<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/NCT02256696</url>
  </required_header>
  <id_info>
    <org_study_id>NA_00093014</org_study_id>
    <secondary_id>#FD-R-004794-01</secondary_id>
    <nct_id>NCT02256696</nct_id>
  </id_info>
  <brief_title>Assessing PA-824 for Tuberculosis (the APT Trial)</brief_title>
  <official_title>A Phase 2 Randomized, Open-Label Trial of PA-824-Containing Regimens Versus Standard Treatment for Drug-Sensitive Sputum Smear-Positive Pulmonary Tuberculosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Cape Town</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Johns Hopkins University</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>
      Assess the mycobactericidal activity of PA-824 (given at 200 mg daily) when added to&#xD;
      first-line tuberculosis (TB) treatment (isoniazid, pyrazinamide, and a rifamycin antibiotic)&#xD;
      over 12 weeks of treatment. Funding Source - FDA Office of Orphan Products Development (OOPD)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phase IIB, 12-week, open-label, single-site, randomized clinical trial with three treatment&#xD;
      groups. Patients with drug-sensitive TB will all receive once daily isoniazid and&#xD;
      pyrazinamide for 8 weeks followed by 4 weeks of daily isoniazid. In addition, Arm 1&#xD;
      participants will receive PA-824 200 mg daily and rifampin 600 mg daily for 12 weeks. Arm 2&#xD;
      participants will receive PA-824 200 mg daily and rifabutin 300 mg daily for 12 weeks. Arm 3&#xD;
      participants (control group) will receive rifampin for 12 weeks and ethambutol for 8 weeks.&#xD;
      Patients will be screened within 1 week of TB diagnosis, will receive 12 weeks of study&#xD;
      treatment and will return for follow-up visits at 4, 12, and 36 weeks after study treatment&#xD;
      completion. All patients will be referred to the local TB treatment program after completion&#xD;
      of study treatment to finish their 24-week TB treatment course.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 29, 2015</start_date>
  <completion_date type="Actual">May 1, 2022</completion_date>
  <primary_completion_date type="Actual">May 1, 2022</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to Sputum Culture Conversion on Liquid Medium</measure>
    <time_frame>12 weeks</time_frame>
    <description>The time (days) it takes for the sputum to convert from positive to negative.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Grade 3 or Higher Adverse Events</measure>
    <time_frame>12 weeks</time_frame>
    <description>Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Permanent Discontinuation of Assigned Study Regimen</measure>
    <time_frame>12 weeks</time_frame>
    <description>If it is in the best interest of a participant to stop the study regimen for any reason</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Culture Conversion on Solid Medium</measure>
    <time_frame>12 weeks</time_frame>
    <description>The time (days) it takes for the sputum to convert form positive to negative on solid medium</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment</measure>
    <time_frame>8 weeks</time_frame>
    <description>Percentage of participants whose sputum converts from positive to negative at Week 8 time point, on solid and liquid media.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin</measure>
    <time_frame>pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14</time_frame>
    <description>AUC of PA-824 when given with either rifampicin or rifabutin to determine steady state Pharmacokinetics (PK) of PA-824.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment</measure>
    <time_frame>pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14</time_frame>
    <description>The Pharmacokinetic results (Cmax) of the study drug when given with a rifampin or a rifabutin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks</measure>
    <time_frame>12 weeks</time_frame>
    <description>Relationship between PA-824 exposure (AUC) and rate of change in TTP over 12 weeks, using non-linear mixed effects modeling. The data is reported as percentage increase in TTP per 10 unit increase in PA-824 AUC (% increase/10 unit increase PA-824 AUC).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">157</enrollment>
  <condition>Pulmonary Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PA-824</intervention_name>
    <description>200 mg QD</description>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_label>Arm 2</arm_group_label>
    <other_name>Pretomanid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampin</intervention_name>
    <description>600 mg QD</description>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_label>Arm 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifabutin</intervention_name>
    <description>300 mg QD</description>
    <arm_group_label>Arm 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pyrazinamide</intervention_name>
    <description>25mg/kg QD</description>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_label>Arm 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ethambutol</intervention_name>
    <description>15mg/kg QD</description>
    <arm_group_label>Arm 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isoniazid</intervention_name>
    <description>300 mg QD</description>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_label>Arm 3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of&#xD;
             expectorated sputum or Gene Xpert positive sputum sample. Patients having&#xD;
             extra-pulmonary manifestations of tuberculosis, in addition to smear-positive&#xD;
             pulmonary disease, are eligible for enrollment.&#xD;
&#xD;
          2. Age &gt; 18 years&#xD;
&#xD;
          3. . Weight ≥ 40 kg and ≤ 80 kg&#xD;
&#xD;
          4. Karnofsky score of at least 60 (requires occasional assistance but is able to care for&#xD;
             most of his/her needs)&#xD;
&#xD;
          5. . Signed informed consent&#xD;
&#xD;
          6. . HIV negative, or positive with CD4 ≥350 cells/cu mm and not currently taking or&#xD;
             planning to take combination antiretroviral therapy for HIV during the study.&#xD;
&#xD;
          7. Ability to adhere with study follow-up&#xD;
&#xD;
        8 Agrees to adhere to contraceptive requirements&#xD;
&#xD;
        -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant or breast-feeding&#xD;
&#xD;
          2. Known intolerance or allergy to any of the study drugs&#xD;
&#xD;
          3. Concomitant disorders or conditions for which isoniazid, rifampin, rifabutin,&#xD;
             pyrazinamide, or ethambutol is contraindicated. These include severe hepatic damage,&#xD;
             acute liver disease of any cause, allergy to the drug, and acute uncontrolled gouty&#xD;
             arthritis.&#xD;
&#xD;
          4. Current or planned therapy, during the intensive phase of TB therapy with cyclosporine&#xD;
             or tacrolimus, which have unacceptable interactions with rifamycins.&#xD;
&#xD;
          5. Any medical or psychosocial condition, which, in the view of the study investigator,&#xD;
             makes study participation inadvisable.&#xD;
&#xD;
          6. Pulmonary silicosis&#xD;
&#xD;
          7. Central nervous system TB&#xD;
&#xD;
          8. ECG at screening with corrected QT interval (QTc) (Fridericia correction) interval&#xD;
             &gt;450 ms or any clinically-significant, in the opinion of the investigator, ECG&#xD;
             abnormality&#xD;
&#xD;
          9. History and/or presence (or evidence) of neuropathy or epilepsy.&#xD;
&#xD;
         10. History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic&#xD;
             examination with a value of 1.0 or higher on age-related eye disease scale 2 (AREDS2)&#xD;
             Clinical Lens Opacity Classification and Grading System scale.&#xD;
&#xD;
         11. Infection with an isolate known to be resistant to a first-line TB drug (for example,&#xD;
             patients with Gene Xpert screening through the local TB program with results&#xD;
             suggesting resistance to rifampin)&#xD;
&#xD;
         12. Laboratory parameters done at, or 14 days prior to, screening (with results available&#xD;
             for review by study personnel) demonstrating any of the following:&#xD;
&#xD;
               -  Serum alanine aminotransferase (ALT) activity &gt; 3 times the upper limit of normal&#xD;
&#xD;
               -  Serum total bilirubin level &gt; 2 times the upper limit of normal&#xD;
&#xD;
               -  Serum creatinine greater than the upper limit of normal&#xD;
&#xD;
               -  Hemoglobin level less than 7.0 g/dL&#xD;
&#xD;
               -  Platelet count less than 100,000/mm3&#xD;
&#xD;
               -  Positive pregnancy test (women of childbearing potential)&#xD;
&#xD;
         13. More than five days of treatment directed against active tuberculosis in the past 6&#xD;
             months -&#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>Kelly E Dooley, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Cape Town Lung Institute</name>
      <address>
        <city>Cape Town</city>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>September 25, 2014</study_first_submitted>
  <study_first_submitted_qc>October 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 6, 2014</study_first_posted>
  <results_first_submitted>May 1, 2023</results_first_submitted>
  <results_first_submitted_qc>June 26, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">July 18, 2023</results_first_posted>
  <last_update_submitted>June 26, 2023</last_update_submitted>
  <last_update_submitted_qc>June 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Pulmonary</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Rifabutin</mesh_term>
    <mesh_term>Isoniazid</mesh_term>
    <mesh_term>Pyrazinamide</mesh_term>
    <mesh_term>Ethambutol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>This plan is in process, to be finalized prior to the end of recruitment.</ipd_description>
    <ipd_time_frame>Within one year of reaching recruitment goals.</ipd_time_frame>
    <ipd_access_criteria>This plan is in process, to be finalized prior to the end of recruitment.</ipd_access_criteria>
  </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 7, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/96/NCT02256696/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 28, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/96/NCT02256696/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Arm 1</title>
          <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
        <group group_id="P2">
          <title>Arm 2</title>
          <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
        <group group_id="P3">
          <title>Arm 3</title>
          <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="56"/>
                <participants group_id="P2" count="53"/>
                <participants group_id="P3" count="48"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="53"/>
                <participants group_id="P2" count="50"/>
                <participants group_id="P3" count="47"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm 1</title>
          <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
        <group group_id="B2">
          <title>Arm 2</title>
          <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
        <group group_id="B3">
          <title>Arm 3</title>
          <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
        <group group_id="B4">
          <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="56"/>
            <count group_id="B2" value="53"/>
            <count group_id="B3" value="48"/>
            <count group_id="B4" value="157"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="25" upper_limit="39"/>
                    <measurement group_id="B2" value="30" lower_limit="23" upper_limit="35"/>
                    <measurement group_id="B3" value="31" lower_limit="23" upper_limit="40"/>
                    <measurement group_id="B4" value="31" lower_limit="23" upper_limit="39"/>
                  </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="13"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="39"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="43"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="39"/>
                    <measurement group_id="B4" value="118"/>
                  </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>Black</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="38"/>
                    <measurement group_id="B2" value="35"/>
                    <measurement group_id="B3" value="29"/>
                    <measurement group_id="B4" value="102"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Colored</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="18"/>
                    <measurement group_id="B4" value="54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="56"/>
                    <measurement group_id="B2" value="53"/>
                    <measurement group_id="B3" value="48"/>
                    <measurement group_id="B4" value="157"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Time to Sputum Culture Conversion on Liquid Medium</title>
        <description>The time (days) it takes for the sputum to convert from positive to negative.</description>
        <time_frame>12 weeks</time_frame>
        <population>Adult (&gt; 18 years) drug sensitive pulmonary TB patients with weight 40 - 80 kg, HIV Negative or Positive with CD4 &gt; 350, not on antiretroviral therapy (ART)</population>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O2">
            <title>Arm 2</title>
            <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O3">
            <title>Arm 3</title>
            <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Sputum Culture Conversion on Liquid Medium</title>
          <description>The time (days) it takes for the sputum to convert from positive to negative.</description>
          <population>Adult (&gt; 18 years) drug sensitive pulmonary TB patients with weight 40 - 80 kg, HIV Negative or Positive with CD4 &gt; 350, not on antiretroviral therapy (ART)</population>
          <units>days</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="53"/>
                <count group_id="O2" value="50"/>
                <count group_id="O3" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Time to culture conversion (mITT)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="53"/>
                    <count group_id="O2" value="50"/>
                    <count group_id="O3" value="47"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42" lower_limit="21" upper_limit="56"/>
                    <measurement group_id="O2" value="28" lower_limit="21" upper_limit="42"/>
                    <measurement group_id="O3" value="56" lower_limit="42" upper_limit="70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Time to culture conversion (per protocol)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="51"/>
                    <count group_id="O2" value="43"/>
                    <count group_id="O3" value="47"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42" lower_limit="21" upper_limit="56"/>
                    <measurement group_id="O2" value="28" lower_limit="21" upper_limit="42"/>
                    <measurement group_id="O3" value="56" lower_limit="42" upper_limit="70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>modified intention to treat (mITT) analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.10</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth.</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.41</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.93</ci_lower_limit>
            <ci_upper_limit>2.12</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>mITT analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.003</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth.</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.89</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.24</ci_lower_limit>
            <ci_upper_limit>2.87</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>per protocol</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.09</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.43</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.95</ci_lower_limit>
            <ci_upper_limit>2.15</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>per protocol</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.005</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.87</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.21</ci_lower_limit>
            <ci_upper_limit>2.89</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Grade 3 or Higher Adverse Events</title>
        <description>Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O2">
            <title>Arm 2</title>
            <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O3">
            <title>Arm 3</title>
            <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Grade 3 or Higher Adverse Events</title>
          <description>Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table</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="56"/>
                <count group_id="O2" value="53"/>
                <count group_id="O3" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="6"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Permanent Discontinuation of Assigned Study Regimen</title>
        <description>If it is in the best interest of a participant to stop the study regimen for any reason</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O2">
            <title>Arm 2</title>
            <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O3">
            <title>Arm 3</title>
            <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Permanent Discontinuation of Assigned Study Regimen</title>
          <description>If it is in the best interest of a participant to stop the study regimen for any reason</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="56"/>
                <count group_id="O2" value="53"/>
                <count group_id="O3" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="7"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Culture Conversion on Solid Medium</title>
        <description>The time (days) it takes for the sputum to convert form positive to negative on solid medium</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O2">
            <title>Arm 2</title>
            <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O3">
            <title>Arm 3</title>
            <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Culture Conversion on Solid Medium</title>
          <description>The time (days) it takes for the sputum to convert form positive to negative on solid medium</description>
          <units>days</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="56"/>
                <count group_id="O2" value="53"/>
                <count group_id="O3" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Time to conversion on solid culture (mITT)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28" lower_limit="14" upper_limit="42"/>
                    <measurement group_id="O2" value="21" lower_limit="14" upper_limit="28"/>
                    <measurement group_id="O3" value="42" lower_limit="21" upper_limit="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Time to conversion on solid culture (per protocol)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28" lower_limit="14" upper_limit="42"/>
                    <measurement group_id="O2" value="21" lower_limit="14" upper_limit="28"/>
                    <measurement group_id="O3" value="42" lower_limit="21" upper_limit="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>mITT analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth.</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.61</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.07</ci_lower_limit>
            <ci_upper_limit>2.44</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>mITT analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.006</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.80</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.18</ci_lower_limit>
            <ci_upper_limit>2.75</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>per protocol analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.60</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.05</ci_lower_limit>
            <ci_upper_limit>2.42</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>per protocol analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.007</p_value>
            <method>Regression, Cox</method>
            <method_desc>adjusted for age and sex at birth</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.84</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.18</ci_lower_limit>
            <ci_upper_limit>2.85</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment</title>
        <description>Percentage of participants whose sputum converts from positive to negative at Week 8 time point, on solid and liquid media.</description>
        <time_frame>8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O2">
            <title>Arm 2</title>
            <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O3">
            <title>Arm 3</title>
            <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment</title>
          <description>Percentage of participants whose sputum converts from positive to negative at Week 8 time point, on solid and liquid media.</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="56"/>
                <count group_id="O2" value="53"/>
                <count group_id="O3" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Liquid media</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="79"/>
                    <measurement group_id="O2" value="89"/>
                    <measurement group_id="O3" value="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Solid media</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="98"/>
                    <measurement group_id="O2" value="100"/>
                    <measurement group_id="O3" value="96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin</title>
        <description>AUC of PA-824 when given with either rifampicin or rifabutin to determine steady state Pharmacokinetics (PK) of PA-824.</description>
        <time_frame>pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14</time_frame>
        <population>This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O2">
            <title>Arm 2</title>
            <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
        </group_list>
        <measure>
          <title>Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin</title>
          <description>AUC of PA-824 when given with either rifampicin or rifabutin to determine steady state Pharmacokinetics (PK) of PA-824.</description>
          <population>This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3.</population>
          <units>mg*h/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
                <count group_id="O2" value="53"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.91" spread="9.87"/>
                    <measurement group_id="O2" value="59.05" spread="13.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment</title>
        <description>The Pharmacokinetic results (Cmax) of the study drug when given with a rifampin or a rifabutin.</description>
        <time_frame>pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14</time_frame>
        <population>This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
          <group group_id="O2">
            <title>Arm 2</title>
            <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
          </group>
        </group_list>
        <measure>
          <title>PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment</title>
          <description>The Pharmacokinetic results (Cmax) of the study drug when given with a rifampin or a rifabutin.</description>
          <population>This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3.</population>
          <units>mg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
                <count group_id="O2" value="53"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.03" spread="0.51"/>
                    <measurement group_id="O2" value="2.69" spread="0.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks</title>
        <description>Relationship between PA-824 exposure (AUC) and rate of change in TTP over 12 weeks, using non-linear mixed effects modeling. The data is reported as percentage increase in TTP per 10 unit increase in PA-824 AUC (% increase/10 unit increase PA-824 AUC).</description>
        <time_frame>12 weeks</time_frame>
        <population>This outcome was measured among all participants receiving study drug (PA-824), as one group.</population>
        <group_list>
          <group group_id="O1">
            <title>Arms 1 and 2 (Pretomanid-containing Arms)</title>
            <description>This is a combined measure drawn from both arms 1 and 2, in which participants received PA-824 (pretomanid)</description>
          </group>
        </group_list>
        <measure>
          <title>Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks</title>
          <description>Relationship between PA-824 exposure (AUC) and rate of change in TTP over 12 weeks, using non-linear mixed effects modeling. The data is reported as percentage increase in TTP per 10 unit increase in PA-824 AUC (% increase/10 unit increase PA-824 AUC).</description>
          <population>This outcome was measured among all participants receiving study drug (PA-824), as one group.</population>
          <units>% increase/10 unit increase PA-824 AUC</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="109"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.4" lower_limit="4.4" upper_limit="15.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Arm 1</title>
          <description>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
        <group group_id="E2">
          <title>Arm 2</title>
          <description>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
PA-824: 200 mg QD&#xD;
Rifabutin: 300 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Isoniazid: 300 mg QD</description>
        </group>
        <group group_id="E3">
          <title>Arm 3</title>
          <description>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks&#xD;
Rifampin: 600 mg QD&#xD;
Pyrazinamide: 25mg/kg QD&#xD;
Ethambutol: 15mg/kg QD&#xD;
Isoniazid: 300 mg QD</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="0" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Increased liver enzymes</sub_title>
                <assessment>Systematic Assessment</assessment>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Pleuritic chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Hemoptysis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </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="3" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Low hemoglobin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Increased blood pressure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Drug induced liver injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="53"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="48"/>
              </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>
    <point_of_contact>
      <name_or_title>Dr. Kelly Dooley</name_or_title>
      <organization>Vanderbilt University</organization>
      <phone>(615) 322-8972</phone>
      <email>kelly.e.dooley@vumc.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02256696
org study id: NA_00093014
secondary id: #FD-R-004794-01
nct id: NCT02256696
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Assess the mycobactericidal activity of PA-824 (given at 200 mg daily) when added to
      first-line tuberculosis (TB) treatment (isoniazid, pyrazinamide, and a rifamycin antibiotic)
      over 12 weeks of treatment. Funding Source - FDA Office of Orphan Products Development (OOPD)
Phase IIB, 12-week, open-label, single-site, randomized clinical trial with three treatment
      groups. Patients with drug-sensitive TB will all receive once daily isoniazid and
      pyrazinamide for 8 weeks followed by 4 weeks of daily isoniazid. In addition, Arm 1
      participants will receive PA-824 200 mg daily and rifampin 600 mg daily for 12 weeks. Arm 2
      participants will receive PA-824 200 mg daily and rifabutin 300 mg daily for 12 weeks. Arm 3
      participants (control group) will receive rifampin for 12 weeks and ethambutol for 8 weeks.
      Patients will be screened within 1 week of TB diagnosis, will receive 12 weeks of study
      treatment and will return for follow-up visits at 4, 12, and 36 weeks after study treatment
      completion. All patients will be referred to the local TB treatment program after completion
      of study treatment to finish their 24-week TB treatment course.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Time to Sputum Culture Conversion on Liquid Medium
time frame: 12 weeks
description: The time (days) it takes for the sputum to convert from positive to negative.
measure: Number of Participants With Grade 3 or Higher Adverse Events
time frame: 12 weeks
description: Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table
measure: Number of Participants With Permanent Discontinuation of Assigned Study Regimen
time frame: 12 weeks
description: If it is in the best interest of a participant to stop the study regimen for any reason
measure: Time to Culture Conversion on Solid Medium
time frame: 12 weeks
description: The time (days) it takes for the sputum to convert form positive to negative on solid medium
measure: Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment
time frame: 8 weeks
description: Percentage of participants whose sputum converts from positive to negative at Week 8 time point, on solid and liquid media.
measure: Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin
time frame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
description: AUC of PA-824 when given with either rifampicin or rifabutin to determine steady state Pharmacokinetics (PK) of PA-824.
measure: PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment
time frame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
description: The Pharmacokinetic results (Cmax) of the study drug when given with a rifampin or a rifabutin.
measure: Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks
time frame: 12 weeks
description: Relationship between PA-824 exposure (AUC) and rate of change in TTP over 12 weeks, using non-linear mixed effects modeling. The data is reported as percentage increase in TTP per 10 unit increase in PA-824 AUC (% increase/10 unit increase PA-824 AUC).
arm group label: Arm 1
arm group type: Experimental
description: PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
arm group label: Arm 2
arm group type: Experimental
description: PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
arm group label: Arm 3
arm group type: Active Comparator
description: Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
intervention type: Drug
intervention name: PA-824
description: 200 mg QD
arm group label: Arm 1
arm group label: Arm 2
other name: Pretomanid
intervention type: Drug
intervention name: Rifampin
description: 600 mg QD
arm group label: Arm 1
arm group label: Arm 3
intervention type: Drug
intervention name: Rifabutin
description: 300 mg QD
arm group label: Arm 2
intervention type: Drug
intervention name: Pyrazinamide
description: 25mg/kg QD
arm group label: Arm 1
arm group label: Arm 2
arm group label: Arm 3
intervention type: Drug
intervention name: Ethambutol
description: 15mg/kg QD
arm group label: Arm 3
intervention type: Drug
intervention name: Isoniazid
description: 300 mg QD
arm group label: Arm 1
arm group label: Arm 2
arm group label: Arm 3
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kelly E Dooley, MD PhD
role: Principal Investigator
affiliation: Johns Hopkins University
facility: 
country: South Africa
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Tuberculosis, Pulmonary
mesh term: Rifampin
mesh term: Rifabutin
mesh term: Isoniazid
mesh term: Pyrazinamide
mesh term: Ethambutol
sharing ipd: Yes
ipd description: This plan is in process, to be finalized prior to the end of recruitment.
ipd time frame: Within one year of reaching recruitment goals.
ipd access criteria: This plan is in process, to be finalized prior to the end of recruitment.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 