<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/NCT03237182</url>
  </required_header>
  <id_info>
    <org_study_id>CAP 020</org_study_id>
    <nct_id>NCT03237182</nct_id>
  </id_info>
  <brief_title>The Individualized M(X) Drug-resistant TB Treatment Strategy Study</brief_title>
  <acronym>InDEX</acronym>
  <official_title>The Individualized M(X) Drug-resistant TB Treatment Strategy Study A Strategy to Improve Treatment Outcomes in Patients With Drug-resistant TB</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre for the AIDS Programme of Research in South Africa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre for the AIDS Programme of Research in South Africa</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized controlled clinical trial comparing treatment success of a gene-derived&#xD;
      individualized drug-resistant Tuberculosis regimen to a standard Tuberculosis regimen based&#xD;
      on South African National Tuberculosis guidelines.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      When drug resistance is detected by molecular methods such as the Xpert MTB/RIF assay,&#xD;
      second-line Multi Drug-Resistant (MDR) Tuberculosis treatment is started in the complete&#xD;
      absence of detailed resistance information. The diagnosis of Multi Drug-Resistant&#xD;
      Tuberculosis is confirmed only on availability of Line Probe Assay (LPA)/Drug Susceptibility&#xD;
      Testing (DST) results. Extremely Drug-Resistant (XDR) Tuberculosis is diagnosed by in vitro&#xD;
      phenotypic resistance to Rifampicin, Isoniazid, fluoroquinolones and injectable second-line&#xD;
      drugs (i.e., amikacin, kanamycin, or capreomycin). Existing culture based Drug Susceptibility&#xD;
      Testing provides results after 6-8 weeks. This duration may be further increased by other&#xD;
      existing laboratory challenges, such as culture contamination.&#xD;
&#xD;
      Furthermore, initial regimens are often not optimal and sometimes completely ineffective as&#xD;
      there is a lack of Drug Susceptibility Testing to support them. More importantly, even&#xD;
      optimal regimens are changed due to patient intolerance of the drug's side effects.&#xD;
&#xD;
      Whole Genome Sequencing (WGS) has the advantage of determining the complete Deoxyribonucleic&#xD;
      acid (DNA) sequence of an organism's genome at a single time point. Using this technology,&#xD;
      genotypic mutations conferring resistance to anti-tuberculosis drugs can be identified. This&#xD;
      information will assist in identifying not only potential resistant drugs, but also&#xD;
      susceptible drugs and thus enable a more accurate and appropriate choice of regimen. In&#xD;
      addition, drugs that will not add value to the treatment outcome, but will increase rates of&#xD;
      adverse drug reactions, can be eliminated earlier, improving drug-resistant TB treatment&#xD;
      outcomes.&#xD;
&#xD;
      In this proposal, we aim to use Mycobacterium Tuberculosis (MTB) whole genome sequencing&#xD;
      prior to the selection of a drug-resistant tuberculosis treatment regimen and thus provide an&#xD;
      individualized treatment strategy for drug-resistant tuberculosis. By adopting this method,&#xD;
      we hope to improve culture negative survival rates at 6 months post treatment initiation .&#xD;
&#xD;
      This study will include 448 adult patients (age ≥ 18 years) that meet inclusion criteria.&#xD;
      Patients referred by provincial satellite facilities with microbiological confirmation of&#xD;
      drug-resistant tuberculosis (e.g. Xpert MTB/RIF assay / Line Probe Assay) to King DinuZulu&#xD;
      Hospital (KDH) will be recruited. Patients randomized to the control arm will receive&#xD;
      standard of care (SOC) treatment. Patients randomized to the intervention arm will be given&#xD;
      an individualized treatment regimen based on whole genome sequencing conducted on&#xD;
      Mycobacteria Growth Indicator Tube (MGIT) positive sputum samples collected at the screening&#xD;
      visit.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    WHO 2022 guidelines for DR-TB treatment are set to change. These guidelines recommend the use&#xD;
    of an all-oral short course BPAL regimen.Therefore ongoing implementation of the study is&#xD;
    considered futile.&#xD;
  </why_stopped>
  <start_date type="Actual">June 14, 2017</start_date>
  <completion_date type="Actual">December 19, 2022</completion_date>
  <primary_completion_date type="Actual">December 19, 2022</primary_completion_date>
  <phase>Phase 4</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>
    <intervention_model_description>Patients randomized to the intervention receive a individualized tuberculosis treatment based on whole genome sequencing and the patients randomized to the control receive the standard of care tuberculosis treatment</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Culture negative survival rate</measure>
    <time_frame>24 months</time_frame>
    <description>To determine if a gene-derived individualized treatment approach in patients with drug-resistant TB will improve culture negative survival rates at 6 months post treatment initiation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Culture negative survival rate</measure>
    <time_frame>30 months</time_frame>
    <description>To determine if a gene-derived individualized treatment approach in patients with drug-resistant TB will improve culture negative survival rates at 6 months post treatment initiation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tuberculosis treatment outcomes</measure>
    <time_frame>30 months</time_frame>
    <description>Treatment outcomes are based on treatment success (cure rates and completion of treatment) or mortality or retention in care or time to culture conversion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rates of adverse events</measure>
    <time_frame>30 months</time_frame>
    <description>Rates of adverse events will be compared between arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Characterization of multi drug-resistant tuberculosis strains</measure>
    <time_frame>30 months</time_frame>
    <description>The minimum inhibitory concentrations of Mtb isolates will be correlated with the genotypic mutations detected and the evolution of drug resistance will be monitored by comparing serial isolates from patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Drug Concentration</measure>
    <time_frame>30 months</time_frame>
    <description>To determine the drug concentrations and long-term drug exposures to DR-TB drug regimens in DBS and hair samples respectively</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure of adherence</measure>
    <time_frame>30 months</time_frame>
    <description>To compare adherence to DR-TB drugs using drug concentrations in DBS samples, hair samples, pill count data and participant self-report</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of HIV drug resistance</measure>
    <time_frame>30 months</time_frame>
    <description>To assess the evolution of HIV drug resistance in patients receiving Bedaquiline and ART for HIV/MDR-TB treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improved assessment and management of DR-TB</measure>
    <time_frame>30 months</time_frame>
    <description>Development of an optimized method for extraction of MTB DNA directly from sputum samples for WGS, compare resistance mutations detected by WGS to current Xpert and LPA; to design a clinical decision-making algorithm for assessment and management of detected resistance mutations</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">205</enrollment>
  <condition>Tuberculosis, Multidrug-Resistant</condition>
  <arm_group>
    <arm_group_label>Individualized treatment for drug resistant tuberculosis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with drug resistance will have whole genome sequencing performed on the respective positive MGIT sample. An individualized TB treatment regimen will be provided to patients based on the whole genome sequencing results</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard treatment regimen for drug resistant tuberculosis</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>As per South African Department of Health Standard of Care for the treatment of drug resistant tuberculosis</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Individualized TB treatment with multiple drugs</intervention_name>
    <description>Patients with drug-resistant TB will receive a combination of any of the following drugs based on whole genome sequencing:&#xD;
rifampicin, rifabutin, isoniazid, high dose isoniazid, pyrazinamide, ethambutol, levofloxacin, moxifloxacin, ofloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, pretomanid, linezolid, sutezolid, clofazimine, bedaquiline, delaminid, para-aminosalicylic acid, imipenem/cilastatin, meropenem, amoxicillin/clavulanate, clarithromycin, azithromycin and thioacetazone</description>
    <arm_group_label>Individualized treatment for drug resistant tuberculosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standardized TB treatment with multiple drugs</intervention_name>
    <description>Patients with drug-resistant TB with receive a combination of any of the following drugs based on South African Department of Health guidelines:&#xD;
rifampicin, rifabutin, isoniazid, high dose isoniazid, pyrazinamide, ethambutol, levofloxacin, moxifloxacin, ofloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, pretomanid, linezolid, sutezolid, clofazimine, bedaquiline, delaminid, para-aminosalicylic acid, imipenem/cilastatin, meropenem, amoxicillin/clavulanate, clarithromycin, azithromycin and thioacetazone</description>
    <arm_group_label>Standard treatment regimen for drug resistant tuberculosis</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          -  Adults ≥ 18 years of age&#xD;
&#xD;
          -  Pulmonary Tuberculosis&#xD;
&#xD;
          -  Microbiological confirmation [e.g. GeneXpert Mycobacterium Tuberculosis (MTB) detected&#xD;
             and Rifampicin (RIF) resistant and / Line Probe Assay (LPA)] of Multi drug-resistant&#xD;
             tuberculosis (MDR-TB) / Pre-Extremely drug-resistant tuberculosis (Pre-XDR-TB) /&#xD;
             Extremely drug-resistant tuberculosis (XDR-TB)&#xD;
&#xD;
          -  Capacity for providing informed consent&#xD;
&#xD;
          -  HIV status - HIV infected and uninfected patients are allowed in the study:&#xD;
&#xD;
               -  Patients already on antiretroviral treatment (ART) will be allowed in the study.&#xD;
                  The antiretroviral treatment regimen will be evaluated for any contraindications&#xD;
                  to the drugs used.&#xD;
&#xD;
               -  HIV infected patients at any CD4 count irrespective of antiretroviral treatment&#xD;
                  commencement and duration will be included in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Persons suffering from any serious acute condition.&#xD;
&#xD;
          -  Any other chronic or clinically significant medical condition that in the opinion of&#xD;
             the attending clinician would render the patient unsuitable for participation in the&#xD;
             study.&#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>Nesri Padayatchi, MBChB, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre for the AIDS Programme of Research in South Africa</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>King Dinuzulu Hospital</name>
      <address>
        <city>Durban</city>
        <state>Kwa-Zulu Natal</state>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
  </location_countries>
  <reference>
    <citation>Musser JM. Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev. 1995 Oct;8(4):496-514. doi: 10.1128/CMR.8.4.496.</citation>
    <PMID>8665467</PMID>
  </reference>
  <reference>
    <citation>Outhred AC, Jelfs P, Suliman B, Hill-Cawthorne GA, Crawford AB, Marais BJ, Sintchenko V. Added value of whole-genome sequencing for management of highly drug-resistant TB. J Antimicrob Chemother. 2015 Apr;70(4):1198-202. doi: 10.1093/jac/dku508. Epub 2014 Dec 9.</citation>
    <PMID>25492392</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 27, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>August 30, 2023</last_update_submitted>
  <last_update_submitted_qc>August 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Centre for the AIDS Programme of Research in South Africa</investigator_affiliation>
    <investigator_full_name>Dr Nesri Padayatchi</investigator_full_name>
    <investigator_title>Deputy Director</investigator_title>
  </responsible_party>
  <keyword>whole genome sequencing;</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>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual participant data that underlie the results of the objectives of the study, after deidentification</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>Beginning 9 months and ending 36 months following article publication</ipd_time_frame>
    <ipd_access_criteria>Investigators wishing to access data from this study will need to contact the PI to request the data. Requests may be submitted up to 36 months following article publication. Investigators will need to complete a proposal for how the data will be used. The proposal will be reviewed by the CAPRISA Scientific Review Committee and the CAPRISA Executive Committee.</ipd_access_criteria>
  </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/NCT03237182
org study id: CAP 020
nct id: NCT03237182
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a randomized controlled clinical trial comparing treatment success of a gene-derived
      individualized drug-resistant Tuberculosis regimen to a standard Tuberculosis regimen based
      on South African National Tuberculosis guidelines.
When drug resistance is detected by molecular methods such as the Xpert MTB/RIF assay,
      second-line Multi Drug-Resistant (MDR) Tuberculosis treatment is started in the complete
      absence of detailed resistance information. The diagnosis of Multi Drug-Resistant
      Tuberculosis is confirmed only on availability of Line Probe Assay (LPA)/Drug Susceptibility
      Testing (DST) results. Extremely Drug-Resistant (XDR) Tuberculosis is diagnosed by in vitro
      phenotypic resistance to Rifampicin, Isoniazid, fluoroquinolones and injectable second-line
      drugs (i.e., amikacin, kanamycin, or capreomycin). Existing culture based Drug Susceptibility
      Testing provides results after 6-8 weeks. This duration may be further increased by other
      existing laboratory challenges, such as culture contamination.

      Furthermore, initial regimens are often not optimal and sometimes completely ineffective as
      there is a lack of Drug Susceptibility Testing to support them. More importantly, even
      optimal regimens are changed due to patient intolerance of the drug's side effects.

      Whole Genome Sequencing (WGS) has the advantage of determining the complete Deoxyribonucleic
      acid (DNA) sequence of an organism's genome at a single time point. Using this technology,
      genotypic mutations conferring resistance to anti-tuberculosis drugs can be identified. This
      information will assist in identifying not only potential resistant drugs, but also
      susceptible drugs and thus enable a more accurate and appropriate choice of regimen. In
      addition, drugs that will not add value to the treatment outcome, but will increase rates of
      adverse drug reactions, can be eliminated earlier, improving drug-resistant TB treatment
      outcomes.

      In this proposal, we aim to use Mycobacterium Tuberculosis (MTB) whole genome sequencing
      prior to the selection of a drug-resistant tuberculosis treatment regimen and thus provide an
      individualized treatment strategy for drug-resistant tuberculosis. By adopting this method,
      we hope to improve culture negative survival rates at 6 months post treatment initiation .

      This study will include 448 adult patients (age ≥ 18 years) that meet inclusion criteria.
      Patients referred by provincial satellite facilities with microbiological confirmation of
      drug-resistant tuberculosis (e.g. Xpert MTB/RIF assay / Line Probe Assay) to King DinuZulu
      Hospital (KDH) will be recruited. Patients randomized to the control arm will receive
      standard of care (SOC) treatment. Patients randomized to the intervention arm will be given
      an individualized treatment regimen based on whole genome sequencing conducted on
      Mycobacteria Growth Indicator Tube (MGIT) positive sputum samples collected at the screening
      visit.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients randomized to the intervention receive a individualized tuberculosis treatment based on whole genome sequencing and the patients randomized to the control receive the standard of care tuberculosis treatment
primary purpose: Treatment
masking: None (Open Label)
measure: Culture negative survival rate
time frame: 24 months
description: To determine if a gene-derived individualized treatment approach in patients with drug-resistant TB will improve culture negative survival rates at 6 months post treatment initiation
measure: Culture negative survival rate
time frame: 30 months
description: To determine if a gene-derived individualized treatment approach in patients with drug-resistant TB will improve culture negative survival rates at 6 months post treatment initiation
measure: Tuberculosis treatment outcomes
time frame: 30 months
description: Treatment outcomes are based on treatment success (cure rates and completion of treatment) or mortality or retention in care or time to culture conversion
measure: Rates of adverse events
time frame: 30 months
description: Rates of adverse events will be compared between arms
measure: Characterization of multi drug-resistant tuberculosis strains
time frame: 30 months
description: The minimum inhibitory concentrations of Mtb isolates will be correlated with the genotypic mutations detected and the evolution of drug resistance will be monitored by comparing serial isolates from patients
measure: Drug Concentration
time frame: 30 months
description: To determine the drug concentrations and long-term drug exposures to DR-TB drug regimens in DBS and hair samples respectively
measure: Measure of adherence
time frame: 30 months
description: To compare adherence to DR-TB drugs using drug concentrations in DBS samples, hair samples, pill count data and participant self-report
measure: Evolution of HIV drug resistance
time frame: 30 months
description: To assess the evolution of HIV drug resistance in patients receiving Bedaquiline and ART for HIV/MDR-TB treatment
measure: Improved assessment and management of DR-TB
time frame: 30 months
description: Development of an optimized method for extraction of MTB DNA directly from sputum samples for WGS, compare resistance mutations detected by WGS to current Xpert and LPA; to design a clinical decision-making algorithm for assessment and management of detected resistance mutations
arm group label: Individualized treatment for drug resistant tuberculosis
arm group type: Experimental
description: Patients with drug resistance will have whole genome sequencing performed on the respective positive MGIT sample. An individualized TB treatment regimen will be provided to patients based on the whole genome sequencing results
arm group label: Standard treatment regimen for drug resistant tuberculosis
arm group type: Active Comparator
description: As per South African Department of Health Standard of Care for the treatment of drug resistant tuberculosis
intervention type: Drug
intervention name: Individualized TB treatment with multiple drugs
description: Patients with drug-resistant TB will receive a combination of any of the following drugs based on whole genome sequencing:
rifampicin, rifabutin, isoniazid, high dose isoniazid, pyrazinamide, ethambutol, levofloxacin, moxifloxacin, ofloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, pretomanid, linezolid, sutezolid, clofazimine, bedaquiline, delaminid, para-aminosalicylic acid, imipenem/cilastatin, meropenem, amoxicillin/clavulanate, clarithromycin, azithromycin and thioacetazone
arm group label: Individualized treatment for drug resistant tuberculosis
intervention type: Drug
intervention name: Standardized TB treatment with multiple drugs
description: Patients with drug-resistant TB with receive a combination of any of the following drugs based on South African Department of Health guidelines:
rifampicin, rifabutin, isoniazid, high dose isoniazid, pyrazinamide, ethambutol, levofloxacin, moxifloxacin, ofloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, pretomanid, linezolid, sutezolid, clofazimine, bedaquiline, delaminid, para-aminosalicylic acid, imipenem/cilastatin, meropenem, amoxicillin/clavulanate, clarithromycin, azithromycin and thioacetazone
arm group label: Standard treatment regimen for drug resistant tuberculosis
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nesri Padayatchi, MBChB, PhD
role: Principal Investigator
affiliation: Centre for the AIDS Programme of Research in South Africa
facility: 
country: South Africa
citation: Musser JM. Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev. 1995 Oct;8(4):496-514. doi: 10.1128/CMR.8.4.496.
PMID: 8665467
citation: Outhred AC, Jelfs P, Suliman B, Hill-Cawthorne GA, Crawford AB, Marais BJ, Sintchenko V. Added value of whole-genome sequencing for management of highly drug-resistant TB. J Antimicrob Chemother. 2015 Apr;70(4):1198-202. doi: 10.1093/jac/dku508. Epub 2014 Dec 9.
PMID: 25492392
responsible party type: Principal Investigator
investigator affiliation: Centre for the AIDS Programme of Research in South Africa
investigator full name: Dr Nesri Padayatchi
investigator title: Deputy Director
mesh term: Tuberculosis
mesh term: Tuberculosis, Multidrug-Resistant
sharing ipd: Yes
ipd description: Individual participant data that underlie the results of the objectives of the study, after deidentification
ipd info type: Study Protocol
ipd time frame: Beginning 9 months and ending 36 months following article publication
ipd access criteria: Investigators wishing to access data from this study will need to contact the PI to request the data. Requests may be submitted up to 36 months following article publication. Investigators will need to complete a proposal for how the data will be used. The proposal will be reviewed by the CAPRISA Scientific Review Committee and the CAPRISA Executive Committee.