<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/NCT02236078</url>
  </required_header>
  <id_info>
    <org_study_id>CDC-NCHHSTP-6435</org_study_id>
    <nct_id>NCT02236078</nct_id>
  </id_info>
  <brief_title>Brief Bactericidal Activity of Anti-Tuberculosis Drugs</brief_title>
  <acronym>BBA</acronym>
  <official_title>Brief Bactericidal Activity of Anti-Tuberculosis Drugs in Drug-Resistant Tuberculosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centers for Disease Control and Prevention</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Kenya Medical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Centers for Disease Control and Prevention</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators will determine the bactericidal activity of high-dose isoniazid against M.&#xD;
      tuberculosis isolates that are (1) susceptible to isoniazid at 2.0 mcg/ml but resistant at&#xD;
      0.1 and 0.4 mcg/ml or (2) susceptible at 0.4 mcg/ml but resistant at 0.1 mcg/ml when tested&#xD;
      in the BD MGIT 960 system. Further, the investigators will investigate the molecular genetic&#xD;
      determinants of these differences in susceptibility.&#xD;
&#xD;
      To achieve these objectives the investigators will carry out an innovative variation on early&#xD;
      bactericidal activity (EBA) study methodology. Patients at risk for drug-resistant TB will be&#xD;
      screened for INH resistance using approved molecular assays. In those with INH-resistant TB,&#xD;
      the investigators will quickly perform phenotypic DSTs using the direct method in the Bactec&#xD;
      Mycobacterium Growth Indicator Tube (MGIT) 960 system, so results will be available within 7&#xD;
      days. If the DST results show the susceptibility patterns noted above, patients will receive&#xD;
      900 mg/d INH (600 mg if &lt;45kg), and assess its effect with serial quantitative sputum&#xD;
      cultures for 6 days. If the concentration of viable bacteria decreases significantly, the&#xD;
      investigators will interpret this to mean the drug is having an effect. If not, the drug is&#xD;
      ineffective. After 6 days, the patients will resume treatment according to national&#xD;
      guidelines.&#xD;
&#xD;
      In case the investigators identify drugs that are effective under these conditions, the&#xD;
      investigators will sequence known and putative genes associated with the action of these&#xD;
      drugs for the mycobacterial isolates from these patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>November 2015</start_date>
  <completion_date type="Actual">September 30, 2020</completion_date>
  <primary_completion_date type="Actual">September 30, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Delta CFU/ml/day</measure>
    <time_frame>6 days</time_frame>
    <description>Change in colony forming units per ml of sputum over 6 days</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time-to-detection (TTD)</measure>
    <time_frame>6 days</time_frame>
    <description>Interval in hours from culture inoculation to detection of mycobacterial growth in MGIT 960</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Acquired isoniazid resistance</measure>
    <time_frame>2 months</time_frame>
    <description>Increased level of resistance to isoniazid</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Tuberculosis</condition>
  <condition>Drug-resistant Tuberculosis</condition>
  <condition>Isoniazid Resistant Tuberculosis (Disorder)</condition>
  <arm_group>
    <arm_group_label>High dose isoniazid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>INH 900 mg daily to be administered orally for 6 days (600 mg for patients weighing &lt;45 kg)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>High dose isoniazid</intervention_name>
    <description>See arm description</description>
    <arm_group_label>High dose isoniazid</arm_group_label>
    <other_name>High dose INH</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  INH resistance by approved molecular genetic test&#xD;
&#xD;
          -  Phenotypic drug susceptibility test results match one of the required patterns&#xD;
&#xD;
          -  Sputum microscopy positive for acid fast bacilli&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Ineligible for MDR TB treatment according to national guidelines&#xD;
&#xD;
          -  HIV infection with CD4 count less than 50&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Incarceration&#xD;
&#xD;
          -  Too sick to participate (Karnofsky score &lt;60, arterial pO2&lt;90, respiratory rate&#xD;
             repeatedly &gt;25/min, clinician's judgment)&#xD;
&#xD;
          -  Hepatic enzymes &gt;3x normal&#xD;
&#xD;
          -  Estimated glomerular filtration rate &lt;60 mL/min/1.73 m2&#xD;
&#xD;
          -  Unable to provide adequate sputum specimen&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sarah E. Smith-Jeffcoat, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>U.S. Centers for Disease Control and Prevention</affiliation>
  </overall_official>
  <overall_official>
    <last_name>J. P. Cegielski, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>JP Cegielski Consulting LLC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institute for Research on Tuberculosis</name>
      <address>
        <city>Chennai</city>
        <state>Tamil Nadu</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <removed_countries>
    <country>Kenya</country>
  </removed_countries>
  <reference>
    <citation>Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Erokhin VV, Ershova J, Gler MT, Kazennyy BY, Kim HJ, Kliiman K, Kurbatova E, Kvasnovsky C, Leimane V, van der Walt M, Via LE, Volchenkov GV, Yagui MA, Kang H; Global PETTS Investigators; Akksilp R, Sitti W, Wattanaamornkiet W, Andreevskaya SN, Chernousova LN, Demikhova OV, Larionova EE, Smirnova TG, Vasilieva IA, Vorobyeva AV, Barry CE 3rd, Cai Y, Shamputa IC, Bayona J, Contreras C, Bonilla C, Jave O, Brand J, Lancaster J, Odendaal R, Chen MP, Diem L, Metchock B, Tan K, Taylor A, Wolfgang M, Cho E, Eum SY, Kwak HK, Lee J, Lee J, Min S, Degtyareva I, Nemtsova ES, Khorosheva T, Kyryanova EV, Egos G, Perez MT, Tupasi T, Hwang SH, Kim CK, Kim SY, Lee HJ, Kuksa L, Norvaisha I, Skenders G, Sture I, Kummik T, Kuznetsova T, Somova T, Levina K, Pariona G, Yale G, Suarez C, Valencia E, Viiklepp P. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 2012 Oct 20;380(9851):1406-17. doi: 10.1016/S0140-6736(12)60734-X. Epub 2012 Aug 30. Erratum In: Lancet. 2012 Oct 20;380(9851):1386.</citation>
    <PMID>22938757</PMID>
  </reference>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>September 8, 2014</study_first_submitted>
  <study_first_submitted_qc>September 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2014</study_first_posted>
  <last_update_submitted>October 13, 2020</last_update_submitted>
  <last_update_submitted_qc>October 13, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 19, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Multidrug-Resistant</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Isoniazid</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02236078
org study id: CDC-NCHHSTP-6435
nct id: NCT02236078
lead sponsor: 
collaborator: 
has dmc: No
The investigators will determine the bactericidal activity of high-dose isoniazid against M.
      tuberculosis isolates that are (1) susceptible to isoniazid at 2.0 mcg/ml but resistant at
      0.1 and 0.4 mcg/ml or (2) susceptible at 0.4 mcg/ml but resistant at 0.1 mcg/ml when tested
      in the BD MGIT 960 system. Further, the investigators will investigate the molecular genetic
      determinants of these differences in susceptibility.

      To achieve these objectives the investigators will carry out an innovative variation on early
      bactericidal activity (EBA) study methodology. Patients at risk for drug-resistant TB will be
      screened for INH resistance using approved molecular assays. In those with INH-resistant TB,
      the investigators will quickly perform phenotypic DSTs using the direct method in the Bactec
      Mycobacterium Growth Indicator Tube (MGIT) 960 system, so results will be available within 7
      days. If the DST results show the susceptibility patterns noted above, patients will receive
      900 mg/d INH (600 mg if <45kg), and assess its effect with serial quantitative sputum
      cultures for 6 days. If the concentration of viable bacteria decreases significantly, the
      investigators will interpret this to mean the drug is having an effect. If not, the drug is
      ineffective. After 6 days, the patients will resume treatment according to national
      guidelines.

      In case the investigators identify drugs that are effective under these conditions, the
      investigators will sequence known and putative genes associated with the action of these
      drugs for the mycobacterial isolates from these patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Delta CFU/ml/day
time frame: 6 days
description: Change in colony forming units per ml of sputum over 6 days
measure: Time-to-detection (TTD)
time frame: 6 days
description: Interval in hours from culture inoculation to detection of mycobacterial growth in MGIT 960
measure: Acquired isoniazid resistance
time frame: 2 months
description: Increased level of resistance to isoniazid
arm group label: High dose isoniazid
arm group type: Experimental
description: INH 900 mg daily to be administered orally for 6 days (600 mg for patients weighing <45 kg)
intervention type: Drug
intervention name: High dose isoniazid
description: See arm description
arm group label: High dose isoniazid
other name: High dose INH
criteria: 
gender: All
minimum age: 8 Years
maximum age: 99 Years
healthy volunteers: No
last name: Sarah E. Smith-Jeffcoat, MPH
role: Principal Investigator
affiliation: U.S. Centers for Disease Control and Prevention
last name: J. P. Cegielski, MD, MPH
role: Principal Investigator
affiliation: JP Cegielski Consulting LLC
facility: 
country: India
country: Kenya
citation: Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Erokhin VV, Ershova J, Gler MT, Kazennyy BY, Kim HJ, Kliiman K, Kurbatova E, Kvasnovsky C, Leimane V, van der Walt M, Via LE, Volchenkov GV, Yagui MA, Kang H; Global PETTS Investigators; Akksilp R, Sitti W, Wattanaamornkiet W, Andreevskaya SN, Chernousova LN, Demikhova OV, Larionova EE, Smirnova TG, Vasilieva IA, Vorobyeva AV, Barry CE 3rd, Cai Y, Shamputa IC, Bayona J, Contreras C, Bonilla C, Jave O, Brand J, Lancaster J, Odendaal R, Chen MP, Diem L, Metchock B, Tan K, Taylor A, Wolfgang M, Cho E, Eum SY, Kwak HK, Lee J, Lee J, Min S, Degtyareva I, Nemtsova ES, Khorosheva T, Kyryanova EV, Egos G, Perez MT, Tupasi T, Hwang SH, Kim CK, Kim SY, Lee HJ, Kuksa L, Norvaisha I, Skenders G, Sture I, Kummik T, Kuznetsova T, Somova T, Levina K, Pariona G, Yale G, Suarez C, Valencia E, Viiklepp P. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 2012 Oct 20;380(9851):1406-17. doi: 10.1016/S0140-6736(12)60734-X. Epub 2012 Aug 30. Erratum In: Lancet. 2012 Oct 20;380(9851):1386.
PMID: 22938757
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Tuberculosis, Multidrug-Resistant
mesh term: Isoniazid