<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/NCT04456153</url>
  </required_header>
  <id_info>
    <org_study_id>STU-2020-0707</org_study_id>
    <nct_id>NCT04456153</nct_id>
  </id_info>
  <brief_title>Atovaquone for Treatment of COVID-19</brief_title>
  <official_title>Atovaquone for Treatment of COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Texas Southwestern Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Texas Southwestern Medical Center</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the current study is to accelerate the use of a clinically available&#xD;
      therapeutic already FDA-approved for other indications in the setting of pandemic COVID-19&#xD;
      addressing a serious and emergent unmet medical need.&#xD;
&#xD;
      This is a randomized, double-blind study of atovaquone therapy in adult participants&#xD;
      hospitalized with COVID-19. Approximately 60 participants who meet all eligibility criteria&#xD;
      may be randomized in a 2:1 atovaquone/placebo ratio into one of the following treatment&#xD;
      groups:&#xD;
&#xD;
      Treatment Group 1: continued standard of care therapy together with an oral dose of 1500 mg&#xD;
      atovaquone twice daily (administered with a meal or snack) for up to 10 days&#xD;
&#xD;
      Treatment Group 2: continued standard of care therapy together with matching placebo&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Design of the ATaQ COVID-19 Trial:&#xD;
&#xD;
      The purpose of the current study is to accelerate the use of a clinically available&#xD;
      therapeutic already FDA-approved for other indications in the setting of pandemic COVID-19&#xD;
      addressing a serious and emergent unmet medical need. In consideration of the information&#xD;
      included in this protocol, the overall risks to participants are outweighed by the potential&#xD;
      benefits of atovaquone experimental therapy for the treatment of COVID-19. The benefit-risk&#xD;
      balance for this study is considered positive.&#xD;
&#xD;
      Inclusion Criteria:&#xD;
&#xD;
        1. Diagnosis of COVID-19 by positive RT-PCR requiring hospitalization within 72 hours&#xD;
&#xD;
        2. Age ≥18 years old&#xD;
&#xD;
        3. Able to provide informed consent, or (as allowed by IRB), immediate availability of&#xD;
           designated legally authorized representative to provide consent by proxy&#xD;
&#xD;
        4. Anticipated hospitalization for &gt;48 hours&#xD;
&#xD;
      Exclusion Criteria&#xD;
&#xD;
      Patients who meet any of the following exclusion criteria are not to be enrolled in this&#xD;
      study:&#xD;
&#xD;
        1. Participation in any other clinical trial with antiviral activity against COVID-19&#xD;
&#xD;
        2. Breastfeeding women&#xD;
&#xD;
        3. Known hypersensitivity to atovaquone or formulation excipient&#xD;
&#xD;
        4. Active treatment with rifampin&#xD;
&#xD;
        5. HIV patients with AIDS requiring treatment for Pneumocystis jirovecii or Toxoplasma&#xD;
           gondii&#xD;
&#xD;
        6. Not expected to survive for 72 hours.&#xD;
&#xD;
        7. &gt;14 days from symptom onset&#xD;
&#xD;
           Randomization:&#xD;
&#xD;
           Patients who meet eligibility criteria and volunteer to participate will be randomized&#xD;
           in a 2:1 ratio to atovaquone or placebo on Day 1 using computerized randomization. An&#xD;
           unblinded investigational pharmacist not otherwise involved in the trial will know&#xD;
           treatment assignment and dispense investigational product. As GI absorption of&#xD;
           atovaquone increased when taken with food, so we will administer with a meal or snack.&#xD;
&#xD;
           Blinding:&#xD;
&#xD;
           Double blinding of treatment assignments will be performed in this study, with the study&#xD;
           team and patients blinded to treatment assignment.&#xD;
&#xD;
           The list of concomitant medications will be assessed only from Day 1 prior to enrollment&#xD;
           to Day 15 or discharge, whichever is earlier.&#xD;
&#xD;
           Patient Enrollment and Treatment Assignment:&#xD;
&#xD;
           Entry into screening does not guarantee enrollment into the study. In order to manage&#xD;
           the total study enrollment, the study researchers may suspend screening and/or&#xD;
           enrollment at any at any time.&#xD;
&#xD;
           Pretreatment Assessments:&#xD;
&#xD;
           Screening Visit&#xD;
&#xD;
           Patients will be screened within 2 days before randomization and dosing to determine&#xD;
           eligibility for participation in the study. Screening will occur under approved HIPAA&#xD;
           waiver for research to identify and screen all hospitalized COVID-19 positive patients&#xD;
           on a daily basis.&#xD;
&#xD;
           Obtain informed consent.&#xD;
&#xD;
           After informed consent has been negotiated and the form signed, the following&#xD;
           assessments will be performed to determine eligibility requirements as specified in the&#xD;
           inclusion and exclusion criteria:&#xD;
&#xD;
             -  Review of focused medical history including the following information (e.g., date&#xD;
                of first symptoms, overall symptoms, exposure source, demographics, baseline&#xD;
                characteristics), allergies and past medical history.&#xD;
&#xD;
             -  Review and record medications and therapies for the current illness&#xD;
&#xD;
             -  Recording of vital signs (heart rate, temperature, blood pressure), body weight,&#xD;
                and height&#xD;
&#xD;
             -  Documentation of respiratory support: Respiratory Rate, Oxygen supplementation:&#xD;
                room air, nasal canula, face mask, non-rebreather, high-flow device, mechanical&#xD;
                ventilation; and FiO2&#xD;
&#xD;
             -  SpO2 at rest or PaO2&#xD;
&#xD;
             -  Radiographic findings&#xD;
&#xD;
           Study patients who qualify and volunteer to participate should be immediately consented&#xD;
           and randomized. Randomization and initiation of dosing should occur on the same day if&#xD;
           possible.&#xD;
&#xD;
           Baseline/Day 1 Assessments&#xD;
&#xD;
           The following evaluations are to be completed at the Day 1 visit. The investigator must&#xD;
           have confirmed eligibility and signing of consent before proceeding with randomization&#xD;
           on the Day 1 visit, followed immediately by first dose of investigational product. The&#xD;
           assessments can be completed by the patient care team and do not need to be repeated by&#xD;
           research personnel. The following assessments must be documented before administering&#xD;
           investigational product, using the most recent data available at the time of&#xD;
           randomization:&#xD;
&#xD;
           Recording of vital signs (heart rate, temperature, blood pressure, body weight, height)&#xD;
&#xD;
           Documentation of respiratory status:&#xD;
&#xD;
           Respiratory rate&#xD;
&#xD;
           Oxygen supplementation and FiO2: room air, nasal canula, face mask, non-rebreather,&#xD;
           noninvasive ventilation or high flow oxygen devices, mechanical ventilation, or ECMO&#xD;
&#xD;
           Oxygenation: (SpO2 or PaO2)&#xD;
&#xD;
           Radiographic findings (if available)&#xD;
&#xD;
           Review AEs and document concomitant medications&#xD;
&#xD;
           Document Ordinal Scale at baseline&#xD;
&#xD;
           Obtain saliva sample and nasopharyngeal swab sample for viral load quantification at day&#xD;
           1 prior to initial dose&#xD;
&#xD;
           Obtain blood for research sample&#xD;
&#xD;
           Daily Study Assessments (Days 2-15):&#xD;
&#xD;
           The following evaluations are to be documented daily from Days 2 - 15 or until discharge&#xD;
           whichever comes earlier, using the data recorded at or closest to 12:00 noon each day:&#xD;
&#xD;
             -  Vital signs (heart rate, temperature, blood pressure), body weight (if available).&#xD;
&#xD;
             -  Documentation of respiratory status: Respiratory rate, Oxygen supplementation and&#xD;
                FiO2: room air, nasal canula, face mask, non-rebreather, noninvasive ventilation or&#xD;
                high flow oxygen devices, mechanical ventilation, or ECMO&#xD;
&#xD;
             -  Oxygenation: (SpO2 or PaO2)&#xD;
&#xD;
             -  Radiographic findings (if available)&#xD;
&#xD;
             -  Review of AEs and document concomitant medications&#xD;
&#xD;
             -  Saliva sample for COVID-19 RT-PCR every 12 hours (Days 2-8)&#xD;
&#xD;
             -  Saliva sample for COVID-19 RT-PCR once daily (Days 9-15)&#xD;
&#xD;
             -  Additional blood draws for biobanking (Day 3, and 5 only)&#xD;
&#xD;
           Clinical Laboratory Assessments:&#xD;
&#xD;
           Clinical laboratory assessments will be conducted as clinically indicated and all&#xD;
           laboratory testing will be completed by local laboratories. Clinical laboratory data to&#xD;
           be captured in the trial database will include serum chemistries, liver function tests,&#xD;
           complete blood counts including absolute neutrophil count, hs-CRP, D-dimer, ferritin,&#xD;
           IL-6, troponin, NTpBNP.&#xD;
&#xD;
           SARS-CoV-2 testing will include RT-qPCR to detect or quantify SARS-CoV-2 or virus&#xD;
           sequencing results from saliva (baseline and daily until discharge or death, and 8 days&#xD;
           and last day of hospitalization or Day 15 if still hospitalized.&#xD;
&#xD;
           Pretreatment and posttreatment samples with detectable SARS-CoV-2 may be sequenced for&#xD;
           resistance monitoring of the viral polymerase gene. For all clinical laboratory tests,&#xD;
           except those at Day 1, when more than 1 result is available in a calendar day, the value&#xD;
           closest to 12:00 noon should be captured in the eCRF. For Day 1 tests, the most recent&#xD;
           result before dosing should be used.&#xD;
&#xD;
           Physical Examination:&#xD;
&#xD;
           No physical examination is mandated by the study protocol beyond the capture of vital&#xD;
           signs (heart rate, respiratory rate, temperature, blood pressure, SpO2 at rest or PaO2)&#xD;
           as documented clinically.&#xD;
&#xD;
           Post-treatment Assessments:&#xD;
&#xD;
           Treatment will continue to complete a 10 Day course or until viral clearance is&#xD;
           documented, whichever occurs first.&#xD;
&#xD;
           Telephone call on Day 15 and 29 for those discharged. The phone call will include a&#xD;
           brief survey on symptoms and information on any re-hospitalizations.&#xD;
&#xD;
           Final review of AEs and concomitant medication.&#xD;
&#xD;
           Vital signs will be captured if still inpatient and the ordinal scale will be assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 22, 2020</start_date>
  <completion_date type="Actual">January 31, 2021</completion_date>
  <primary_completion_date type="Actual">January 31, 2021</primary_completion_date>
  <phase>Phase 2</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary Analysis</measure>
    <time_frame>Day 1 to Day 10</time_frame>
    <description>Between group differences in viral load (Log copy number/ml) using generalized linear mixed-effect models of repeated measures (GLMM), using data from all available samples</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary Between Group Differences in Viral Load</measure>
    <time_frame>baseline to day7</time_frame>
    <description>Change in viral load at Day 3, 5, and 7 days. This shows the group differences between intervention and placebo and log 10 viral load at specific days 3, 5, and 7 for atovaquone arm and placebo arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Viral Load at Day 10 Stratified by Sex</measure>
    <time_frame>baseline to day 10</time_frame>
    <description>Between group differences in viral load (Log copy number/ml) using GLMM stratified by</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage With 2 Log Viral Load Drop at Day 3</measure>
    <time_frame>baseline to day 3</time_frame>
    <description>Between group comparison of time to drop in viral load (Log copy number/ml) of 2 log units using Kaplan-Meier estimation. Examined the percentage of participants who achieved this viral load drop in 3 days.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Change in Ordinal Scale ≥2 Points by Day 15.</measure>
    <time_frame>Day 15</time_frame>
    <description>Ordinal scale 1 indicated death, and higher scores were various degrees of hospitalizations and incapacity to being out of hospital. Ordinal Scale 1-7 with higher score indicating improvement in clinical status. Change of ≥2 points on the ordinal scale by Day 15 using chi-square analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve Copies/ml*Day at Day 7</measure>
    <time_frame>day 7</time_frame>
    <description>This is a alternative method of measurement of area which examines the viral load ( copies/ml )(y-axis) by day (x-axis) using the trapezoidal method. The area under the curve was calculated via the trapezoidal rule. As such, this is a numeric value that is different than the traditional use of the term &quot;mean&quot; or &quot;median.&quot; However, in order to calculate a measure of error associated with this quantity, bootstrapping with 500 replications would need to be performed to assess statistical significance or lack thereof. The mean of the bootstrap samples could be reported as the &quot;mean area under the curve.&quot;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stratifed by Remdesivir</measure>
    <time_frame>day 10</time_frame>
    <description>change in log RNA 10 day 1 to 10 stratified by remdesivir by GLMM</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>standard of care therapy with atovaquone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The first treatment group will receive continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>standard of care therapy with matching placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The second treatment group will receive continued standard of care therapy together with matching placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Experimental Group</intervention_name>
    <description>Continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days</description>
    <arm_group_label>standard of care therapy with atovaquone</arm_group_label>
    <other_name>Atovaquone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Group</intervention_name>
    <description>Continued standard of care therapy together with matching placebo</description>
    <arm_group_label>standard of care therapy with matching placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of COVID-19 by positive RT-PCR requiring hospitalization within 72 hours&#xD;
&#xD;
          2. Age ≥18 years old&#xD;
&#xD;
          3. Able to provide informed consent, or (as allowed by IRB), immediate availability of&#xD;
             designated legally authorized representative to provide consent by proxy&#xD;
&#xD;
          4. Anticipated hospitalization for &gt;48 hours&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participation in any other clinical trial with antiviral activity against COVID-19&#xD;
&#xD;
          2. Breastfeeding women&#xD;
&#xD;
          3. Known hypersensitivity to atovaquone or formulation excipient&#xD;
&#xD;
          4. Active treatment with rifampin&#xD;
&#xD;
          5. HIV patients with AIDS requiring treatment for Pneumocystis jirovecii or Toxoplasma&#xD;
             gondii&#xD;
&#xD;
          6. Not expected to survive for 72 hours. 7) &gt;14 days from symptom onset&#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>Mamta Jain, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hesham Sadek, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ezimamaka Ajufo, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Reuben Arasaratnam, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>James De Lemos, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Helen King, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Amneris Luque, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jessica Meisner, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Satish Mocherla, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>John Schoggins, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Texas Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>June 30, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 2, 2020</study_first_posted>
  <results_first_submitted>November 10, 2021</results_first_submitted>
  <results_first_submitted_qc>December 12, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">December 14, 2021</results_first_posted>
  <last_update_submitted>December 12, 2021</last_update_submitted>
  <last_update_submitted_qc>December 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Texas Southwestern Medical Center</investigator_affiliation>
    <investigator_full_name>Mamta K. Jain, MD,MPH</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atovaquone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no specified plan made.</ipd_description>
  </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>February 16, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/53/NCT04456153/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Standard of Care Therapy With Matching Placebo</title>
          <description>The second treatment group will receive continued standard of care therapy together with matching placebo.&#xD;
Placebo Group: Continued standard of care therapy together with matching placebo</description>
        </group>
        <group group_id="P2">
          <title>Standard of Care Therapy With Atovaquone</title>
          <description>The first treatment group will receive continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days.&#xD;
Experimental Group: Continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="41"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="41"/>
              </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>Standard of Care Therapy With Atovaquone</title>
          <description>The first treatment group will receive continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days.</description>
        </group>
        <group group_id="B2">
          <title>Standard of Care Therapy With Matching Placebo</title>
          <description>The second treatment group will receive continued standard of care therapy together with matching placebo.</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="41"/>
            <count group_id="B2" value="19"/>
            <count group_id="B3" value="60"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="51.64" lower_limit="42.5" upper_limit="60.8"/>
                    <measurement group_id="B2" value="49.4" lower_limit="41" upper_limit="59.6"/>
                    <measurement group_id="B3" value="50.9" lower_limit="41.9" upper_limit="59.6"/>
                  </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="15"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="38"/>
                  </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="29"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</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>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>non-Hispanic White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                  </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="41"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>log 10 viral load (copies/mL)</title>
          <units>log 10 RNA copies/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>atovaquone</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5.25" spread="0.278"/>
                    <measurement group_id="B2" value="0" spread="0"/>
                    <measurement group_id="B3" value="5.25" spread="0.278"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Placebo</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0" spread="0"/>
                    <measurement group_id="B2" value="4.79" spread="0.408"/>
                    <measurement group_id="B3" value="4.79" spread="0.408"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Primary Analysis</title>
        <description>Between group differences in viral load (Log copy number/ml) using generalized linear mixed-effect models of repeated measures (GLMM), using data from all available samples</description>
        <time_frame>Day 1 to Day 10</time_frame>
        <population>Change in viral load from day 1 to day 10 between intervention arm and placebo</population>
        <group_list>
          <group group_id="O1">
            <title>Overall Group</title>
            <description>Comparison of experimental group to placebo</description>
          </group>
          <group group_id="O2">
            <title>Atovaquone Group With Standard of Care Treatment</title>
            <description>This arm received atovaquone 2: 1 in addition to the standard of care.</description>
          </group>
          <group group_id="O3">
            <title>Placebo Plus Standard of Care</title>
            <description>This arm received matched placebo in addition to the standard of care.</description>
          </group>
        </group_list>
        <measure>
          <title>Primary Analysis</title>
          <description>Between group differences in viral load (Log copy number/ml) using generalized linear mixed-effect models of repeated measures (GLMM), using data from all available samples</description>
          <population>Change in viral load from day 1 to day 10 between intervention arm and placebo</population>
          <units>log 10 (copies/mL)</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="60"/>
                <count group_id="O2" value="41"/>
                <count group_id="O3" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.906" lower_limit="-3.090" upper_limit="0.123"/>
                    <measurement group_id="O2" value="2.629" lower_limit="1.652" upper_limit="3.606"/>
                    <measurement group_id="O3" value="4.073" lower_limit="3.131" upper_limit="5.015"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.170</p_value>
            <method>GLMM</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Secondary Between Group Differences in Viral Load</title>
        <description>Change in viral load at Day 3, 5, and 7 days. This shows the group differences between intervention and placebo and log 10 viral load at specific days 3, 5, and 7 for atovaquone arm and placebo arm.</description>
        <time_frame>baseline to day7</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Difference Between Atovaquone and Placebo</title>
            <description>Comparison of experimental group to placebo</description>
          </group>
          <group group_id="O2">
            <title>Atovaquone Plus Standard of Care</title>
            <description>Log 10 viral load of atovaquone group at Day 3, 5, 7</description>
          </group>
          <group group_id="O3">
            <title>Placebo Plus Standard of Care</title>
            <description>Log 10 viral load of placebo group at Day 3, 5, and 7</description>
          </group>
        </group_list>
        <measure>
          <title>Secondary Between Group Differences in Viral Load</title>
          <description>Change in viral load at Day 3, 5, and 7 days. This shows the group differences between intervention and placebo and log 10 viral load at specific days 3, 5, and 7 for atovaquone arm and placebo arm.</description>
          <units>log 10 (copies/mL)</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="60"/>
                <count group_id="O2" value="41"/>
                <count group_id="O3" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>day 1 to 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.129" lower_limit="-0.571" upper_limit="0.829"/>
                    <measurement group_id="O2" value="5.342" lower_limit="4.548" upper_limit="6.135"/>
                    <measurement group_id="O3" value="4.406" lower_limit="3.609" upper_limit="5.203"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>day 1 to 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.107" lower_limit="-0.610" upper_limit="0.823"/>
                    <measurement group_id="O2" value="4.329" lower_limit="3.785" upper_limit="4.874"/>
                    <measurement group_id="O3" value="3.760" lower_limit="2.948" upper_limit="4.572"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>day 1 to 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.766" lower_limit="-1.534" upper_limit="0.002"/>
                    <measurement group_id="O2" value="3.804" lower_limit="3.230" upper_limit="4.378"/>
                    <measurement group_id="O3" value="4.108" lower_limit="3.270" upper_limit="4.946"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>0.051</p_value>
            <method>GLMM</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Viral Load at Day 10 Stratified by Sex</title>
        <description>Between group differences in viral load (Log copy number/ml) using GLMM stratified by</description>
        <time_frame>baseline to day 10</time_frame>
        <population>Between group differences Day 1 to day 10</population>
        <group_list>
          <group group_id="O1">
            <title>Stratified by Sex: Men</title>
            <description>Comparison of change in viral load from Day 1 to day 10 between placebo and atovaquone</description>
          </group>
          <group group_id="O2">
            <title>Stratified by Sex: Women</title>
            <description>Comparison of change in viral load from Day 1 to day 10 between placebo and atovaquone</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Viral Load at Day 10 Stratified by Sex</title>
          <description>Between group differences in viral load (Log copy number/ml) using GLMM stratified by</description>
          <population>Between group differences Day 1 to day 10</population>
          <units>log 10 viral load (copies/mL)</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="38"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.8732" lower_limit="-3.8342" upper_limit="0.08779"/>
                    <measurement group_id="O2" value="0.555" lower_limit="-1.9539" upper_limit="3.0639"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage With 2 Log Viral Load Drop at Day 3</title>
        <description>Between group comparison of time to drop in viral load (Log copy number/ml) of 2 log units using Kaplan-Meier estimation. Examined the percentage of participants who achieved this viral load drop in 3 days.</description>
        <time_frame>baseline to day 3</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atovaquone</title>
            <description>Atovaquone plus standard of care therapy. Proportion who had 2 log drop at Day 3</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo plus standard of care therapy. Proportion who had 2 log drop at Day 3</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage With 2 Log Viral Load Drop at Day 3</title>
          <description>Between group comparison of time to drop in viral load (Log copy number/ml) of 2 log units using Kaplan-Meier estimation. Examined the percentage of participants who achieved this viral load drop in 3 days.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="41"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Change in Ordinal Scale ≥2 Points by Day 15.</title>
        <description>Ordinal scale 1 indicated death, and higher scores were various degrees of hospitalizations and incapacity to being out of hospital. Ordinal Scale 1-7 with higher score indicating improvement in clinical status. Change of ≥2 points on the ordinal scale by Day 15 using chi-square analysis</description>
        <time_frame>Day 15</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atovaquone</title>
            <description>Atovaquone group at Day 15. Number of participants who had &gt; or = 2 point change in ordinal score</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo at Day 15. Number of participants who had &gt; or = 2 point change in ordinal score</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Change in Ordinal Scale ≥2 Points by Day 15.</title>
          <description>Ordinal scale 1 indicated death, and higher scores were various degrees of hospitalizations and incapacity to being out of hospital. Ordinal Scale 1-7 with higher score indicating improvement in clinical status. Change of ≥2 points on the ordinal scale by Day 15 using chi-square analysis</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="40"/>
                <count group_id="O2" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.68</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under the Curve Copies/ml*Day at Day 7</title>
        <description>This is a alternative method of measurement of area which examines the viral load ( copies/ml )(y-axis) by day (x-axis) using the trapezoidal method. The area under the curve was calculated via the trapezoidal rule. As such, this is a numeric value that is different than the traditional use of the term &quot;mean&quot; or &quot;median.&quot; However, in order to calculate a measure of error associated with this quantity, bootstrapping with 500 replications would need to be performed to assess statistical significance or lack thereof. The mean of the bootstrap samples could be reported as the &quot;mean area under the curve.&quot;</description>
        <time_frame>day 7</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atovaquone</title>
            <description>Atovaquone plus standard of care</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo plus standard of care</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve Copies/ml*Day at Day 7</title>
          <description>This is a alternative method of measurement of area which examines the viral load ( copies/ml )(y-axis) by day (x-axis) using the trapezoidal method. The area under the curve was calculated via the trapezoidal rule. As such, this is a numeric value that is different than the traditional use of the term &quot;mean&quot; or &quot;median.&quot; However, in order to calculate a measure of error associated with this quantity, bootstrapping with 500 replications would need to be performed to assess statistical significance or lack thereof. The mean of the bootstrap samples could be reported as the &quot;mean area under the curve.&quot;</description>
          <units>copies/mL*day</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="41"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.39"/>
                    <measurement group_id="O2" value="36.09"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.76</p_value>
            <method>trapezoidal method</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Stratifed by Remdesivir</title>
        <description>change in log RNA 10 day 1 to 10 stratified by remdesivir by GLMM</description>
        <time_frame>day 10</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Stratified With Remdesivir</title>
            <description>Participants who received remdesivir as part of standard of care</description>
          </group>
          <group group_id="O2">
            <title>Stratified Without Remdesivir</title>
            <description>Participants who did not receive remdesivir as part of standard of care</description>
          </group>
        </group_list>
        <measure>
          <title>Stratifed by Remdesivir</title>
          <description>change in log RNA 10 day 1 to 10 stratified by remdesivir by GLMM</description>
          <units>log 10 RNA copies/mL</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="36"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.754" lower_limit="-2.440" upper_limit="0.933"/>
                    <measurement group_id="O2" value="-2.010" lower_limit="-4.513" upper_limit="0.494"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>During hospitalization for an average of 10 days</time_frame>
      <desc>Collected grade 3 or 4 adverse events</desc>
      <group_list>
        <group group_id="E1">
          <title>Atovaquone</title>
          <description>Atovaquone plus standard of care. Grade 3 and 4 adverse events were collected.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Matching placebo plus standard of care</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="6" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>hypoxic respiratory failure</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Non-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="2" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Transaminitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </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 study was not powered for clinical endpoints.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Mamta K. Jain</name_or_title>
      <organization>UT Southwestern Medical Center</organization>
      <phone>2140648-9914</phone>
      <email>mamta.jain@utsouthwestern.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/NCT04456153
org study id: STU-2020-0707
nct id: NCT04456153
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of the current study is to accelerate the use of a clinically available
      therapeutic already FDA-approved for other indications in the setting of pandemic COVID-19
      addressing a serious and emergent unmet medical need.

      This is a randomized, double-blind study of atovaquone therapy in adult participants
      hospitalized with COVID-19. Approximately 60 participants who meet all eligibility criteria
      may be randomized in a 2:1 atovaquone/placebo ratio into one of the following treatment
      groups:

      Treatment Group 1: continued standard of care therapy together with an oral dose of 1500 mg
      atovaquone twice daily (administered with a meal or snack) for up to 10 days

      Treatment Group 2: continued standard of care therapy together with matching placebo
Design of the ATaQ COVID-19 Trial:

      The purpose of the current study is to accelerate the use of a clinically available
      therapeutic already FDA-approved for other indications in the setting of pandemic COVID-19
      addressing a serious and emergent unmet medical need. In consideration of the information
      included in this protocol, the overall risks to participants are outweighed by the potential
      benefits of atovaquone experimental therapy for the treatment of COVID-19. The benefit-risk
      balance for this study is considered positive.

      Inclusion Criteria:

        1. Diagnosis of COVID-19 by positive RT-PCR requiring hospitalization within 72 hours

        2. Age ≥18 years old

        3. Able to provide informed consent, or (as allowed by IRB), immediate availability of
           designated legally authorized representative to provide consent by proxy

        4. Anticipated hospitalization for >48 hours

      Exclusion Criteria

      Patients who meet any of the following exclusion criteria are not to be enrolled in this
      study:

        1. Participation in any other clinical trial with antiviral activity against COVID-19

        2. Breastfeeding women

        3. Known hypersensitivity to atovaquone or formulation excipient

        4. Active treatment with rifampin

        5. HIV patients with AIDS requiring treatment for Pneumocystis jirovecii or Toxoplasma
           gondii

        6. Not expected to survive for 72 hours.

        7. >14 days from symptom onset

           Randomization:

           Patients who meet eligibility criteria and volunteer to participate will be randomized
           in a 2:1 ratio to atovaquone or placebo on Day 1 using computerized randomization. An
           unblinded investigational pharmacist not otherwise involved in the trial will know
           treatment assignment and dispense investigational product. As GI absorption of
           atovaquone increased when taken with food, so we will administer with a meal or snack.

           Blinding:

           Double blinding of treatment assignments will be performed in this study, with the study
           team and patients blinded to treatment assignment.

           The list of concomitant medications will be assessed only from Day 1 prior to enrollment
           to Day 15 or discharge, whichever is earlier.

           Patient Enrollment and Treatment Assignment:

           Entry into screening does not guarantee enrollment into the study. In order to manage
           the total study enrollment, the study researchers may suspend screening and/or
           enrollment at any at any time.

           Pretreatment Assessments:

           Screening Visit

           Patients will be screened within 2 days before randomization and dosing to determine
           eligibility for participation in the study. Screening will occur under approved HIPAA
           waiver for research to identify and screen all hospitalized COVID-19 positive patients
           on a daily basis.

           Obtain informed consent.

           After informed consent has been negotiated and the form signed, the following
           assessments will be performed to determine eligibility requirements as specified in the
           inclusion and exclusion criteria:

             -  Review of focused medical history including the following information (e.g., date
                of first symptoms, overall symptoms, exposure source, demographics, baseline
                characteristics), allergies and past medical history.

             -  Review and record medications and therapies for the current illness

             -  Recording of vital signs (heart rate, temperature, blood pressure), body weight,
                and height

             -  Documentation of respiratory support: Respiratory Rate, Oxygen supplementation:
                room air, nasal canula, face mask, non-rebreather, high-flow device, mechanical
                ventilation; and FiO2

             -  SpO2 at rest or PaO2

             -  Radiographic findings

           Study patients who qualify and volunteer to participate should be immediately consented
           and randomized. Randomization and initiation of dosing should occur on the same day if
           possible.

           Baseline/Day 1 Assessments

           The following evaluations are to be completed at the Day 1 visit. The investigator must
           have confirmed eligibility and signing of consent before proceeding with randomization
           on the Day 1 visit, followed immediately by first dose of investigational product. The
           assessments can be completed by the patient care team and do not need to be repeated by
           research personnel. The following assessments must be documented before administering
           investigational product, using the most recent data available at the time of
           randomization:

           Recording of vital signs (heart rate, temperature, blood pressure, body weight, height)

           Documentation of respiratory status:

           Respiratory rate

           Oxygen supplementation and FiO2: room air, nasal canula, face mask, non-rebreather,
           noninvasive ventilation or high flow oxygen devices, mechanical ventilation, or ECMO

           Oxygenation: (SpO2 or PaO2)

           Radiographic findings (if available)

           Review AEs and document concomitant medications

           Document Ordinal Scale at baseline

           Obtain saliva sample and nasopharyngeal swab sample for viral load quantification at day
           1 prior to initial dose

           Obtain blood for research sample

           Daily Study Assessments (Days 2-15):

           The following evaluations are to be documented daily from Days 2 - 15 or until discharge
           whichever comes earlier, using the data recorded at or closest to 12:00 noon each day:

             -  Vital signs (heart rate, temperature, blood pressure), body weight (if available).

             -  Documentation of respiratory status: Respiratory rate, Oxygen supplementation and
                FiO2: room air, nasal canula, face mask, non-rebreather, noninvasive ventilation or
                high flow oxygen devices, mechanical ventilation, or ECMO

             -  Oxygenation: (SpO2 or PaO2)

             -  Radiographic findings (if available)

             -  Review of AEs and document concomitant medications

             -  Saliva sample for COVID-19 RT-PCR every 12 hours (Days 2-8)

             -  Saliva sample for COVID-19 RT-PCR once daily (Days 9-15)

             -  Additional blood draws for biobanking (Day 3, and 5 only)

           Clinical Laboratory Assessments:

           Clinical laboratory assessments will be conducted as clinically indicated and all
           laboratory testing will be completed by local laboratories. Clinical laboratory data to
           be captured in the trial database will include serum chemistries, liver function tests,
           complete blood counts including absolute neutrophil count, hs-CRP, D-dimer, ferritin,
           IL-6, troponin, NTpBNP.

           SARS-CoV-2 testing will include RT-qPCR to detect or quantify SARS-CoV-2 or virus
           sequencing results from saliva (baseline and daily until discharge or death, and 8 days
           and last day of hospitalization or Day 15 if still hospitalized.

           Pretreatment and posttreatment samples with detectable SARS-CoV-2 may be sequenced for
           resistance monitoring of the viral polymerase gene. For all clinical laboratory tests,
           except those at Day 1, when more than 1 result is available in a calendar day, the value
           closest to 12:00 noon should be captured in the eCRF. For Day 1 tests, the most recent
           result before dosing should be used.

           Physical Examination:

           No physical examination is mandated by the study protocol beyond the capture of vital
           signs (heart rate, respiratory rate, temperature, blood pressure, SpO2 at rest or PaO2)
           as documented clinically.

           Post-treatment Assessments:

           Treatment will continue to complete a 10 Day course or until viral clearance is
           documented, whichever occurs first.

           Telephone call on Day 15 and 29 for those discharged. The phone call will include a
           brief survey on symptoms and information on any re-hospitalizations.

           Final review of AEs and concomitant medication.

           Vital signs will be captured if still inpatient and the ordinal scale will be assessed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Primary Analysis
time frame: Day 1 to Day 10
description: Between group differences in viral load (Log copy number/ml) using generalized linear mixed-effect models of repeated measures (GLMM), using data from all available samples
measure: Secondary Between Group Differences in Viral Load
time frame: baseline to day7
description: Change in viral load at Day 3, 5, and 7 days. This shows the group differences between intervention and placebo and log 10 viral load at specific days 3, 5, and 7 for atovaquone arm and placebo arm.
measure: Change in Viral Load at Day 10 Stratified by Sex
time frame: baseline to day 10
description: Between group differences in viral load (Log copy number/ml) using GLMM stratified by
measure: Percentage With 2 Log Viral Load Drop at Day 3
time frame: baseline to day 3
description: Between group comparison of time to drop in viral load (Log copy number/ml) of 2 log units using Kaplan-Meier estimation. Examined the percentage of participants who achieved this viral load drop in 3 days.
measure: Number of Participants With Change in Ordinal Scale ≥2 Points by Day 15.
time frame: Day 15
description: Ordinal scale 1 indicated death, and higher scores were various degrees of hospitalizations and incapacity to being out of hospital. Ordinal Scale 1-7 with higher score indicating improvement in clinical status. Change of ≥2 points on the ordinal scale by Day 15 using chi-square analysis
measure: Area Under the Curve Copies/ml*Day at Day 7
time frame: day 7
description: This is a alternative method of measurement of area which examines the viral load ( copies/ml )(y-axis) by day (x-axis) using the trapezoidal method. The area under the curve was calculated via the trapezoidal rule. As such, this is a numeric value that is different than the traditional use of the term "mean" or "median." However, in order to calculate a measure of error associated with this quantity, bootstrapping with 500 replications would need to be performed to assess statistical significance or lack thereof. The mean of the bootstrap samples could be reported as the "mean area under the curve."
measure: Stratifed by Remdesivir
time frame: day 10
description: change in log RNA 10 day 1 to 10 stratified by remdesivir by GLMM
arm group label: standard of care therapy with atovaquone
arm group type: Experimental
description: The first treatment group will receive continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days.
arm group label: standard of care therapy with matching placebo
arm group type: Placebo Comparator
description: The second treatment group will receive continued standard of care therapy together with matching placebo.
intervention type: Drug
intervention name: Experimental Group
description: Continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days
arm group label: standard of care therapy with atovaquone
other name: Atovaquone
intervention type: Drug
intervention name: Placebo Group
description: Continued standard of care therapy together with matching placebo
arm group label: standard of care therapy with matching placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mamta Jain, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: Hesham Sadek, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: Ezimamaka Ajufo, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: Reuben Arasaratnam, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: James De Lemos, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: Helen King, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: Amneris Luque, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: Jessica Meisner, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: Satish Mocherla, M.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
last name: John Schoggins, Ph.D.
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Mamta K. Jain, MD,MPH
investigator title: Professor of Medicine
mesh term: COVID-19
mesh term: Atovaquone
sharing ipd: No
ipd description: There is no specified plan made.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This study was not powered for clinical endpoints.
point of contact: 