prohibits consistent use of study drugs&#xD;
&#xD;
          9. Pregnant, intention to become pregnant, or breastfeeding&#xD;
&#xD;
         10. Woman of child bearing age who are NOT using two forms of birth control OR practicing&#xD;
             complete abstinence&#xD;
&#xD;
         11. Excessive ingestion of ethanol, determined by an AUDIT score of &gt;8&#xD;
&#xD;
         12. Substance abuse&#xD;
&#xD;
         13. History of medical non-compliance&#xD;
&#xD;
         14. Quantiferon TB positive&#xD;
&#xD;
         15. The following laboratory values (&lt; 30 days before enrollment):&#xD;
&#xD;
               -  Hemoglobin &lt; 8.5 mg/dL&#xD;
&#xD;
               -  Absolute neutrophil count &lt; 1000 cells/mm3&#xD;
&#xD;
               -  ALT &gt; 2 x upper limit of normal&#xD;
&#xD;
               -  Platelet count &lt; 100,000/uL&#xD;
&#xD;
               -  Creatinine clearance &lt; 60 mL/min&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joshua T Schiffer, MD MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fred Hutchinson Cancer Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Florian Hladik, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>2 West Clinic at Harborview Medical Center</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Reeves DB, Duke ER, Hughes SM, Prlic M, Hladik F, Schiffer JT. Anti-proliferative therapy for HIV cure: a compound interest approach. Sci Rep. 2017 Jun 21;7(1):4011. doi: 10.1038/s41598-017-04160-3.</citation>
    <PMID>28638104</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>August 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <results_first_submitted>August 23, 2020</results_first_submitted>
  <results_first_submitted_qc>November 10, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">December 3, 2020</results_first_posted>
  <last_update_submitted>November 10, 2020</last_update_submitted>
  <last_update_submitted_qc>November 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fred Hutchinson Cancer Center</investigator_affiliation>
    <investigator_full_name>Joshua Schiffer</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>Antiretroviral treatment</keyword>
  <keyword>Mycophenolate mofetil</keyword>
  <keyword>Cure</keyword>
  <keyword>Latency</keyword>
  <keyword>Reservoir</keyword>
  <keyword>CD4 T cell</keyword>
  <keyword>Anti-proliferation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mycophenolic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 12, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/41/NCT03262441/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited from the University of Washington AIDS Clinical Trials Unit at Harborview Medical Center in Seattle. The first participant enrolled February 12, 2018 and the last participant enrolled in August 14, 2018.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Mycophenolate Mofetil</title>
          <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Mycophenolate Mofetil</title>
          <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="5"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 T Cells Over 12 Months</title>
        <description>Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 &amp; 12 months</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mycophenolate Mofetil</title>
            <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 T Cells Over 12 Months</title>
          <description>Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 &amp; 12 months</description>
          <units>log10 caDNA copies per 10^6 T-cells/week</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.00033" lower_limit="-0.0020" upper_limit="0.0014"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Slope</param_type>
            <param_value>-0.00033</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.0020</ci_lower_limit>
            <ci_upper_limit>0.0014</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 Effector Memory CD4+ T Cells Over 12 Months</title>
        <description>Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 3 time points between 0 &amp; 12 months</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mycophenolate Mofetil</title>
            <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 Effector Memory CD4+ T Cells Over 12 Months</title>
          <description>Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 3 time points between 0 &amp; 12 months</description>
          <units>log10 caDNA copies per 10^6 T-cells/week</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.001" lower_limit="-0.0036" upper_limit="0.0056"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Slope</param_type>
            <param_value>0.001</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.0036</ci_lower_limit>
            <ci_upper_limit>0.0056</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Cell-associated Intact HIV DNA (Ca-iDNA) Levels Per 10^6 T Cells Over 12 Months</title>
        <description>Regression slope of change in cell-associated intact HIV DNA (ca-iDNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 &amp; 12 months</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mycophenolate Mofetil</title>
            <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cell-associated Intact HIV DNA (Ca-iDNA) Levels Per 10^6 T Cells Over 12 Months</title>
          <description>Regression slope of change in cell-associated intact HIV DNA (ca-iDNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 &amp; 12 months</description>
          <units>log10 caDNA copies per 10^6 T-cells/week</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".0024" lower_limit="-0.0030" upper_limit="0.0078"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Slope</param_type>
            <param_value>0.0024</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.003</ci_lower_limit>
            <ci_upper_limit>0.0078</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Blood CD4+ T Cells Per mm^3 Blood</title>
        <description>Frequency of participants with any time point with &lt;200 CD4+ T cells per mm^3 from 4 sampled time points between 0 &amp; 12 months</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mycophenolate Mofetil</title>
            <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
          </group>
        </group_list>
        <measure>
          <title>Blood CD4+ T Cells Per mm^3 Blood</title>
          <description>Frequency of participants with any time point with &lt;200 CD4+ T cells per mm^3 from 4 sampled time points between 0 &amp; 12 months</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Opportunistic Infection</title>
        <description>Number of participants experiencing opportunistic infection</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mycophenolate Mofetil</title>
            <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Opportunistic Infection</title>
          <description>Number of participants experiencing opportunistic infection</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>20 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Mycophenolate Mofetil</title>
          <description>Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months&#xD;
Mycophenolate Mofetil 500Mg Tab: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Finger cellulitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>This was a small and uncontrolled study.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Joshua Schiffer</name_or_title>
      <organization>Fred Hutchinson Cancer Research Center</organization>
      <phone>(206)667-7359</phone>
      <email>jschiffe@fredhutch.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03262441
org study id: 8589
secondary id: STUDY00002182
secondary id: 109614-62-RGRL
secondary id: ACTU-2100
nct id: NCT03262441
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is an open label, randomized Phase II study to determine whether Mycophenolate mofetil
      (MMF) given over 22 months meaningfully decreases the size of participants' HIV reservoir.

      In addition to primary safety endpoints, the following hypotheses regarding drug efficacy
      will be tested:

        1. MMF will be well tolerated and will not decrease adherence to or antiviral efficacy of
           ART.

        2. Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during
           treatment with MMF and ART.

        3. There will be no excess risk of opportunistic infections in MMF-treated study
           participants.

        4. MMF therapy will lead to a progressive decrease in reservoir size over 22 months of
           treatment.

        5. MMF therapy will lead to a continual shift in HIV reservoir composition from primarily
           effector memory CD4+ T cells (TEM) and central memory CD4+ T cells (TCM), to primarily
           stem cell like memory (TSCM) and naïve (TN) CD4+ T cells.

        6. MMF will eliminate detectable measures of the HIV reservoir, including by
           cell-associated DNA/mRNA and quantitative viral outgrowth.

        7. MMF will not decrease the humoral immune response to routine annual influenza
           vaccination.
This is an open-label, randomized pilot trial to determine whether MMF given over 22 months
      meaningfully decreases the size of the HIV reservoir.

      At the University of Washington in Seattle, investigators will enroll 5 study participants
      who have been on ≥2 years of suppressive ART. Study participants will be followed closely for
      at least 22 months with safety labs and serial measurements of the HIV reservoir
      (specifically, cell-associated HIV DNA and mRNA (ca-DNA & ca-RNA), quantitative viral
      outgrowth assay (QVOA), and single copy plasma viral load (scVL)). A "go/no-go" decision will
      occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir
      measured with ca-DNA.

      All participants will be offered enrollment in a sub-study in which an anoscopy with rectum
      biopsies is performed on 3 occasions to assess the reservoir in the gastrointestinal
      lymphatic tissue (GALT).

      Investigators will vaccinate study participants with the annual influenza vaccine and analyze
      their humoral response to this vaccine approximately one month later with a routine blood
      draw done in conjunction with a safety labs blood draw.

      Investigators hypothesize that low doses of MMF will be well tolerated among healthy
      HIV-infected study participants who have fully ART-suppressed HIV. Investigators hypothesize
      that the incidence of opportunistic infections will not exceed that of comparable larger
      cohorts of HIV-treated patients. Of note, certain opportunistic infections such as herpes
      zoster or HSV-2 recurrence continue to occur despite suppressive ART, while pneumocystis
      pneumonia, CMV end organ disease, cryptococcus and many other opportunistic infections are
      much less common in this context. Therefore, in the event of an infection, Investigators will
      confer with the data safety management (DSM) panel to discuss whether this event is directly
      attributable to MMF. Finally, investigators hypothesize that peripheral blood CD4+ and CD8+ T
      cell counts will remain unchanged throughout MMF therapy, and that HIV replication will
      remain controlled on ART with addition of MMF.

      Investigators hypothesize at least a 0.25-log reduction in cell-associated HIV DNA at
      one-year intervals in study participants who have a demonstrated anti-proliferative response
      to MMF treatment. Investigators hypothesize that cell-associated HIV DNA will undergo a shift
      from predominant residence in TCM and TEM to predominant residence in TN and TSCM. In regards
      to our sub-study, investigators predict that reservoir depletion will occur with equivalent
      rates in blood and GALT.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA & ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). "Go/no-go" decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA.
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 T Cells Over 12 Months
time frame: 12 months
description: Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 & 12 months
measure: Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 Effector Memory CD4+ T Cells Over 12 Months
time frame: 12 months
description: Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 3 time points between 0 & 12 months
measure: Change in Cell-associated Intact HIV DNA (Ca-iDNA) Levels Per 10^6 T Cells Over 12 Months
time frame: 12 months
description: Regression slope of change in cell-associated intact HIV DNA (ca-iDNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 & 12 months
measure: Blood CD4+ T Cells Per mm^3 Blood
time frame: 12 months
description: Frequency of participants with any time point with <200 CD4+ T cells per mm^3 from 4 sampled time points between 0 & 12 months
measure: Incidence of Opportunistic Infection
time frame: 12 months
description: Number of participants experiencing opportunistic infection
arm group label: Mycophenolate mofetil
arm group type: Experimental
description: Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months
intervention type: Drug
intervention name: Mycophenolate Mofetil 500Mg Tab
description: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months
arm group label: Mycophenolate mofetil
other name: Mycophenolate Mofetil Tablets USP Roxane Laboratories
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Joshua T Schiffer, MD MSc
role: Principal Investigator
affiliation: Fred Hutchinson Cancer Center
last name: Florian Hladik, MD PhD
role: Principal Investigator
affiliation: University of Washington
facility: 
country: United States
citation: Reeves DB, Duke ER, Hughes SM, Prlic M, Hladik F, Schiffer JT. Anti-proliferative therapy for HIV cure: a compound interest approach. Sci Rep. 2017 Jun 21;7(1):4011. doi: 10.1038/s41598-017-04160-3.
PMID: 28638104
responsible party type: Principal Investigator
investigator affiliation: Fred Hutchinson Cancer Center
investigator full name: Joshua Schiffer
investigator title: Principal Investigator
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Mycophenolic Acid
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This was a small and uncontrolled study.
point of contact: 