<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/NCT02193776</url>
  </required_header>
  <id_info>
    <org_study_id>NC-005-(J-M-Pa-Z)</org_study_id>
    <nct_id>NCT02193776</nct_id>
  </id_info>
  <brief_title>A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis.</brief_title>
  <acronym>NC-005</acronym>
  <official_title>A Phase 2 Open-Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide During 8 Weeks of Treatment in Adult Subjects With Newly Diagnosed Drug-Sensitive or Multi Drug-Resistant, Smear-Positive Pulmonary Tuberculosis.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Global Alliance for TB Drug Development</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Global Alliance for TB Drug Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the mycobactericidal activity of combinations of&#xD;
      bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks&#xD;
      of treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The trial design is a phase 2, multi-center, open-label, partially randomized clinical trial&#xD;
      in four parallel treatment groups. Subjects with drug-sensitive tuberculosis (DS-TB) will be&#xD;
      randomized to receive either J(loading dose/three times a week)PaZ; or J(200mg)PaZ; or HRZE.&#xD;
      Subjects with multi drug-resistant tuberculosis will receive J(200mg)MPaZ. The HRZE treatment&#xD;
      arm is included as a control for the drug-sensitive treatments and as a control for the&#xD;
      quantitative laboratory mycobacteriology testing.&#xD;
&#xD;
      A total of approximately 240 male and female, newly diagnosed subjects with drug-sensitive or&#xD;
      multi drug-resistant, smear positive pulmonary tuberculosis aged 18 to 75 years (inclusive)&#xD;
      will be included in the study. A total of 180 subjects with drug-sensitive tuberculosis (60&#xD;
      per treatment arm) will be randomized. Up to 60 subjects with multi-drug resistant&#xD;
      tuberculosis will be assigned.&#xD;
&#xD;
      All subjects will have up to a maximum of 9 days screening, receive 8 weeks of treatment, and&#xD;
      have follow-up visits at 2 and 12 weeks after study treatment completion or last dose of&#xD;
      investigational medicinal product in the case of early withdrawal. Subjects who withdraw from&#xD;
      the study after receiving &lt; 14 days of investigational medicinal product, will only attend a&#xD;
      follow-up visit at 2 weeks after last dose of investigational medicinal product.&#xD;
&#xD;
      Upon treatment completion, the subjects with drug-sensitive tuberculosis will be provided&#xD;
      with sufficient doses of standard of care tuberculosis treatment, as appropriate, to cover&#xD;
      the time period from attending their last visit at the study clinic until their scheduled&#xD;
      visit at the TB clinic. All subjects with drug sensitive and multi-drug resistant&#xD;
      tuberculosis will be referred to the local community tuberculosis clinics for standard&#xD;
      anti-tuberculosis chemotherapy according to National Tuberculosis Guidelines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 23, 2014</start_date>
  <completion_date type="Actual">February 7, 2018</completion_date>
  <primary_completion_date type="Actual">February 8, 2016</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>Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System</measure>
    <time_frame>Day 0 to Day 56 (8 weeks)</time_frame>
    <description>The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP[0-56]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment Emergent Adverse Events (TEAEs)</measure>
    <time_frame>First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days)</time_frame>
    <description>A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">240</enrollment>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>DS-TB: J(loading dose/t.i.w.)PaZ</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects with DS-TB. J(loading dose/t.i.w.)PaZ: Bedaquiline 400mg once daily Days 1-14, 200mg three times per week Days 15-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DS-TB: J(200mg)PaZ</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects with DS-TB. J(200mg)PaZ: Bedaquiline 200mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MDR-TB: J(200mg)MPaZ</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects with MDR-TB. J(200mg)MPaZ: Bedaquiline 200mg once daily Days 1-56; plus moxifloxacin 400mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DS-TB: HRZE</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects with DS-TB. HRZE tablets (Isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 400mg plus ethambutol 275mg combination tablets) dosed once daily Days 1-56 per the Subject's weight as follows: 30-37kg: 2 tablets; 38-54kg: 3 tablets; 55-70kg: 4 tablets; 71kg and over: 5 tablets.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PA-824</intervention_name>
    <description>oral</description>
    <arm_group_label>DS-TB: J(200mg)PaZ</arm_group_label>
    <arm_group_label>DS-TB: J(loading dose/t.i.w.)PaZ</arm_group_label>
    <arm_group_label>MDR-TB: J(200mg)MPaZ</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>bedaquiline</intervention_name>
    <description>oral</description>
    <arm_group_label>DS-TB: J(200mg)PaZ</arm_group_label>
    <arm_group_label>DS-TB: J(loading dose/t.i.w.)PaZ</arm_group_label>
    <arm_group_label>MDR-TB: J(200mg)MPaZ</arm_group_label>
    <other_name>TMC207</other_name>
    <other_name>Sirturo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>moxifloxacin</intervention_name>
    <description>oral</description>
    <arm_group_label>MDR-TB: J(200mg)MPaZ</arm_group_label>
    <other_name>BAY 12-8039</other_name>
    <other_name>Avelox</other_name>
    <other_name>Avalon</other_name>
    <other_name>Avelon</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>pyrazinamide</intervention_name>
    <description>oral</description>
    <arm_group_label>DS-TB: J(200mg)PaZ</arm_group_label>
    <arm_group_label>DS-TB: J(loading dose/t.i.w.)PaZ</arm_group_label>
    <arm_group_label>MDR-TB: J(200mg)MPaZ</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet</intervention_name>
    <description>oral</description>
    <arm_group_label>DS-TB: HRZE</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provide written, informed consent prior to all trial-related procedures. Male or&#xD;
             female, aged between 18 and 75 years inclusive.&#xD;
&#xD;
          2. Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.&#xD;
&#xD;
          3. Tested at the trial appointed laboratory: M. Tb positive on molecular test (e.g.&#xD;
             GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for&#xD;
             acid-fast bacilli (at least 1+ on the IUATLD/WHO scale.&#xD;
&#xD;
               -  For DS-TB treatment arms (defined as sensitive to rifampicin based on molecular&#xD;
                  sensitivity testing), Subjects should be:&#xD;
&#xD;
                    1. either newly diagnosed or untreated for at least 3 years after cure from a&#xD;
                       previous episode (Subject can give a history of cure and previous&#xD;
                       treatment); AND&#xD;
&#xD;
                    2. Previous TB treatment must be discontinued as per exclusion criteria 16.&#xD;
&#xD;
               -  For MDR-TB treatment arm (defined as resistant to rifampicin based on molecular&#xD;
                  sensitivity testing), Subjects should be:&#xD;
&#xD;
                    1. sensitive to moxifloxacin by molecular sensitivity testing; AND&#xD;
&#xD;
                    2. either newly diagnosed or could have previously been treated for DS-TB&#xD;
                       and/or MDR-TB (&lt; 7 days of treatment). Previous MDR-TB treatment must be&#xD;
                       discontinued as per exclusion criteria 17.&#xD;
&#xD;
          4. A chest X-ray picture which in the opinion of the Investigator is compatible with TB.&#xD;
&#xD;
          5. Ability to produce an adequate volume of sputum as estimated from a screening Coached&#xD;
             Spot Sputum Sample assessment (estimated 10 ml or more overnight production).&#xD;
&#xD;
          6. Be of non-childbearing potential or using effective methods of birth control, as&#xD;
             defined below:&#xD;
&#xD;
        Non-childbearing potential:&#xD;
&#xD;
          1. Subject - not heterosexually active or practices sexual abstinence; or&#xD;
&#xD;
          2. Female Subject/sexual partner - bilateral oophorectomy, bilateral tubal ligation&#xD;
             and/or hysterectomy or has been postmenopausal with a history of no menses for at&#xD;
             least 12 consecutive months; or&#xD;
&#xD;
          3. Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy&#xD;
             minimally three months prior to screening.&#xD;
&#xD;
        Effective birth control methods:&#xD;
&#xD;
        A double contraceptive method should be used as follows:&#xD;
&#xD;
          1. Double barrier method which can include any 2 of the following: a male condom,&#xD;
             diaphragm, cervical cap, or female condom (male and female condoms should not be used&#xD;
             together); or&#xD;
&#xD;
          2. Barrier method (one of the above) combined with hormone-based contraceptives or an&#xD;
             intra-uterine device for the female Subject/partner; and are willing to continue&#xD;
             practicing birth control methods throughout treatment and for 6 months (both male and&#xD;
             female Subjects) after the last dose of study medication or discontinuation from study&#xD;
             medication in case of premature discontinuation.&#xD;
&#xD;
        (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore,&#xD;
        hormone-based contraceptives alone cannot be used by female Subjects or female partners of&#xD;
        male Subjects to prevent pregnancy).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Medical Criteria&#xD;
&#xD;
          1. Evidence of clinically significant (as judged by the Investigator), metabolic,&#xD;
             gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary,&#xD;
             neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities&#xD;
             (other than the indication being studied) including malaria. A rapid test for malaria&#xD;
             may be carried out if indicated.&#xD;
&#xD;
          2. Karnofsky performance status score of &lt; 60%.&#xD;
&#xD;
          3. Poor general condition where any delay in treatment cannot be tolerated per discretion&#xD;
             of the Investigator.&#xD;
&#xD;
          4. Clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB,&#xD;
             urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.&#xD;
&#xD;
          5. History of allergy or hypersensitivity to any of the study Investigational Medicinal&#xD;
             Products or related substances.&#xD;
&#xD;
          6. Known or suspected current alcohol and/or drug abuse (positive urine drug screen) or&#xD;
             history thereof within the past 2 years that is, in the opinion of the Investigator,&#xD;
             sufficient to compromise the safety and/or cooperation of the Subject.&#xD;
&#xD;
          7. For HIV infected Subjects:&#xD;
&#xD;
               1. having a CD4+ count &lt;100 cells/µL;&#xD;
&#xD;
               2. with an AIDS-defining opportunistic infection or malignancies (except pulmonary&#xD;
                  TB);&#xD;
&#xD;
               3. currently treated with or will need to initiate antiretroviral therapy (ART)&#xD;
                  which is not compatible with the allowed ARTs and is not considered an&#xD;
                  appropriate candidate for switching to a regimen of ARVs which is allowed as&#xD;
                  follows:&#xD;
&#xD;
                    -  Triple nucleoside reverse transcriptase inhibitor (NRTI) based regimen&#xD;
                       consisting of zidovudine, lamivudine, and abacavir;&#xD;
&#xD;
                    -  Nevirapine based regimen consisting of nevirapine in combination with any&#xD;
                       NRTIs;&#xD;
&#xD;
                    -  Lopinavir/ritonavir (Aluvia™) based regimen consisting of&#xD;
                       lopinavir/ritonavir (Aluvia™) in combination with any NRTIs;&#xD;
&#xD;
                    -  Raltegravir in combination with nucleoside reverse transcriptase inhibitors&#xD;
                       (NRTIs);&#xD;
&#xD;
               4. cannot ensure a 2 week interval between commencing IMP and the start of ART.&#xD;
&#xD;
          8. Having participated in other clinical study/ies with investigational agent/s within 8&#xD;
             weeks prior to trial start.&#xD;
&#xD;
          9. Significant cardiac arrhythmia requiring medication.&#xD;
&#xD;
         10. Subjects with the following at screening (per measurements and reading done by Central&#xD;
             ECG):&#xD;
&#xD;
               1. Marked prolongation of QT/QTc interval, e.g. confirmed demonstration of QTcF&#xD;
                  (Fridericia correction) or QTcB (Bazett correction) interval &gt;450 ms at&#xD;
                  screening;&#xD;
&#xD;
               2. History of additional risk factors for Torsade de Pointes, e.g. heart failure,&#xD;
                  hypokalemia, family history of Long QT Syndrome;&#xD;
&#xD;
               3. Use of concomitant medications that are known to prolong the QT/QTc interval (see&#xD;
                  exclusion criteria 19);&#xD;
&#xD;
               4. Any clinically significant, in the opinion of the Investigator, ECG abnormality.&#xD;
&#xD;
         11. Females who are pregnant, breast-feeding, or planning to conceive a child during the&#xD;
             study or within 6 months of cessation of treatment. Males planning to conceive a child&#xD;
             during the study or within 6 months of cessation of treatment.&#xD;
&#xD;
         12. Diabetes Mellitus resulting in hospitalization in the past year.&#xD;
&#xD;
         13. Evidence of lens opacity on slit lamp ophthalmologic examination as defined by a&#xD;
             grading of &gt;1+ on the AREDS2 grading system.&#xD;
&#xD;
         14. For males, any history of a clinically significant abnormality in the reproductive&#xD;
             system.&#xD;
&#xD;
             Specific Treatments&#xD;
&#xD;
         15. Previously received treatment with PA-824, bedaquiline or moxifloxacin as part of a&#xD;
             clinical trial.&#xD;
&#xD;
         16. For the DS-TB treatment arms: treatment with any drug active against M. Tb within the&#xD;
             3 years prior to Day 1 (including but not limited to isoniazid, ethambutol, amikacin,&#xD;
             bedaquiline, clofazimine, cycloserine, fluoroquinolones, rifabutin, rifampicin,&#xD;
             streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide,&#xD;
             thioacetazone, capreomycin, thioamides, metronidazole). Exceptions include the use of&#xD;
             fluoroquinolones and metronidazole as short-term treatment (≤2 weeks) for Non-M.Tb&#xD;
             infections. Treatment should have been discontinued at least 3 months prior to Day 1.&#xD;
             Subjects who have previously received isoniazid prophylactically may be included in&#xD;
             the trial as long as that treatment is/was discontinued at least 7 days prior to&#xD;
             randomization into this trial.&#xD;
&#xD;
         17. MDR-TB Subjects may have previously been treated for DS-TB with first-line TB drugs&#xD;
             (isoniazid, rifampicin, ethambutol, pyrazinamide and/or streptomycin) and/or received&#xD;
             ≤7 days MDR-TB treatment, provided that treatment is/was discontinued at least 7 days&#xD;
             prior to randomization. It should be confirmed that the MDR-TB treatment can be safely&#xD;
             stopped and the screening period is long enough to allow for a washout period of 5&#xD;
             times the longest half-life of the drugs.&#xD;
&#xD;
         18. Any diseases or conditions in which the use of the standard TB drugs or any of their&#xD;
             components is contra-indicated, including but not limited to acute gout, allergy to&#xD;
             any TB drug, their component or to the IMP.&#xD;
&#xD;
         19. Use of any drug within 30 days prior to dosing known to prolong QTc interval&#xD;
             (including but not limited to amiodarone, bepridil, chloroquine, chlorpromazine,&#xD;
             cisapride, cyclobenzaprine, clarithromycin, disopyramide dofetilide, domperidone,&#xD;
             droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl,&#xD;
             mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol,&#xD;
             sparfloxacin, thioridazine). Exceptions may be made for Subjects that have received 3&#xD;
             days or less of one of these drugs or substances, if there has been a wash-out period&#xD;
             before administration of IMP equivalent to at least 5 half-lives of that drug or&#xD;
             substance. Subjects who have taken drugs with long elimination half-lives such as&#xD;
             amiodarone should be discussed with the Sponsor.&#xD;
&#xD;
         20. Use of any drugs or substances within 30 days prior to dosing known to be strong&#xD;
             inhibitors or inducers of cytochrome P450 enzymes (including but not limited to&#xD;
             quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene,&#xD;
             metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin,&#xD;
             cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may be made for&#xD;
             Subjects that have received 3 days or less of one of these drugs or substances, if&#xD;
             there has been a wash-out period before administration of IMP equivalent to at least 5&#xD;
             half-lives of that drug or substance.&#xD;
&#xD;
         21. Any ARVs other than allowable ARVs detailed in exclusion criteria no. 7 above.&#xD;
&#xD;
             Based on Laboratory Abnormalities:&#xD;
&#xD;
         22. Subjects with the following toxicities at screening as defined by the enhanced&#xD;
             Division of Microbiology and Infectious Disease (DMID) adult toxicity table:&#xD;
&#xD;
               1. serum magnesium and calcium (corrected for albumin) levels outside of the&#xD;
                  laboratory's reference range&#xD;
&#xD;
               2. lipase grade 3 or greater (&gt;2.0 x ULN);&#xD;
&#xD;
               3. creatinine grade 2 or greater (&gt;1.5 x ULN);&#xD;
&#xD;
               4. hemoglobin grade 4 (&lt;6.5 g/dL);&#xD;
&#xD;
               5. platelets &gt; grade 2 (under 50x10(9) cells/L);&#xD;
&#xD;
               6. serum potassium less than the lower limit of normal for the laboratory;&#xD;
&#xD;
               7. aspartate aminotransferase (AST) grade 3 or greater (≥3.0 x ULN) to be excluded;&#xD;
&#xD;
               8. alanine aminotransferase (ALT) grade 3 or greater (≥3.0 x ULN) to be excluded;&#xD;
&#xD;
               9. alkaline phosphatase (ALP) grade 4 (&gt;8.0 x ULN) to be excluded, grade 3 (≥3.0 -&#xD;
                  8.0 x ULN) must be discussed with and approved by the Sponsor Medical Monitor;&#xD;
&#xD;
              10. total bilirubin grade 3 or greater (≥2.0 x ULN, or ≥1.50 x ULN when accompanied&#xD;
                  by any increase in other liver function test) to be excluded, grade 2 (≥1.50 x&#xD;
                  ULN, or ≥1.25 x ULN when accompanied by any increase in other liver function&#xD;
                  test) must be discussed with and approved by the Sponsor Medical Monitor&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rodney Dawson</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Cape Town Lung Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Aurum Institute: Tembisa Hospital</name>
      <address>
        <city>Tembisa</city>
        <state>Gauteng</state>
        <zip>1632</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klerksdorp Tshepong Hospital</name>
      <address>
        <city>Jouberton</city>
        <state>Klerksdorp</state>
        <zip>2570</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>TASK Applied Science</name>
      <address>
        <city>Cape Town</city>
        <zip>7531</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Cape Town Lung Institute (Pty) Ltd</name>
      <address>
        <city>Cape Town</city>
        <zip>7937</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>THINK: Tuberculosis &amp; HIV Investigative Network of KwaZulu-Natal</name>
      <address>
        <city>Durban</city>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU Themba Lethu Clinic</name>
      <address>
        <city>Johannesburg</city>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Witwatersrand, Clinical HIV Research Unit (CHRU), Helen Joseph Hospital</name>
      <address>
        <city>Johannesburg</city>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ifakara Health Institute</name>
      <address>
        <city>Bagamoyo</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NIMR-Mbeya Medical Research Centre (MMRC)</name>
      <address>
        <city>Mbeya</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uganda Case Western Reserve University Research Collaboration</name>
      <address>
        <city>Kampala</city>
        <country>Uganda</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
    <country>Tanzania</country>
    <country>Uganda</country>
  </location_countries>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>July 16, 2014</study_first_submitted>
  <study_first_submitted_qc>July 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 18, 2014</study_first_posted>
  <results_first_submitted>February 22, 2019</results_first_submitted>
  <results_first_submitted_qc>May 28, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">July 26, 2019</results_first_posted>
  <last_update_submitted>May 28, 2019</last_update_submitted>
  <last_update_submitted_qc>May 28, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tuberculosis</keyword>
  <keyword>Multi Drug-Resistant Tuberculosis</keyword>
  <keyword>Drug-Sensitive Tuberculosis</keyword>
  <keyword>PA-824</keyword>
  <keyword>Bedaquiline</keyword>
  <keyword>Moxifloxacin</keyword>
  <keyword>Pyrazinamide</keyword>
  <keyword>Quinolone</keyword>
  <keyword>Pretomanid</keyword>
  <keyword>NC-005</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Pulmonary</mesh_term>
    <mesh_term>Hypersensitivity</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Moxifloxacin</mesh_term>
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Isoniazid</mesh_term>
    <mesh_term>Pyrazinamide</mesh_term>
    <mesh_term>Ethambutol</mesh_term>
    <mesh_term>Bedaquiline</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 19, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/76/NCT02193776/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 14, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/76/NCT02193776/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This trial was conducted at 10 centers in 3 countries (South Africa, Tanzania, and Uganda) from 23 October 2014. Adult male and female participants with drug-sensitive (DS) or multi-drug resistant (MDR) smear-positive pulmonary tuberculosis (TB) were recruited into this open-label multi-center study.</recruitment_details>
      <pre_assignment_details>Participants were confirmed positive for M.tuberculosis on molecular test. DS-TB participants were to be sensitive to rifampicin and newly diagnosed with pulmonary TB (or untreated for at least 3 years). MDR-TB participants were to be resistant to rifampicin, sensitive to moxifloxacin and newly diagnosed with pulmonary TB (or treated for &lt;=7 days).</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide</title>
          <description>Participants with DS-TB were randomized to receive 400 milligrams (mg) bedaquiline once daily on Days 1 to 14, 200 mg three times a week (t.i.w) during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="P2">
          <title>DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide</title>
          <description>Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="P3">
          <title>DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol)</title>
          <description>Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kilograms (kg): 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="P4">
          <title>MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide</title>
          <description>Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="59"/>
                <participants group_id="P2" count="60"/>
                <participants group_id="P3" count="61"/>
                <participants group_id="P4" count="60"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Completed Day 70 Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="54"/>
                <participants group_id="P2" count="56"/>
                <participants group_id="P3" count="60"/>
                <participants group_id="P4" count="60"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Completed Day 140 Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="52"/>
                <participants group_id="P2" count="52"/>
                <participants group_id="P3" count="58"/>
                <participants group_id="P4" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="51"/>
                <participants group_id="P2" count="53"/>
                <participants group_id="P3" count="59"/>
                <participants group_id="P4" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Consent withdrawn</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Failure to comply with protocol</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Investigator/Sponsor decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse event/Specific toxicity</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The safety analysis population included all participants who were randomized (for the DS participant population) or assigned (for the MDR participant population) to study drug and who received at least 1 administration of study drug.</population>
      <group_list>
        <group group_id="B1">
          <title>DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide</title>
          <description>Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="B2">
          <title>DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide</title>
          <description>Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="B3">
          <title>DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol)</title>
          <description>Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="B4">
          <title>MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide</title>
          <description>Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="B5">
          <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="59"/>
            <count group_id="B2" value="60"/>
            <count group_id="B3" value="61"/>
            <count group_id="B4" value="60"/>
            <count group_id="B5" value="240"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="35.1" spread="13.03"/>
                    <measurement group_id="B2" value="33.9" spread="10.45"/>
                    <measurement group_id="B3" value="33.3" spread="8.60"/>
                    <measurement group_id="B4" value="34.0" spread="12.68"/>
                    <measurement group_id="B5" value="34.1" spread="11.26"/>
                  </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="14"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="17"/>
                    <measurement group_id="B5" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="46"/>
                    <measurement group_id="B4" value="43"/>
                    <measurement group_id="B5" value="182"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="49"/>
                    <measurement group_id="B3" value="49"/>
                    <measurement group_id="B4" value="53"/>
                    <measurement group_id="B5" value="197"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="5"/>
                    <measurement group_id="B5" value="41"/>
                  </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 group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System</title>
        <description>The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP[0-56]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).</description>
        <time_frame>Day 0 to Day 56 (8 weeks)</time_frame>
        <population>The modified intention-to-treat analysis population included all participants included in the safety analysis population for whom valid corresponding efficacy data were available. Pyrazinamide resistant participants were excluded from this analysis population (applicable to both participants with DS-TB and MDR-TB).</population>
        <group_list>
          <group group_id="O1">
            <title>DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide</title>
            <description>Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
          </group>
          <group group_id="O2">
            <title>DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide</title>
            <description>Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
          </group>
          <group group_id="O3">
            <title>DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol)</title>
            <description>Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.</description>
          </group>
          <group group_id="O4">
            <title>MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide</title>
            <description>Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System</title>
          <description>The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP[0-56]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).</description>
          <population>The modified intention-to-treat analysis population included all participants included in the safety analysis population for whom valid corresponding efficacy data were available. Pyrazinamide resistant participants were excluded from this analysis population (applicable to both participants with DS-TB and MDR-TB).</population>
          <units>percentage change in TTP/day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="57"/>
                <count group_id="O2" value="56"/>
                <count group_id="O3" value="59"/>
                <count group_id="O4" value="37"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.878" spread="1.604"/>
                    <measurement group_id="O2" value="5.182" spread="1.466"/>
                    <measurement group_id="O3" value="4.046" spread="1.129"/>
                    <measurement group_id="O4" value="5.194" spread="1.068"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment Emergent Adverse Events (TEAEs)</title>
        <description>A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively.</description>
        <time_frame>First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days)</time_frame>
        <population>The safety analysis population included all participants who were randomized (for the DS participant population) or assigned (for the MDR participant population) to study drug and received at least 1 administration of study drug.</population>
        <group_list>
          <group group_id="O1">
            <title>DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide</title>
            <description>Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
          </group>
          <group group_id="O2">
            <title>DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide</title>
            <description>Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
          </group>
          <group group_id="O3">
            <title>DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol)</title>
            <description>Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.</description>
          </group>
          <group group_id="O4">
            <title>MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide</title>
            <description>Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment Emergent Adverse Events (TEAEs)</title>
          <description>A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively.</description>
          <population>The safety analysis population included all participants who were randomized (for the DS participant population) or assigned (for the MDR participant population) to study drug and received at least 1 administration of study drug.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="59"/>
                <count group_id="O2" value="60"/>
                <count group_id="O3" value="61"/>
                <count group_id="O4" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50"/>
                    <measurement group_id="O2" value="45"/>
                    <measurement group_id="O3" value="44"/>
                    <measurement group_id="O4" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Drug-related TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38"/>
                    <measurement group_id="O2" value="29"/>
                    <measurement group_id="O3" value="29"/>
                    <measurement group_id="O4" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEAE leading to death</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any serious TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Drug-related serious TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEAE leading to discontinuation of study drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEAE leading to early withdrawal from study</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade III TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="17"/>
                    <measurement group_id="O3" value="14"/>
                    <measurement group_id="O4" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade IV TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="7"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>TEAEs were collected from first study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days).</time_frame>
      <desc>The safety analysis population included all participants who were randomized (for the DS participant population) or assigned (for the MDR participant population) to study drug and received at least 1 administration of study drug. All-cause mortality is defined as death due to any cause for entire duration of study.</desc>
      <group_list>
        <group group_id="E1">
          <title>DS-TB: Bedaquiline (Loading Dose/t.i.w)+ PA-824 + Pyrazinamide</title>
          <description>Participants with DS-TB were randomized to receive 400 mg bedaquiline once daily on Days 1 to 14, 200 mg t.i.w during Days 15 to 56 + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="E2">
          <title>DS-TB: Bedaquiline (200 mg) + PA-824 + Pyrazinamide</title>
          <description>Participants with DS-TB were randomized to receive 200 mg bedaquiline + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="E3">
          <title>DS-TB: HRZE (Isoniazid+Rifampicin+Pyrazinamide+Ethambutol)</title>
          <description>Participants with DS-TB were randomized to receive combination tablets containing 75 mg isoniazid + 150 mg rifampicin + 400 mg pyrazinamide + 275 mg ethambutol orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8) with the daily dose per the participant's weight as follows: 30 to 37 kg: 2 tablets; 38 to 54 kg: 3 tablets; 55 to 70 kg: 4 tablets; 71 kg and over: 5 tablets. Participants then entered a follow-up period up to Month 26.</description>
        </group>
        <group group_id="E4">
          <title>MDR-TB: Bedaquiline (200 mg)+Moxifloxacin+PA-824+Pyrazinamide</title>
          <description>Participants with MDR-TB received 200 mg bedaquiline + 400 mg moxifloxacin + 200 mg pretomanid (PA-824) + 1500 mg pyrazinamide orally once daily on Days 1 to 56 during the treatment period (from Day 1 to Week 8). Participants then entered a follow-up period up to Month 26.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (17.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Pericardial effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </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="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Acute hepatic failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Bronchopneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Malaria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pulmonary tuberculosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal failure acute</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Haemoptysis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pneumothorax spontaneous</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pulmonary artery aneurysm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pulmonary oedema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (17.1)</default_vocab>
        <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="50" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="45" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="44" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="57" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="7" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Vulvovaginal candidiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood uric acid increased</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="27" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="10" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="13" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Haemoptysis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pleuritic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus generalised</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="59"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="61"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="60"/>
              </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>The Investigator or any Sub-Investigator shall submit any oral or written publication or abstract concerning this study to the Sponsor not less than thirty (30) days prior to submission to any journal, other publication or meeting for review and removal of confidential information.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Almari Conradie, Director, Clinical Operations</name_or_title>
      <organization>TB Alliance</organization>
      <phone>+27 12 991 6328</phone>
      <email>almari.conradie@tballiance.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/NCT02193776
org study id: NC-005-(J-M-Pa-Z)
nct id: NCT02193776
lead sponsor: 
has dmc: Yes
The purpose of this study is to determine the mycobactericidal activity of combinations of
      bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks
      of treatment.
The trial design is a phase 2, multi-center, open-label, partially randomized clinical trial
      in four parallel treatment groups. Subjects with drug-sensitive tuberculosis (DS-TB) will be
      randomized to receive either J(loading dose/three times a week)PaZ; or J(200mg)PaZ; or HRZE.
      Subjects with multi drug-resistant tuberculosis will receive J(200mg)MPaZ. The HRZE treatment
      arm is included as a control for the drug-sensitive treatments and as a control for the
      quantitative laboratory mycobacteriology testing.

      A total of approximately 240 male and female, newly diagnosed subjects with drug-sensitive or
      multi drug-resistant, smear positive pulmonary tuberculosis aged 18 to 75 years (inclusive)
      will be included in the study. A total of 180 subjects with drug-sensitive tuberculosis (60
      per treatment arm) will be randomized. Up to 60 subjects with multi-drug resistant
      tuberculosis will be assigned.

      All subjects will have up to a maximum of 9 days screening, receive 8 weeks of treatment, and
      have follow-up visits at 2 and 12 weeks after study treatment completion or last dose of
      investigational medicinal product in the case of early withdrawal. Subjects who withdraw from
      the study after receiving < 14 days of investigational medicinal product, will only attend a
      follow-up visit at 2 weeks after last dose of investigational medicinal product.

      Upon treatment completion, the subjects with drug-sensitive tuberculosis will be provided
      with sufficient doses of standard of care tuberculosis treatment, as appropriate, to cover
      the time period from attending their last visit at the study clinic until their scheduled
      visit at the TB clinic. All subjects with drug sensitive and multi-drug resistant
      tuberculosis will be referred to the local community tuberculosis clinics for standard
      anti-tuberculosis chemotherapy according to National Tuberculosis Guidelines.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System
time frame: Day 0 to Day 56 (8 weeks)
description: The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP[0-56]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
time frame: First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days)
description: A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively.
arm group label: DS-TB: J(loading dose/t.i.w.)PaZ
arm group type: Experimental
description: Subjects with DS-TB. J(loading dose/t.i.w.)PaZ: Bedaquiline 400mg once daily Days 1-14, 200mg three times per week Days 15-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
arm group label: DS-TB: J(200mg)PaZ
arm group type: Experimental
description: Subjects with DS-TB. J(200mg)PaZ: Bedaquiline 200mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
arm group label: MDR-TB: J(200mg)MPaZ
arm group type: Experimental
description: Subjects with MDR-TB. J(200mg)MPaZ: Bedaquiline 200mg once daily Days 1-56; plus moxifloxacin 400mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
arm group label: DS-TB: HRZE
arm group type: Active Comparator
description: Subjects with DS-TB. HRZE tablets (Isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 400mg plus ethambutol 275mg combination tablets) dosed once daily Days 1-56 per the Subject's weight as follows: 30-37kg: 2 tablets; 38-54kg: 3 tablets; 55-70kg: 4 tablets; 71kg and over: 5 tablets.
intervention type: Drug
intervention name: PA-824
description: oral
arm group label: DS-TB: J(200mg)PaZ
arm group label: DS-TB: J(loading dose/t.i.w.)PaZ
arm group label: MDR-TB: J(200mg)MPaZ
intervention type: Drug
intervention name: bedaquiline
description: oral
arm group label: DS-TB: J(200mg)PaZ
arm group label: DS-TB: J(loading dose/t.i.w.)PaZ
arm group label: MDR-TB: J(200mg)MPaZ
other name: TMC207
other name: Sirturo
intervention type: Drug
intervention name: moxifloxacin
description: oral
arm group label: MDR-TB: J(200mg)MPaZ
other name: BAY 12-8039
other name: Avelox
other name: Avalon
other name: Avelon
intervention type: Drug
intervention name: pyrazinamide
description: oral
arm group label: DS-TB: J(200mg)PaZ
arm group label: DS-TB: J(loading dose/t.i.w.)PaZ
arm group label: MDR-TB: J(200mg)MPaZ
intervention type: Drug
intervention name: isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet
description: oral
arm group label: DS-TB: HRZE
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Rodney Dawson
role: Principal Investigator
affiliation: University of Cape Town Lung Institute
facility: 
facility: 
facility: 
facility: 
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facility: 
country: South Africa
country: Tanzania
country: Uganda
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Tuberculosis, Pulmonary
mesh term: Hypersensitivity
mesh term: Moxifloxacin
mesh term: Rifampin
mesh term: Isoniazid
mesh term: Pyrazinamide
mesh term: Ethambutol
mesh term: Bedaquiline
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 