<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/NCT03828201</url>
  </required_header>
  <id_info>
    <org_study_id>H39017</org_study_id>
    <secondary_id>U01AI152980</secondary_id>
    <nct_id>NCT03828201</nct_id>
  </id_info>
  <brief_title>Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB</brief_title>
  <acronym>DRAMATIC</acronym>
  <official_title>Prospective, Randomized, Partially Blinded, Phase 2 Study of the Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine for Treatment of Patients With MDR-TB</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boston University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Otsuka Pharmaceutical Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Westat</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Harvard Medical School (HMS and HSDM)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Lung Hospital, Vietnam</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>De La Salle Health Sciences Institute, Philippines</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis (TB) that is resistant to at least&#xD;
      isoniazid and rifampicin, the two most important anti-TB drugs. It occurs in 3.6% of newly&#xD;
      diagnosed TB patients in the world and 17% of patients who have been previously treated. In&#xD;
      2017, approximately 600,000 people were estimated to have acquired MDR-TB. However, only 25%&#xD;
      of persons with MDR-TB were diagnosed and started on treatment, reflecting inadequate&#xD;
      diagnostic capacity and lack of TB treatment capacity.&#xD;
&#xD;
      In this multicenter, randomized, partially blinded, four-arm, phase 2 study, the&#xD;
      investigators will examine the efficacy and safety of an all-oral regimen of bedaquiline,&#xD;
      delamanid, levofloxacin, linezolid, and clofazimine given for 16, 24, 32 or 40 weeks&#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 drugs in treating TB. In 2017, approximately&#xD;
      558,000 new people were estimated to have developed MDR-TB, and 8.5% of the cases had&#xD;
      extensively drug-resistant tuberculosis (XDR-TB).(1) Current WHO-endorsed MDR-TB treatment&#xD;
      regimens take 9-20 months to complete and are associated with substantial toxicity, including&#xD;
      deafness from injectable agents, hepatitis from pyrazinamide and severe neuropathy from&#xD;
      linezolid. Given the long duration and toxicities of MDR-TB regimens, it is perhaps not&#xD;
      surprising that WHO reports that only 25% of patients with MDR-TB are enrolled into&#xD;
      WHO-endorsed treatment regimens. Thus, there is an urgent need for shorter, less toxic&#xD;
      treatments for MDR-TB. This proposal will determine the efficacy, safety, tolerability and&#xD;
      optimal duration of a novel, all oral MDR-TB treatment regimen while addressing three major&#xD;
      challenges with innovations that have the potential to transform future trials.&#xD;
&#xD;
      The proposed DRAMATIC (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical)&#xD;
      Trial is a multicenter, randomized, partially blinded, four-arm, phase 2 trial that will&#xD;
      examine an injectable- and pyrazinamide-sparing regimen of bedaquiline, delamanid,&#xD;
      levofloxacin, linezolid, and clofazimine. The DRAMATIC regimen limits the administration of&#xD;
      linezolid to the initial 8 weeks of treatment, the window before linezolid-related neuropathy&#xD;
      occurs. Animal and human studies provide evidence for the potential efficacy of this 5-drug&#xD;
      regimen, but the optimal duration of treatment remains uncertain.(2-4)&#xD;
&#xD;
      Primary Objectives:&#xD;
&#xD;
        1. Describe the relationship between the duration of the experimental regimen and the&#xD;
           proportion of participants with sustained cure at 76 weeks after randomization without&#xD;
           treatment failure or relapse.&#xD;
&#xD;
        2. Describe the relationship between baseline prognostic risk strata and sustained cure at&#xD;
           76 weeks after randomization without treatment failure or relapse.&#xD;
&#xD;
        3. Evaluate the association between novel biologic markers and sustained cure at 76 weeks&#xD;
           after randomization without treatment failure or relapse.&#xD;
&#xD;
           Secondary Objectives:&#xD;
&#xD;
        4. Identify the shortest duration of the study regimen that has acceptable safety and&#xD;
           efficacy for a Phase 3 clinical trial of the DRAMATIC regimen for treatment of MDR-TB.&#xD;
&#xD;
        5. Describe the frequency, magnitude, time course of and risk factors for QTc prolongation&#xD;
           associated with the study regimen.&#xD;
&#xD;
        6. Demonstrate the feasibility and efficiency of implementing the new duration-randomized&#xD;
           design in a multi-centre randomized trial of drug-resistant TB.&#xD;
&#xD;
        7. Determine if time to sputum culture conversion predicts optimal duration of treatment&#xD;
           when stratified by extent of disease.&#xD;
&#xD;
        8. Describe the relationship between the duration of the experimental regimen and the&#xD;
           proportion of participants with sustained cure at 104 weeks after randomization without&#xD;
           treatment failure or relapse.&#xD;
&#xD;
        9. Assess vital status at 132 weeks post randomization.&#xD;
&#xD;
      Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability&#xD;
      of TB control programs to treat the growing number of patients. The DRAMATIC Trial will&#xD;
      employ an innovative and efficient new design to establish a robust, nontoxic MDR-TB&#xD;
      treatment regimen and identify the minimal duration for which it needs to be administered.&#xD;
      These results will speed the process of moving forward to a confirmatory phase 3 clinical&#xD;
      trial and increase the likelihood that such a trial is successful.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 7, 2022</start_date>
  <completion_date type="Anticipated">July 2025</completion_date>
  <primary_completion_date type="Anticipated">July 2025</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>Treatment Efficacy - Frequency of &quot;successful treatment&quot; outcomes</measure>
    <time_frame>Week 76</time_frame>
    <description>A participant's outcome will be classified as successful if, at 76 weeks after initiation of treatment, they have a &quot;negative&quot; sputum culture and were not previously classified as unsuccessful; if the participant is unable to produce sputum at that time, the outcome will be classified as successful if they had a negative culture result at the last visit at which they had a sputum culture result.&#xD;
A participant's outcome will be classified as unsuccessful if any of the following occur prior to week 76: Addition or replacement of 2 or more anti-tuberculosis (TB) drugs from the assigned regimen, the participant has a positive culture for M. tuberculosis and that isolate is not demonstrated to be genetically different from the initial isolate, undergoing surgery for multidrug-resistant TB (MDR-TB), lost to follow-up, surgery for MDR-TB, extended treatment, and death.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Treatment Safety - Frequency of participants with grade 3, 4, or 5 adverse events</measure>
    <time_frame>44 weeks</time_frame>
    <description>The primary outcome for safety are Grade 3, 4, or 5 adverse events</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy outcome- Frequency of participants who survive</measure>
    <time_frame>Week 132</time_frame>
    <description>Evaluate survival at 132 weeks post randomization.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">220</enrollment>
  <condition>Tuberculosis, Multidrug-Resistant</condition>
  <arm_group>
    <arm_group_label>Investigational: DRAMATIC-16 weeks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>delamanid 300 mg orally, by mouth (PO) once a day (QD), 16 weeks levofloxacin 1000 mg PO QD, 16 weeks clofazimine 100 mg PO QD, 16 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Investigational: DRAMATIC-24 weeks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>delamanid 300 mg orally, by mouth (PO) once a day (QD), 24 weeks levofloxacin 1000 mg PO QD, 24 weeks clofazimine 100 mg PO QD, 24 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Investigational: DRAMATIC-32 weeks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>delamanid 300 mg orally, by mouth (PO) once a day (QD), 32 weeks levofloxacin 1000 mg PO QD, 32 weeks clofazimine 100 mg PO QD, 32 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Investigational: DRAMATIC-40 weeks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>delamanid 300 mg orally, by mouth (PO) once a day (QD), 40 weeks levofloxacin 1000 mg PO QD, 40 weeks clofazimine 100 mg PO QD, 40 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Delamanid</intervention_name>
    <description>Frequency: daily Route of administration: oral&#xD;
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>Investigational: DRAMATIC-16 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-24 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-32 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-40 weeks</arm_group_label>
    <other_name>Deltyba</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levofloxacin</intervention_name>
    <description>Frequency: daily Route of administration: oral&#xD;
Levofloxacin 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>Investigational: DRAMATIC-16 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-24 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-32 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-40 weeks</arm_group_label>
    <other_name>Levaquin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bedaquiline</intervention_name>
    <description>Frequency: daily Route of administration: oral&#xD;
Bedaquiline is indicated for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.</description>
    <arm_group_label>Investigational: DRAMATIC-16 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-24 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-32 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-40 weeks</arm_group_label>
    <other_name>Sirturo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clofazimine</intervention_name>
    <description>Frequency: daily Route of administration: oral&#xD;
Clofazimine has shown activity against multidrug-resistant tuberculosis (MDR-TB) and is now recommended by the World Health Organization (WHO) to treat drug resistant tuberculosis as a &quot;Group B&quot; drug. It is thought that clofazimine acts by inhibiting the formation of matrixes within the DNA and thus delaying the growth of the bacterium. Clofazimine first received FDA approval in 1986, although its use in the treatment of MDR-TB has not been approved by any stringent regulatory authorities and it is therefore used &quot;off-label&quot; for this function.</description>
    <arm_group_label>Investigational: DRAMATIC-16 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-24 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-32 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-40 weeks</arm_group_label>
    <other_name>Lamprene</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Linezolid</intervention_name>
    <description>Frequency: daily Route of administration: oral&#xD;
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>Investigational: DRAMATIC-16 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-24 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-32 weeks</arm_group_label>
    <arm_group_label>Investigational: DRAMATIC-40 weeks</arm_group_label>
    <other_name>Zyvox</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males and females age ≥12 years. Prior to study procedures, if ≥18 years of age,&#xD;
             provides informed consent; if &lt;18 years of age, child provides informed assent and has&#xD;
             a parent or guardian who provides informed consent on the participant's behalf.&#xD;
&#xD;
          2. Has pulmonary TB based on investigator assessment of all available information (e.g.,&#xD;
             chest radiograph, sputum smear, culture, molecular testing).&#xD;
&#xD;
          3. Has a sputum sample that is positive for M. tuberculosis that is rifamycin-resistant&#xD;
             and fluoroquinolone-susceptible by molecular assay.&#xD;
&#xD;
          4. Is HIV seropositive or seronegative; HIV serostatus must be assessed at screening if&#xD;
             either (a) HIV serostatus is unknown, or (b) the last documented negative HIV test was&#xD;
             more than two (2) months prior to screening.&#xD;
&#xD;
          5. Willing to attend scheduled follow-up visits and undergo study assessments.&#xD;
&#xD;
          6. Participants of child-bearing potential must agree either (a) to practice an adequate&#xD;
             birth control (defined as one of the following oral contraceptives, intrauterine&#xD;
             devices, contraceptive implants under the skin, contraceptive rings or patches or&#xD;
             injections, diaphragms with spermicide or condoms with foam) or (b) to abstain from&#xD;
             heterosexual intercourse during study regimen.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Current MTB isolate is known at screening to be fluoroquinolone-resistant.&#xD;
&#xD;
          2. History of allergy (hypersensitivity) or intolerability to one or more agents in the&#xD;
             investigational regimens (i.e., Arms 1 and 2)&#xD;
&#xD;
          3. History of serotonin syndrome&#xD;
&#xD;
          4. History of symptomatic ventricular arrhythmia or is taking anti-arrhythmic agents&#xD;
&#xD;
          5. History of optic neuropathy or peripheral neuropathy&#xD;
&#xD;
          6. History of Ehlers-Danlos Syndrome, Marfan Syndrome or aortic aneurism&#xD;
&#xD;
          7. History of prior treatment with delamanid or linezolid for TB for greater than one&#xD;
             month.&#xD;
&#xD;
          8. Has at screening received ≥14 days of second-line anti-TB drugs during current TB&#xD;
             episode&#xD;
&#xD;
          9. Has at screening a Karnofsky score of ≤40 or, in the opinion of the Investigator, is&#xD;
             unlikely to survive 76 weeks.&#xD;
&#xD;
         10. Has at screening laboratory results that meet one or more of the following criteria:&#xD;
&#xD;
               -  Hemoglobin concentration &lt;7.0 g/dL (&lt;70 g/L)&#xD;
&#xD;
               -  Platelet count of &lt;80,000/mm3&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &lt;2000/ mm3&#xD;
&#xD;
               -  Serum creatinine &gt;2.0 mg/dL (&gt;177 µmol/L)&#xD;
&#xD;
               -  Serum ALT &gt;3x upper limit of normal (ULN)&#xD;
&#xD;
               -  Total bilirubin &gt;3x upper limit of normal (ULN)&#xD;
&#xD;
               -  Serum albumin &lt;2.8 g/dL (&lt;28 g/L)&#xD;
&#xD;
               -  For women of childbearing potential, a positive or indeterminate serum pregnancy&#xD;
                  test&#xD;
&#xD;
         11. For women of childbearing potential, has a positive or indeterminate urine pregnancy&#xD;
             test on the day of randomization.&#xD;
&#xD;
         12. Has at screening a mean QTcF &gt;450 msec based on three ECGs.&#xD;
&#xD;
         13. At screening requires ongoing use of prohibited drugs indicated in section 4.2&#xD;
&#xD;
         14. At screening, has weight less than 33 Kg.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Charles Horsburgh, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Payam Nahid, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Pawandeep Kaur, MPH</last_name>
    <phone>(617) 358-2421</phone>
    <email>kaurp@bu.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Charles Horsburgh, MD</last_name>
    <phone>(617) 358-3758</phone>
    <email>rhorsbu@bu.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>De La Salle Health Sciences Institute</name>
      <address>
        <city>Dasmariñas</city>
        <zip>4114</zip>
        <country>Philippines</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melchor Frias, MD</last_name>
    </contact>
    <investigator>
      <last_name>Melchor Frias, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Maria Tarcela Gler, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>National Lung Hospital</name>
      <address>
        <city>Hanoi</city>
        <country>Vietnam</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Viet Nhung, MD</last_name>
    </contact>
    <investigator>
      <last_name>Viet Nhung, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Philippines</country>
    <country>Vietnam</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 29, 2019</study_first_submitted>
  <study_first_submitted_qc>January 31, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>June 9, 2023</last_update_submitted>
  <last_update_submitted_qc>June 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 12, 2023</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, Boston University</investigator_title>
  </responsible_party>
  <keyword>bedaquiline (BDQ)</keyword>
  <keyword>delamanid (DLM)</keyword>
  <keyword>linezolid (LZD)</keyword>
  <keyword>levofloxacin (LFX)</keyword>
  <keyword>clofazimine (CF)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Multidrug-Resistant</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>Bedaquiline</mesh_term>
    <mesh_term>Clofazimine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03828201
org study id: H39017
secondary id: U01AI152980
nct id: NCT03828201
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis (TB) that is resistant to at least
      isoniazid and rifampicin, the two most important anti-TB drugs. It occurs in 3.6% of newly
      diagnosed TB patients in the world and 17% of patients who have been previously treated. In
      2017, approximately 600,000 people were estimated to have acquired MDR-TB. However, only 25%
      of persons with MDR-TB were diagnosed and started on treatment, reflecting inadequate
      diagnostic capacity and lack of TB treatment capacity.

      In this multicenter, randomized, partially blinded, four-arm, phase 2 study, the
      investigators will examine the efficacy and safety of an all-oral regimen of bedaquiline,
      delamanid, levofloxacin, linezolid, and clofazimine given for 16, 24, 32 or 40 weeks
Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least
      isoniazid and rifampicin, the two most important drugs in treating TB. In 2017, approximately
      558,000 new people were estimated to have developed MDR-TB, and 8.5% of the cases had
      extensively drug-resistant tuberculosis (XDR-TB).(1) Current WHO-endorsed MDR-TB treatment
      regimens take 9-20 months to complete and are associated with substantial toxicity, including
      deafness from injectable agents, hepatitis from pyrazinamide and severe neuropathy from
      linezolid. Given the long duration and toxicities of MDR-TB regimens, it is perhaps not
      surprising that WHO reports that only 25% of patients with MDR-TB are enrolled into
      WHO-endorsed treatment regimens. Thus, there is an urgent need for shorter, less toxic
      treatments for MDR-TB. This proposal will determine the efficacy, safety, tolerability and
      optimal duration of a novel, all oral MDR-TB treatment regimen while addressing three major
      challenges with innovations that have the potential to transform future trials.

      The proposed DRAMATIC (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical)
      Trial is a multicenter, randomized, partially blinded, four-arm, phase 2 trial that will
      examine an injectable- and pyrazinamide-sparing regimen of bedaquiline, delamanid,
      levofloxacin, linezolid, and clofazimine. The DRAMATIC regimen limits the administration of
      linezolid to the initial 8 weeks of treatment, the window before linezolid-related neuropathy
      occurs. Animal and human studies provide evidence for the potential efficacy of this 5-drug
      regimen, but the optimal duration of treatment remains uncertain.(2-4)

      Primary Objectives:

        1. Describe the relationship between the duration of the experimental regimen and the
           proportion of participants with sustained cure at 76 weeks after randomization without
           treatment failure or relapse.

        2. Describe the relationship between baseline prognostic risk strata and sustained cure at
           76 weeks after randomization without treatment failure or relapse.

        3. Evaluate the association between novel biologic markers and sustained cure at 76 weeks
           after randomization without treatment failure or relapse.

           Secondary Objectives:

        4. Identify the shortest duration of the study regimen that has acceptable safety and
           efficacy for a Phase 3 clinical trial of the DRAMATIC regimen for treatment of MDR-TB.

        5. Describe the frequency, magnitude, time course of and risk factors for QTc prolongation
           associated with the study regimen.

        6. Demonstrate the feasibility and efficiency of implementing the new duration-randomized
           design in a multi-centre randomized trial of drug-resistant TB.

        7. Determine if time to sputum culture conversion predicts optimal duration of treatment
           when stratified by extent of disease.

        8. Describe the relationship between the duration of the experimental regimen and the
           proportion of participants with sustained cure at 104 weeks after randomization without
           treatment failure or relapse.

        9. Assess vital status at 132 weeks post randomization.

      Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability
      of TB control programs to treat the growing number of patients. The DRAMATIC Trial will
      employ an innovative and efficient new design to establish a robust, nontoxic MDR-TB
      treatment regimen and identify the minimal duration for which it needs to be administered.
      These results will speed the process of moving forward to a confirmatory phase 3 clinical
      trial and increase the likelihood that such a trial is successful.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Treatment Efficacy - Frequency of "successful treatment" outcomes
time frame: Week 76
description: A participant's outcome will be classified as successful if, at 76 weeks after initiation of treatment, they have a "negative" sputum culture and were not previously classified as unsuccessful; if the participant is unable to produce sputum at that time, the outcome will be classified as successful if they had a negative culture result at the last visit at which they had a sputum culture result.
A participant's outcome will be classified as unsuccessful if any of the following occur prior to week 76: Addition or replacement of 2 or more anti-tuberculosis (TB) drugs from the assigned regimen, the participant has a positive culture for M. tuberculosis and that isolate is not demonstrated to be genetically different from the initial isolate, undergoing surgery for multidrug-resistant TB (MDR-TB), lost to follow-up, surgery for MDR-TB, extended treatment, and death.
measure: Treatment Safety - Frequency of participants with grade 3, 4, or 5 adverse events
time frame: 44 weeks
description: The primary outcome for safety are Grade 3, 4, or 5 adverse events
measure: Efficacy outcome- Frequency of participants who survive
time frame: Week 132
description: Evaluate survival at 132 weeks post randomization.
arm group label: Investigational: DRAMATIC-16 weeks
arm group type: Experimental
description: delamanid 300 mg orally, by mouth (PO) once a day (QD), 16 weeks levofloxacin 1000 mg PO QD, 16 weeks clofazimine 100 mg PO QD, 16 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only
arm group label: Investigational: DRAMATIC-24 weeks
arm group type: Experimental
description: delamanid 300 mg orally, by mouth (PO) once a day (QD), 24 weeks levofloxacin 1000 mg PO QD, 24 weeks clofazimine 100 mg PO QD, 24 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only
arm group label: Investigational: DRAMATIC-32 weeks
arm group type: Experimental
description: delamanid 300 mg orally, by mouth (PO) once a day (QD), 32 weeks levofloxacin 1000 mg PO QD, 32 weeks clofazimine 100 mg PO QD, 32 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only
arm group label: Investigational: DRAMATIC-40 weeks
arm group type: Experimental
description: delamanid 300 mg orally, by mouth (PO) once a day (QD), 40 weeks levofloxacin 1000 mg PO QD, 40 weeks clofazimine 100 mg PO QD, 40 weeks bedaquiline 200 mg PO QD x 8 wk then 100 mg PO QD remainder linezolid 1200 mg PO QD, Initial 8 weeks only
intervention type: Drug
intervention name: Delamanid
description: Frequency: daily Route of administration: oral
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: Investigational: DRAMATIC-16 weeks
arm group label: Investigational: DRAMATIC-24 weeks
arm group label: Investigational: DRAMATIC-32 weeks
arm group label: Investigational: DRAMATIC-40 weeks
other name: Deltyba
intervention type: Drug
intervention name: Levofloxacin
description: Frequency: daily Route of administration: oral
Levofloxacin 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: Investigational: DRAMATIC-16 weeks
arm group label: Investigational: DRAMATIC-24 weeks
arm group label: Investigational: DRAMATIC-32 weeks
arm group label: Investigational: DRAMATIC-40 weeks
other name: Levaquin
intervention type: Drug
intervention name: Bedaquiline
description: Frequency: daily Route of administration: oral
Bedaquiline is indicated for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.
arm group label: Investigational: DRAMATIC-16 weeks
arm group label: Investigational: DRAMATIC-24 weeks
arm group label: Investigational: DRAMATIC-32 weeks
arm group label: Investigational: DRAMATIC-40 weeks
other name: Sirturo
intervention type: Drug
intervention name: Clofazimine
description: Frequency: daily Route of administration: oral
Clofazimine has shown activity against multidrug-resistant tuberculosis (MDR-TB) and is now recommended by the World Health Organization (WHO) to treat drug resistant tuberculosis as a "Group B" drug. It is thought that clofazimine acts by inhibiting the formation of matrixes within the DNA and thus delaying the growth of the bacterium. Clofazimine first received FDA approval in 1986, although its use in the treatment of MDR-TB has not been approved by any stringent regulatory authorities and it is therefore used "off-label" for this function.
arm group label: Investigational: DRAMATIC-16 weeks
arm group label: Investigational: DRAMATIC-24 weeks
arm group label: Investigational: DRAMATIC-32 weeks
arm group label: Investigational: DRAMATIC-40 weeks
other name: Lamprene
intervention type: Drug
intervention name: Linezolid
description: Frequency: daily Route of administration: oral
Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.
arm group label: Investigational: DRAMATIC-16 weeks
arm group label: Investigational: DRAMATIC-24 weeks
arm group label: Investigational: DRAMATIC-32 weeks
arm group label: Investigational: DRAMATIC-40 weeks
other name: Zyvox
criteria: 
gender: All
minimum age: 12 Years
maximum age: N/A
healthy volunteers: No
last name: Charles Horsburgh, MD
role: Principal Investigator
affiliation: Boston University
last name: Payam Nahid, MD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Pawandeep Kaur, MPH
phone: (617) 358-2421
email: kaurp@bu.edu
last name: Charles Horsburgh, MD
phone: (617) 358-3758
email: rhorsbu@bu.edu
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
country: Philippines
country: Vietnam
responsible party type: Principal Investigator
investigator affiliation: Boston University
investigator full name: Charles R Horsburgh
investigator title: Professor of Epidemiology, Boston University
mesh term: Tuberculosis
mesh term: Tuberculosis, Multidrug-Resistant
mesh term: Levofloxacin
mesh term: Linezolid
mesh term: Bedaquiline
mesh term: Clofazimine
sharing ipd: No