<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/NCT03002012</url>
  </required_header>
  <id_info>
    <org_study_id>U01AI125003</org_study_id>
    <secondary_id>U01AI125003</secondary_id>
    <secondary_id>33238</secondary_id>
    <nct_id>NCT03002012</nct_id>
  </id_info>
  <brief_title>Cryptococcal Antigen Screening Plus Sertraline</brief_title>
  <acronym>C-ASSERT</acronym>
  <official_title>Cryptococcal Antigen Screening Plus Sertraline</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Infectious Diseases Institute, Uganda</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mbarara University of Science and Technology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Minnesota</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cryptococcal meningitis or &quot;Crypto&quot; is a life threatening fungal infection around the brain&#xD;
      that requires hospitalization for treatment for 14 days and then continued therapy. Crypto&#xD;
      causes 15-20% of HIV/AIDS-related deaths worldwide. However, this infection can be detected&#xD;
      before one develops symptoms and becomes ill. People can be screened for infection by a blood&#xD;
      test to detect &quot;cryptococcal antigen,&quot; (called CrAg), which is part of the fungus, in blood.&#xD;
      The World Health Organization and over 22 countries worldwide recommend CrAg screening of all&#xD;
      persons with advanced AIDS entering or re-entering into HIV care.&#xD;
&#xD;
      However, it is not known how best to treat people with cryptococcal antigen in their blood,&#xD;
      who don't otherwise yet have symptoms of infection around their brain. If no treatment is&#xD;
      given, almost all people will develop infection of the brain and/or die. International&#xD;
      guidelines suggest using both HIV medicines and an anti-fungal medicine, called fluconazole,&#xD;
      to treat this early infection. However, despite this treatment approximately 1 in 4 people&#xD;
      may get sick and/or die.&#xD;
&#xD;
      Researchers have recently discovered another medicine that may work against the Cryptococcus&#xD;
      fungus. This medicine is called Sertraline, and it is actually a medicine that has been used&#xD;
      for more than 25 years to treat depression (sadness). Sertraline is one of the most commonly&#xD;
      used medicines worldwide.&#xD;
&#xD;
      The purpose of this research clinical trial is to determine if standard fluconazole&#xD;
      antifungal therapy plus a high dose of Sertraline, will be better than standard fluconazole&#xD;
      therapy alone for treating early disseminated cryptococcal infection in persons who are&#xD;
      asymptomatic and do not yet have infection of the brain (i.e. meningitis).&#xD;
&#xD;
      This study seeks to test if Sertraline will improve survival through 6-months. Prior studies&#xD;
      have shown that &gt;90% of those who survive 6-months will survive &gt;5 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a double-blind, randomized placebo-controlled clinical trial testing sertraline as an&#xD;
      antifungal medicine in combination with fluconazole for treatment of HIV-infected persons&#xD;
      with AIDS and asymptomatic cryptococcal antigenemia (CrAg+).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    SAEs with n=1 serotonin syndrome, n=2 SAEs after sertraline interruption.&#xD;
  </why_stopped>
  <start_date type="Actual">November 15, 2017</start_date>
  <completion_date type="Actual">March 13, 2018</completion_date>
  <primary_completion_date type="Actual">March 13, 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>6 Month Meningitis-free Survival</measure>
    <time_frame>6 months</time_frame>
    <description>Cryptococcal meningitis free survival with retention-in-care through 6 months&#xD;
Those who die of any cause are failures&#xD;
Those developing symptomatic cryptococcal meningitis are failures&#xD;
Those lost to follow up and unable to be tracked are considered failures</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>6-month Survival</measure>
    <time_frame>6 months</time_frame>
    <description>Survival through 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis</measure>
    <time_frame>6 months</time_frame>
    <description>Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Clinical Adverse Events (Grade 3-5)</measure>
    <time_frame>6 months</time_frame>
    <description>Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Laboratory Grade 3-5 Adverse Events</measure>
    <time_frame>6 months</time_frame>
    <description>Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-Cause Premature Study Drug/Placebo Discontinuation</measure>
    <time_frame>6 months</time_frame>
    <description>Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time</measure>
    <time_frame>12 weeks</time_frame>
    <description>Prevalence of depression by Patient Health Questionnaire (PHQ-9) over 6 months as measured at baseline, 4 weeks, 8 weeks, and 12 weeks. The PHQ-9 is a 9-item instrument for screening, diagnosing, monitoring, and measuring the severity of depression. Items are rated on a scale from 0 (not at all) to 3 (nearly every day). Total score is a sum of 9 item scores (Range 0-27). Greater scores indicate greater depressive symptoms. PHQ-9 scores of: 0-4 Minimal/No depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderate severe depression; 20-27 Severe depression. This endpoint reports the median (interquartile range) of the PHQ-9 scores over time.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Adherence to Study Drug</measure>
    <time_frame>12 weeks</time_frame>
    <description>Participants' percent adherence to study drug regiment by pharmacy medication counts, representing the percent of the total prescribed medication taken by participants.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Cryptococcosis</condition>
  <condition>Cryptococcal Infections</condition>
  <condition>AIDS-Related Opportunistic Infections</condition>
  <arm_group>
    <arm_group_label>Sertraline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fluconazole Standard of Care + Sertraline</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Fluconazole Standard of Care + Placebo Oral Tablet</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sertraline</intervention_name>
    <description>sertraline 400mg/day</description>
    <arm_group_label>Sertraline</arm_group_label>
    <other_name>Zoloft</other_name>
    <other_name>Lustral</other_name>
    <other_name>Sertraline hydrochloride</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>matched placebo tablet</description>
    <arm_group_label>Control</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fluconazole</intervention_name>
    <description>Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Sertraline</arm_group_label>
    <other_name>Fluconazole 200mg tab</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV-infected&#xD;
&#xD;
          -  Cryptococcal antigen (CrAg) positive in blood&#xD;
&#xD;
          -  Age &gt;=18 years&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  Women of childbearing potential who are participating in sexual activity that could&#xD;
             lead to pregnancy must agree to use one reliable method of contraception while&#xD;
             receiving fluconazole &gt;=400mg/day&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior history of cryptococcal meningitis&#xD;
&#xD;
          -  Suspected meningitis or mania&#xD;
&#xD;
          -  Suspected/known cirrhosis, jaundice, or alanine aminotransferase (ALT) &gt;5x upper limit&#xD;
             of normal&#xD;
&#xD;
          -  Receiving an antidepressant medicine&#xD;
&#xD;
          -  Receiving antifungal therapy, &gt;1 week&#xD;
&#xD;
          -  Pregnant or Breastfeeding&#xD;
&#xD;
          -  Contraindication to sertraline or fluconazole&#xD;
&#xD;
          -  Current rifampin use or other prohibited medication&#xD;
&#xD;
          -  Electrocardiogram corrected QT interval (QTc) &gt;450ms&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth K Nalintya, MBChB MPH</last_name>
    <role>Study Director</role>
    <affiliation>Infectious Disease Institute</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Radha Rajasingham, MD</last_name>
    <role>Study Director</role>
    <affiliation>University of Minnesota</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Infectious Disease Institute, Makerere University</name>
      <address>
        <city>Kampala</city>
        <zip>22418</zip>
        <country>Uganda</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Uganda</country>
  </location_countries>
  <link>
    <url>http://preventcrypto.org</url>
    <description>PreventCrypto.org has information and training materials for cryptococcal antigen screening and treatment</description>
  </link>
  <link>
    <url>http://www.gaffi.org/</url>
    <description>Global Action Fund for Fungal Infections (GAFFI)</description>
  </link>
  <results_reference>
    <citation>Boulware DR, Nalintya E, Rajasingham R, Kirumira P, Naluyima R, Turya F, Namanda S, Rutakingirwa MK, Skipper CP, Nikweri Y, Hullsiek KH, Bangdiwala AS, Meya DB. Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial. Med Mycol. 2020 Nov 10;58(8):1037-1043. doi: 10.1093/mmy/myaa033.</citation>
    <PMID>32415846</PMID>
  </results_reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <results_first_submitted>July 24, 2019</results_first_submitted>
  <results_first_submitted_qc>December 10, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">December 26, 2019</results_first_posted>
  <last_update_submitted>June 2, 2020</last_update_submitted>
  <last_update_submitted_qc>June 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cryptococcal antigen</keyword>
  <keyword>preemptive treatment</keyword>
  <keyword>CRAG+</keyword>
  <keyword>sertraline</keyword>
  <keyword>fluconazole</keyword>
  <keyword>randomized clinical trial</keyword>
  <keyword>HIV</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Opportunistic Infections</mesh_term>
    <mesh_term>AIDS-Related Opportunistic Infections</mesh_term>
    <mesh_term>Cryptococcosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fluconazole</mesh_term>
    <mesh_term>Sertraline</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>A formal written data sharing plan exists. Protocol and trial documents can be shared. De-identified data can be shared after trial completion.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Available for at least 5 years</ipd_time_frame>
    <ipd_access_criteria>Upon request to the Principal Investigator</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 10, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/12/NCT03002012/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 6, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/12/NCT03002012/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Sertraline</title>
          <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
        </group>
        <group group_id="P2">
          <title>Control</title>
          <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 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="11"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Sertraline</title>
          <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
        </group>
        <group group_id="B2">
          <title>Control</title>
          <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="11"/>
            <count group_id="B2" value="11"/>
            <count group_id="B3" value="22"/>
          </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="32" lower_limit="26" upper_limit="32"/>
                    <measurement group_id="B2" value="35" lower_limit="32" upper_limit="38"/>
                    <measurement group_id="B3" value="32" lower_limit="29" upper_limit="35"/>
                  </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="6"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="9"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="22"/>
                  </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>Uganda</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>On Antiretroviral Therapy (ART) at Radomization</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>On ART</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not on ART</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>CD4 Cell Count</title>
          <units>cells/mm3</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="38" lower_limit="12" upper_limit="86"/>
                    <measurement group_id="B2" value="50" lower_limit="7" upper_limit="83"/>
                    <measurement group_id="B3" value="42" lower_limit="7" upper_limit="86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>6 Month Meningitis-free Survival</title>
        <description>Cryptococcal meningitis free survival with retention-in-care through 6 months&#xD;
Those who die of any cause are failures&#xD;
Those developing symptomatic cryptococcal meningitis are failures&#xD;
Those lost to follow up and unable to be tracked are considered failures</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Meningitis-free Survival</title>
          <description>Cryptococcal meningitis free survival with retention-in-care through 6 months&#xD;
Those who die of any cause are failures&#xD;
Those developing symptomatic cryptococcal meningitis are failures&#xD;
Those lost to follow up and unable to be tracked are considered failures</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6-month Survival</title>
        <description>Survival through 6 months</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>6-month Survival</title>
          <description>Survival through 6 months</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis</title>
        <description>Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis</title>
          <description>Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months</description>
          <units>meningitis events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Clinical Adverse Events (Grade 3-5)</title>
        <description>Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Clinical Adverse Events (Grade 3-5)</title>
          <description>Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months</description>
          <units>number of grade 3-5 adverse events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Laboratory Grade 3-5 Adverse Events</title>
        <description>Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Laboratory Grade 3-5 Adverse Events</title>
          <description>Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale</description>
          <units>number of grade 3-5 adverse events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>All-Cause Premature Study Drug/Placebo Discontinuation</title>
        <description>Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>All-Cause Premature Study Drug/Placebo Discontinuation</title>
          <description>Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time</title>
        <description>Prevalence of depression by Patient Health Questionnaire (PHQ-9) over 6 months as measured at baseline, 4 weeks, 8 weeks, and 12 weeks. The PHQ-9 is a 9-item instrument for screening, diagnosing, monitoring, and measuring the severity of depression. Items are rated on a scale from 0 (not at all) to 3 (nearly every day). Total score is a sum of 9 item scores (Range 0-27). Greater scores indicate greater depressive symptoms. PHQ-9 scores of: 0-4 Minimal/No depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderate severe depression; 20-27 Severe depression. This endpoint reports the median (interquartile range) of the PHQ-9 scores over time.</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time</title>
          <description>Prevalence of depression by Patient Health Questionnaire (PHQ-9) over 6 months as measured at baseline, 4 weeks, 8 weeks, and 12 weeks. The PHQ-9 is a 9-item instrument for screening, diagnosing, monitoring, and measuring the severity of depression. Items are rated on a scale from 0 (not at all) to 3 (nearly every day). Total score is a sum of 9 item scores (Range 0-27). Greater scores indicate greater depressive symptoms. PHQ-9 scores of: 0-4 Minimal/No depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderate severe depression; 20-27 Severe depression. This endpoint reports the median (interquartile range) of the PHQ-9 scores over time.</description>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" lower_limit="2" upper_limit="7"/>
                    <measurement group_id="O2" value="5" lower_limit="3" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6" lower_limit="1" upper_limit="9"/>
                    <measurement group_id="O2" value="3" lower_limit="2" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2" lower_limit="0" upper_limit="9"/>
                    <measurement group_id="O2" value="2" lower_limit="0" upper_limit="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Adherence to Study Drug</title>
        <description>Participants' percent adherence to study drug regiment by pharmacy medication counts, representing the percent of the total prescribed medication taken by participants.</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sertraline</title>
            <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
          </group>
        </group_list>
        <measure>
          <title>Adherence to Study Drug</title>
          <description>Participants' percent adherence to study drug regiment by pharmacy medication counts, representing the percent of the total prescribed medication taken by participants.</description>
          <units>Percent of total prescribed medication t</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="100" lower_limit="100" upper_limit="100"/>
                    <measurement group_id="O2" value="100" lower_limit="96" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="100" lower_limit="94" upper_limit="100"/>
                    <measurement group_id="O2" value="100" lower_limit="97" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97" lower_limit="88" upper_limit="100"/>
                    <measurement group_id="O2" value="100" lower_limit="96" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89" lower_limit="63" upper_limit="100"/>
                    <measurement group_id="O2" value="100" lower_limit="100" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Through week 24</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Sertraline</title>
          <description>Fluconazole Standard of Care + Sertraline&#xD;
Sertraline: sertraline 400mg/day&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).</description>
        </group>
        <group group_id="E2">
          <title>Control</title>
          <description>Fluconazole Standard of Care + Placebo Oral Tablet&#xD;
Placebo Oral Tablet: matched placebo tablet&#xD;
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 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="11"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute Gastrointestinal bleeding</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <description>Death due to probable meningitis</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Meningitis</sub_title>
                <description>Meningitis complicated by CSF leak</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Psychosis with Serotonin Syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Mania with Psychotic Disorder</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary Embolism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Trial was terminated early by the NIAID DSMB for excess harm.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>David Boulware</name_or_title>
      <organization>University of Minnesota</organization>
      <phone>612-624-1966</phone>
      <email>boulw001@umn.edu</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/NCT03002012
org study id: U01AI125003
secondary id: U01AI125003
secondary id: 33238
nct id: NCT03002012
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Cryptococcal meningitis or "Crypto" is a life threatening fungal infection around the brain
      that requires hospitalization for treatment for 14 days and then continued therapy. Crypto
      causes 15-20% of HIV/AIDS-related deaths worldwide. However, this infection can be detected
      before one develops symptoms and becomes ill. People can be screened for infection by a blood
      test to detect "cryptococcal antigen," (called CrAg), which is part of the fungus, in blood.
      The World Health Organization and over 22 countries worldwide recommend CrAg screening of all
      persons with advanced AIDS entering or re-entering into HIV care.

      However, it is not known how best to treat people with cryptococcal antigen in their blood,
      who don't otherwise yet have symptoms of infection around their brain. If no treatment is
      given, almost all people will develop infection of the brain and/or die. International
      guidelines suggest using both HIV medicines and an anti-fungal medicine, called fluconazole,
      to treat this early infection. However, despite this treatment approximately 1 in 4 people
      may get sick and/or die.

      Researchers have recently discovered another medicine that may work against the Cryptococcus
      fungus. This medicine is called Sertraline, and it is actually a medicine that has been used
      for more than 25 years to treat depression (sadness). Sertraline is one of the most commonly
      used medicines worldwide.

      The purpose of this research clinical trial is to determine if standard fluconazole
      antifungal therapy plus a high dose of Sertraline, will be better than standard fluconazole
      therapy alone for treating early disseminated cryptococcal infection in persons who are
      asymptomatic and do not yet have infection of the brain (i.e. meningitis).

      This study seeks to test if Sertraline will improve survival through 6-months. Prior studies
      have shown that >90% of those who survive 6-months will survive >5 years.
This is a double-blind, randomized placebo-controlled clinical trial testing sertraline as an
      antifungal medicine in combination with fluconazole for treatment of HIV-infected persons
      with AIDS and asymptomatic cryptococcal antigenemia (CrAg+).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: 6 Month Meningitis-free Survival
time frame: 6 months
description: Cryptococcal meningitis free survival with retention-in-care through 6 months
Those who die of any cause are failures
Those developing symptomatic cryptococcal meningitis are failures
Those lost to follow up and unable to be tracked are considered failures
measure: 6-month Survival
time frame: 6 months
description: Survival through 6 months
measure: Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis
time frame: 6 months
description: Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months
measure: Number of Clinical Adverse Events (Grade 3-5)
time frame: 6 months
description: Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months
measure: Number of Laboratory Grade 3-5 Adverse Events
time frame: 6 months
description: Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale
measure: All-Cause Premature Study Drug/Placebo Discontinuation
time frame: 6 months
description: Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months
measure: Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time
time frame: 12 weeks
description: Prevalence of depression by Patient Health Questionnaire (PHQ-9) over 6 months as measured at baseline, 4 weeks, 8 weeks, and 12 weeks. The PHQ-9 is a 9-item instrument for screening, diagnosing, monitoring, and measuring the severity of depression. Items are rated on a scale from 0 (not at all) to 3 (nearly every day). Total score is a sum of 9 item scores (Range 0-27). Greater scores indicate greater depressive symptoms. PHQ-9 scores of: 0-4 Minimal/No depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderate severe depression; 20-27 Severe depression. This endpoint reports the median (interquartile range) of the PHQ-9 scores over time.
measure: Adherence to Study Drug
time frame: 12 weeks
description: Participants' percent adherence to study drug regiment by pharmacy medication counts, representing the percent of the total prescribed medication taken by participants.
arm group label: Sertraline
arm group type: Experimental
description: Fluconazole Standard of Care + Sertraline
arm group label: Control
arm group type: Placebo Comparator
description: Fluconazole Standard of Care + Placebo Oral Tablet
intervention type: Drug
intervention name: Sertraline
description: sertraline 400mg/day
arm group label: Sertraline
other name: Zoloft
other name: Lustral
other name: Sertraline hydrochloride
intervention type: Drug
intervention name: Placebo Oral Tablet
description: matched placebo tablet
arm group label: Control
other name: Placebo
intervention type: Drug
intervention name: Fluconazole
description: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).
arm group label: Control
arm group label: Sertraline
other name: Fluconazole 200mg tab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Elizabeth K Nalintya, MBChB MPH
role: Study Director
affiliation: Infectious Disease Institute
last name: Radha Rajasingham, MD
role: Study Director
affiliation: University of Minnesota
facility: 
country: Uganda
url: http://preventcrypto.org
description: PreventCrypto.org has information and training materials for cryptococcal antigen screening and treatment
url: http://www.gaffi.org/
description: Global Action Fund for Fungal Infections (GAFFI)
citation: Boulware DR, Nalintya E, Rajasingham R, Kirumira P, Naluyima R, Turya F, Namanda S, Rutakingirwa MK, Skipper CP, Nikweri Y, Hullsiek KH, Bangdiwala AS, Meya DB. Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial. Med Mycol. 2020 Nov 10;58(8):1037-1043. doi: 10.1093/mmy/myaa033.
PMID: 32415846
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Opportunistic Infections
mesh term: AIDS-Related Opportunistic Infections
mesh term: Cryptococcosis
mesh term: Fluconazole
mesh term: Sertraline
sharing ipd: Yes
ipd description: A formal written data sharing plan exists. Protocol and trial documents can be shared. De-identified data can be shared after trial completion.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Available for at least 5 years
ipd access criteria: Upon request to the Principal Investigator
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Trial was terminated early by the NIAID DSMB for excess harm.
point of contact: 