<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/NCT02975570</url>
  </required_header>
  <id_info>
    <org_study_id>H-36160</org_study_id>
    <nct_id>NCT02975570</nct_id>
  </id_info>
  <brief_title>Efficacy and Tolerability of Delamanid, Linezolid, Pyrazinamide and Levofloxacin</brief_title>
  <acronym>DAZZLE</acronym>
  <official_title>Prospective, Randomized, Open Label Phase 3 Study of the Efficacy and Tolerability of Delamanid, Linezolid, Pyrazinamide and Levofloxacin for Treatment of Patients With Fluoroquinolone-susceptible Multidrugresistant--Tuberculosis (MDR-TB)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boston University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Westat</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Boston University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The proposed study will randomize adults (18 years of age or older) with pulmonary MDR-TB&#xD;
      with sputum that contains M. tuberculosis that is isoniazid and rifampin resistant by&#xD;
      MTBDRplus and fluoroquinolone susceptible by MTBDRsl HIV seropositive (with or without&#xD;
      antiretroviral therapy) or negative (but not unknown) and Karnofsky score of &gt;60 at sites in&#xD;
      Moldova, Peru, and the Philippines.&#xD;
&#xD;
      Patients with MDR-TB will be randomized to oral regimen of delamanid (DLM), linezolid (LZD),&#xD;
      levofloxacin (LFX) and pyrazinamide (PZA) for 24, 32, 40, 48 or 56 weeks or World Health&#xD;
      Organization (WHO) standard of care MDR-TB regimen (9-month &quot;modified Bangladesh&quot; regimen or&#xD;
      WHO standard MDR-TB regimen).&#xD;
&#xD;
      Primary Objective&#xD;
&#xD;
      1. Determine the shortest duration of the delamanid-containing oral regimen that is&#xD;
      non-inferior to the blended WHO standard regimen.&#xD;
&#xD;
      Secondary Objective&#xD;
&#xD;
        1. Define the safety and tolerability of the oral delamanid, linezolid, levofloxacin and&#xD;
           pyrazinamide regimen.&#xD;
&#xD;
        2. Determine if baseline PZA susceptibility is associated with shorter time to non-inferior&#xD;
           treatment duration.&#xD;
&#xD;
        3. Identify the relationship between delamanid and linezolid serum drug levels and time to&#xD;
           sputum culture conversion among patients on the delamanid-containing oral regimen.&#xD;
&#xD;
        4. Identify the relationship between delamanid and linezolid serum drug levels and&#xD;
           occurrence of adverse events among patients on the delamanid-containing oral regimen.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least&#xD;
      isoniazid and rifampicin, the two most important anti-TB drugs. WHO has estimated that over&#xD;
      480,000 new cases of MDR-TB occurred in 127 countries in 2014, causing 150,000 deaths; this&#xD;
      represents a 70% increase in the number of cases since 2000. MDR-TB cure rates are&#xD;
      substantially lower than the 85+% cure expected in drug-susceptible TB. The MDR-TB treatment&#xD;
      regimen currently recommended by WHO includes at least 4 second-line drugs plus PZA for 18-24&#xD;
      months, including an injectable agent for the induction phase of 6-8 month. However, the&#xD;
      average global success rate of such treatment among patients treated in TB programs is only&#xD;
      50%. More recently, an alternative treatment regimen, known as the &quot;Bangladesh&quot; regimen, has&#xD;
      become available.This regimen uses 7 drugs given for 9 months but still includes an&#xD;
      injectable agent, which is the cause of the most common and severe toxicities seen when&#xD;
      treating MDR-TB. In selected patients this regimen has been able to achieve over 80% cures,&#xD;
      but use has been restricted to geographic areas where previous use of second-line drugs is&#xD;
      rare. Alternatives will be necessary for other settings and patients with prior second-line&#xD;
      drug exposure.&#xD;
&#xD;
      Treatment-limiting side effects are common when using second-line drugs for long periods of&#xD;
      time. Overall, 69-73% of patients with MDR-TB treated with the WHO standard regimen are&#xD;
      reported to have experienced at least one side effect, and 29%-55% discontinued one or more&#xD;
      study drugs because of inability to tolerate a drug. The Bangladesh regimen also has&#xD;
      substantial toxicity, with 63% of participants experiencing adverse drug reactions in one&#xD;
      report. Thus, while this regimen is shorter and slightly better tolerated than the WHO&#xD;
      standard regimen, it still does not provide an easily tolerated alternative, largely because&#xD;
      it contains an injectable agent.&#xD;
&#xD;
      The 20-24 month regimen currently in use exposes patients to drug toxicity over prolonged&#xD;
      periods of time and demands substantial human resources. Patients receiving these regimens&#xD;
      require two years of directly observed therapy with careful monitoring for drug toxicity.&#xD;
      Reduction in the duration of treatment would free up program staff to treat additional MDR-TB&#xD;
      patients. Development of a shorter treatment regimen will greatly enhance the ability of&#xD;
      programs to keep up with the anticipated increase in patients needing treatment.&#xD;
&#xD;
      This application proposes a study to determine whether the 9-month oral regime that uses&#xD;
      Delaminid, Linezolid, Levofloxacin and Pyrazinamide is as good as the current WHO standard of&#xD;
      care regimen.&#xD;
&#xD;
      The study proposes to randomize approximately 300 adults in Peru, Moldova and Phillipines&#xD;
      where MDR-TB is common.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    The study could not be conducted since funding was not obtained.&#xD;
  </why_stopped>
  <start_date type="Anticipated">August 2017</start_date>
  <completion_date type="Anticipated">August 2022</completion_date>
  <primary_completion_date type="Anticipated">August 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Successful outcome at 18 months after randomization using culture results, follow up visits,</measure>
    <time_frame>18 months</time_frame>
    <description>Successful outcome:if they have a -ve liq culture result 18 mos post rand not having been prev. classified as unsuccessful. If pt unable to produce sputum at 18 mos, the outcome will be classified as successful if they have a -ve culture at last visit at which they were able to produce sputum. Unsuccessful outcome: any of the foll occur, if patient 1)d/c from allocated study treatment &amp; restarted on a diff MDR-TB regimen; 2)has surgery for MDR-TB; 3)treatment extended beyond the scheduled end of treatment for any reason other than making up of missed treatment; 4)restarted on MDR-TB treatment post the sched end of treatment; 5)Allocated treatment changed for any reason other than d/c of PZA when isolate is resistant to PZA; 6)death at any point up to 18 mos post-rand; 7)has a +ve sputum culture 8 wks before the sched completion; 8)has +ve sputum culture after culture conversion by dates specified in criterion number 7; 9)ltfu at any time post rand &amp; before completion of the 18 mos f/u</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary - Adverse Events</measure>
    <time_frame>18 months</time_frame>
    <description>Adverse Events (AE) grade 3 and above, regardless of relatedness to drugs in the patient's MDR-TB treatment regimen</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Tuberculosis Multi Drug Resistant Active</condition>
  <arm_group>
    <arm_group_label>DAZZLE-24 wks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 24 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DAZZLE-32 wks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 32 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DAZZLE-40 wks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen: delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 40 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DAZZLE-48 wks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 48 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DAZZLE-56 wks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 56 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>WHO MDR-TB regimen- 9 mos or 20-24 mos</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>MDR-TB treatment with 9-month or 20-24 month WHO approved regimen. The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Delamanid</intervention_name>
    <description>Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.</description>
    <arm_group_label>DAZZLE-24 wks</arm_group_label>
    <arm_group_label>DAZZLE-32 wks</arm_group_label>
    <arm_group_label>DAZZLE-40 wks</arm_group_label>
    <arm_group_label>DAZZLE-48 wks</arm_group_label>
    <arm_group_label>DAZZLE-56 wks</arm_group_label>
    <other_name>Deltyba</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Linezolid</intervention_name>
    <description>Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.</description>
    <arm_group_label>DAZZLE-24 wks</arm_group_label>
    <arm_group_label>DAZZLE-32 wks</arm_group_label>
    <arm_group_label>DAZZLE-40 wks</arm_group_label>
    <arm_group_label>DAZZLE-48 wks</arm_group_label>
    <arm_group_label>DAZZLE-56 wks</arm_group_label>
    <other_name>Zyvox</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levofloxacin</intervention_name>
    <description>Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.</description>
    <arm_group_label>DAZZLE-24 wks</arm_group_label>
    <arm_group_label>DAZZLE-32 wks</arm_group_label>
    <arm_group_label>DAZZLE-40 wks</arm_group_label>
    <arm_group_label>DAZZLE-48 wks</arm_group_label>
    <arm_group_label>DAZZLE-56 wks</arm_group_label>
    <other_name>Levaquin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pyrazinamide</intervention_name>
    <description>Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.</description>
    <arm_group_label>DAZZLE-24 wks</arm_group_label>
    <arm_group_label>DAZZLE-32 wks</arm_group_label>
    <arm_group_label>DAZZLE-40 wks</arm_group_label>
    <arm_group_label>DAZZLE-48 wks</arm_group_label>
    <arm_group_label>DAZZLE-56 wks</arm_group_label>
    <other_name>Zinamide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>WHO MDR-TB regimen</intervention_name>
    <description>The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine. Short (9 mos) or longer (20-24 mos) treatment schedules can be used.</description>
    <arm_group_label>WHO MDR-TB regimen- 9 mos or 20-24 mos</arm_group_label>
    <other_name>5-agent treatment regimen for MDR-TB</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men and women age ≥18 years&#xD;
&#xD;
          2. Subject has pulmonary TB&#xD;
&#xD;
          3. Sputum Smear, culture or Xpert MTB/RIF assay positive, with Hain MTBDRplus showing&#xD;
             Rifampin (RIF) resistance and Isoniazid (INH) resistance and Hain MTBDRsl showing&#xD;
             Fluoroquinolone susceptibility.&#xD;
&#xD;
          4. Patients within two weeks (≤14 days) of starting second-line anti-TB drugs&#xD;
&#xD;
          5. HIV seropositive or seronegative but not unknown HIV serostatus. If the last&#xD;
             documented negative HIV test was more than 3 months prior to randomization the current&#xD;
             serostatus must be assessed.&#xD;
&#xD;
          6. Karnofsky score of &gt; 60 (see Appendix B) at screening and randomization&#xD;
&#xD;
          7. Willingness by the patient to attend scheduled follow-up visits and undergo study&#xD;
             assessments.&#xD;
&#xD;
          8. Women with child-bearing potential must agree to practice an adequate birth control or&#xD;
             to abstain from heterosexual intercourse during study regimen.&#xD;
&#xD;
          9. Laboratory parameters (performed within 14 days prior to randomization):&#xD;
&#xD;
               -  Estimated Serum creatinine &lt; 2.0&#xD;
&#xD;
               -  Hemoglobin concentration ≥ 7.0 g/dL&#xD;
&#xD;
               -  Platelet count of ≥ 80,000/mm3&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt; 2000/ mm3&#xD;
&#xD;
               -  Negative pregnancy test (for women of childbearing potential) during&#xD;
                  randomization/baseline&#xD;
&#xD;
               -  CD4 count if HIV infected (within 6 months)&#xD;
&#xD;
               -  Serum ALT and total bilirubin &lt;3 times upper limit of normal&#xD;
&#xD;
               -  Serum albumin &gt; 2.8 g/dL&#xD;
&#xD;
         10. Able to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known quinolone-resistance&#xD;
&#xD;
          2. History of serotonin syndrome&#xD;
&#xD;
          3. History of symptomatic arrhythmia, or taking anti-arrhythmic agents&#xD;
&#xD;
          4. Previous treatment with delamanid or linezolid&#xD;
&#xD;
          5. Known allergy or intolerability to quinolone or pyrazinamide&#xD;
&#xD;
          6. Patients who are pregnant or who are unwilling to use proper contraceptives at&#xD;
             childbearing age&#xD;
&#xD;
          7. Medical history of galactose intolerance, Lapp lactase deficiency, glucose-galactose&#xD;
             malabsorption&#xD;
&#xD;
          8. The need for ongoing use of prohibited drugs while on study drugs (see section 5.6&#xD;
             below)&#xD;
&#xD;
          9. History of optic neuropathy or peripheral neuropathy&#xD;
&#xD;
         10. History of hypersensitivity reaction to the study drugs&#xD;
&#xD;
         11. Patient is eligible for delamanid or bedaquiline under national program criteria&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>C. Robert Horsburgh, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston University</affiliation>
  </overall_official>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>October 21, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 29, 2016</study_first_posted>
  <last_update_submitted>September 7, 2017</last_update_submitted>
  <last_update_submitted_qc>September 7, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Boston University</investigator_affiliation>
    <investigator_full_name>Charles R Horsburgh</investigator_full_name>
    <investigator_title>Professor of Epidemiology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Levofloxacin</mesh_term>
    <mesh_term>Linezolid</mesh_term>
    <mesh_term>Pyrazinamide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02975570
org study id: H-36160
nct id: NCT02975570
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The proposed study will randomize adults (18 years of age or older) with pulmonary MDR-TB
      with sputum that contains M. tuberculosis that is isoniazid and rifampin resistant by
      MTBDRplus and fluoroquinolone susceptible by MTBDRsl HIV seropositive (with or without
      antiretroviral therapy) or negative (but not unknown) and Karnofsky score of >60 at sites in
      Moldova, Peru, and the Philippines.

      Patients with MDR-TB will be randomized to oral regimen of delamanid (DLM), linezolid (LZD),
      levofloxacin (LFX) and pyrazinamide (PZA) for 24, 32, 40, 48 or 56 weeks or World Health
      Organization (WHO) standard of care MDR-TB regimen (9-month "modified Bangladesh" regimen or
      WHO standard MDR-TB regimen).

      Primary Objective

      1. Determine the shortest duration of the delamanid-containing oral regimen that is
      non-inferior to the blended WHO standard regimen.

      Secondary Objective

        1. Define the safety and tolerability of the oral delamanid, linezolid, levofloxacin and
           pyrazinamide regimen.

        2. Determine if baseline PZA susceptibility is associated with shorter time to non-inferior
           treatment duration.

        3. Identify the relationship between delamanid and linezolid serum drug levels and time to
           sputum culture conversion among patients on the delamanid-containing oral regimen.

        4. Identify the relationship between delamanid and linezolid serum drug levels and
           occurrence of adverse events among patients on the delamanid-containing oral regimen.
Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least
      isoniazid and rifampicin, the two most important anti-TB drugs. WHO has estimated that over
      480,000 new cases of MDR-TB occurred in 127 countries in 2014, causing 150,000 deaths; this
      represents a 70% increase in the number of cases since 2000. MDR-TB cure rates are
      substantially lower than the 85+% cure expected in drug-susceptible TB. The MDR-TB treatment
      regimen currently recommended by WHO includes at least 4 second-line drugs plus PZA for 18-24
      months, including an injectable agent for the induction phase of 6-8 month. However, the
      average global success rate of such treatment among patients treated in TB programs is only
      50%. More recently, an alternative treatment regimen, known as the "Bangladesh" regimen, has
      become available.This regimen uses 7 drugs given for 9 months but still includes an
      injectable agent, which is the cause of the most common and severe toxicities seen when
      treating MDR-TB. In selected patients this regimen has been able to achieve over 80% cures,
      but use has been restricted to geographic areas where previous use of second-line drugs is
      rare. Alternatives will be necessary for other settings and patients with prior second-line
      drug exposure.

      Treatment-limiting side effects are common when using second-line drugs for long periods of
      time. Overall, 69-73% of patients with MDR-TB treated with the WHO standard regimen are
      reported to have experienced at least one side effect, and 29%-55% discontinued one or more
      study drugs because of inability to tolerate a drug. The Bangladesh regimen also has
      substantial toxicity, with 63% of participants experiencing adverse drug reactions in one
      report. Thus, while this regimen is shorter and slightly better tolerated than the WHO
      standard regimen, it still does not provide an easily tolerated alternative, largely because
      it contains an injectable agent.

      The 20-24 month regimen currently in use exposes patients to drug toxicity over prolonged
      periods of time and demands substantial human resources. Patients receiving these regimens
      require two years of directly observed therapy with careful monitoring for drug toxicity.
      Reduction in the duration of treatment would free up program staff to treat additional MDR-TB
      patients. Development of a shorter treatment regimen will greatly enhance the ability of
      programs to keep up with the anticipated increase in patients needing treatment.

      This application proposes a study to determine whether the 9-month oral regime that uses
      Delaminid, Linezolid, Levofloxacin and Pyrazinamide is as good as the current WHO standard of
      care regimen.

      The study proposes to randomize approximately 300 adults in Peru, Moldova and Phillipines
      where MDR-TB is common.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Successful outcome at 18 months after randomization using culture results, follow up visits,
time frame: 18 months
description: Successful outcome:if they have a -ve liq culture result 18 mos post rand not having been prev. classified as unsuccessful. If pt unable to produce sputum at 18 mos, the outcome will be classified as successful if they have a -ve culture at last visit at which they were able to produce sputum. Unsuccessful outcome: any of the foll occur, if patient 1)d/c from allocated study treatment & restarted on a diff MDR-TB regimen; 2)has surgery for MDR-TB; 3)treatment extended beyond the scheduled end of treatment for any reason other than making up of missed treatment; 4)restarted on MDR-TB treatment post the sched end of treatment; 5)Allocated treatment changed for any reason other than d/c of PZA when isolate is resistant to PZA; 6)death at any point up to 18 mos post-rand; 7)has a +ve sputum culture 8 wks before the sched completion; 8)has +ve sputum culture after culture conversion by dates specified in criterion number 7; 9)ltfu at any time post rand & before completion of the 18 mos f/u
measure: Secondary - Adverse Events
time frame: 18 months
description: Adverse Events (AE) grade 3 and above, regardless of relatedness to drugs in the patient's MDR-TB treatment regimen
arm group label: DAZZLE-24 wks
arm group type: Experimental
description: Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 24 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).
arm group label: DAZZLE-32 wks
arm group type: Experimental
description: Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 32 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).
arm group label: DAZZLE-40 wks
arm group type: Experimental
description: Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen: delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 40 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).
arm group label: DAZZLE-48 wks
arm group type: Experimental
description: Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 48 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).
arm group label: DAZZLE-56 wks
arm group type: Experimental
description: Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 56 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).
arm group label: WHO MDR-TB regimen- 9 mos or 20-24 mos
arm group type: Active Comparator
description: MDR-TB treatment with 9-month or 20-24 month WHO approved regimen. The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine.
intervention type: Drug
intervention name: Delamanid
description: Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.
arm group label: DAZZLE-24 wks
arm group label: DAZZLE-32 wks
arm group label: DAZZLE-40 wks
arm group label: DAZZLE-48 wks
arm group label: DAZZLE-56 wks
other name: Deltyba
intervention type: Drug
intervention name: Linezolid
description: Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.
arm group label: DAZZLE-24 wks
arm group label: DAZZLE-32 wks
arm group label: DAZZLE-40 wks
arm group label: DAZZLE-48 wks
arm group label: DAZZLE-56 wks
other name: Zyvox
intervention type: Drug
intervention name: Levofloxacin
description: Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.
arm group label: DAZZLE-24 wks
arm group label: DAZZLE-32 wks
arm group label: DAZZLE-40 wks
arm group label: DAZZLE-48 wks
arm group label: DAZZLE-56 wks
other name: Levaquin
intervention type: Drug
intervention name: Pyrazinamide
description: Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.
arm group label: DAZZLE-24 wks
arm group label: DAZZLE-32 wks
arm group label: DAZZLE-40 wks
arm group label: DAZZLE-48 wks
arm group label: DAZZLE-56 wks
other name: Zinamide
intervention type: Drug
intervention name: WHO MDR-TB regimen
description: The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine. Short (9 mos) or longer (20-24 mos) treatment schedules can be used.
arm group label: WHO MDR-TB regimen- 9 mos or 20-24 mos
other name: 5-agent treatment regimen for MDR-TB
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: C. Robert Horsburgh, MD
role: Principal Investigator
affiliation: Boston University
responsible party type: Principal Investigator
investigator affiliation: Boston University
investigator full name: Charles R Horsburgh
investigator title: Professor of Epidemiology
mesh term: Tuberculosis
mesh term: Levofloxacin
mesh term: Linezolid
mesh term: Pyrazinamide
sharing ipd: Undecided