<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/NCT02245347</url>
  </required_header>
  <id_info>
    <org_study_id>12.LO.1694</org_study_id>
    <nct_id>NCT02245347</nct_id>
  </id_info>
  <brief_title>Genome Sequencing of Multidrug Resistant Tuberculosis (MDR TB) in Sputum</brief_title>
  <acronym>MDRTB01</acronym>
  <official_title>Genome Sequencing of MDR TB in Sputum</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St George's Healthcare NHS Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St George's Healthcare NHS Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Drug resistant tuberculosis is a growing problem world wide. The current methods for&#xD;
      diagnosis are time consuming and may delay diagnosis and treatment for many weeks. In this&#xD;
      study the investigators wish to take sputum samples from patients to see if the investigators&#xD;
      can validate a molecular DNA based process for prompt identification of drug resistant&#xD;
      tuberculosis. The investigators wish to extract and amplify DNA from drug resistant&#xD;
      tuberculosis and identify genes within it that confer resistance.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Drug resistant M. tuberculosis is an increasing problem in the United Kingdom and abroad. In&#xD;
      the United Kingdom (UK) as a whole the number of isolates that were shown to be resistant to&#xD;
      at least one of the first line drugs was nearly 400, with the total number of isolates&#xD;
      approaching 5000. A total of 9040 cases were reported in the UK in 2009 and of these 6.9%&#xD;
      demonstrated resistance to at least one first line drug(1). In certain populations the&#xD;
      incidence of drug resistance is higher: in London, homeless patients, those who have been in&#xD;
      prison and those from certain countries abroad, particularly Eastern Europe.&#xD;
&#xD;
      The difficulty of drug resistant tuberculosis is that the treatment duration, cost and&#xD;
      complexity is increased. Typically the patient will be on treatment for 18 months or more and&#xD;
      the Health Protection Agency (HPA) has estimated the cost of this as being upto £50000.&#xD;
&#xD;
      Current diagnosis rests on the culture of the M. tuberculosis and drug sensitivity testing.&#xD;
      This can take six or eight weeks, meaning that patients may be on ineffective therapy for&#xD;
      some time, leading to further transmission and deterioration of the patient's clinical&#xD;
      condition. In this study the investigators would hope to develop a new test to improve and&#xD;
      expedite the diagnosis of multi- drug resistant or MDR TB.&#xD;
&#xD;
      The predominant mechanism by which resistance occurs in M. tuberculosis is by the development&#xD;
      and selection of mutants containing single nucleotide polymorphisms (SNP's)(2). Present&#xD;
      commercial assays enable only a common subset (5-10) of the (900+) documented resistance&#xD;
      mutations to be detected (www.tbdreamdb.com). It is highly likely that many more exist&#xD;
      particularly in regions of the genome that may modulate sensitivity or resistance. This&#xD;
      complexity is compounded by the requirement to treat TB with cocktails of antibiotics even&#xD;
      for fully drug sensitive M.tuberculosis for which treatment consists of isoniazid (H),&#xD;
      rifampicin (R), pyrazinamide (Z) and ethambutol (E). Multidrug resistant (MDR) and&#xD;
      extensively drug resistant (XDR) TB cases are treated with second line drugs such as&#xD;
      moxifloxacin, amikacin, capreomycin, para-aminosalicylic acid (PAS), thiocetazone and others&#xD;
      for which genotypic markers of resistance are not tested. Such complex treatment combinations&#xD;
      increase the need to screen multiple gene targets with the imperative to treat immediately&#xD;
      with correct combinations of antibiotics.&#xD;
&#xD;
      The large number of mutations makes exhaustive detection of all known SNP's impossible with&#xD;
      existing diagnostic procedures. Whole genome sequencing offers the potential to interrogate&#xD;
      the genome of clinical isolates of M. tuberculosis for all known mutations and from this to&#xD;
      infer an antimicrobial sensitivity pattern.&#xD;
&#xD;
      The extensive cost of treating and managing MDR cases(3) could potentially be reduced by&#xD;
      obtaining a rapid genomic resistance profile early within the patients treatment. Cost&#xD;
      benefit analysis of immediate whole genome sequencing (WGS) on all TB cases would be highly&#xD;
      beneficial financially as well as clinically. The investigators propose to conduct a limited&#xD;
      pilot study to assess the potential to acquire whole genome sequence directly from sputum&#xD;
      specimens, early in a patient's treatment and to retrospectively define the potential impact&#xD;
      of the availability of this data on patient care. This proposal will thus provide an evidence&#xD;
      base for WGS to be developed into a routine diagnostic test/process with medical potential&#xD;
      both at local National Health Service (NHS) level and globally so as to improve care pathways&#xD;
      for MDR and XDR TB.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>April 2013</start_date>
  <primary_completion_date type="Anticipated">April 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Identification and sequencing of mycobacterial DNA from sputum samples</measure>
    <time_frame>within 24 hours of sample collection</time_frame>
    <description>To see if mycobacterial DNA can be identified and sequenced from sputum and if the results correlate with the Microtiter Plate Methods done phenotypically in the standard manner.</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Patients with expected MDR TB</arm_group_label>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Sputum samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Smear positive patients with confirmed or suspected TB&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Any patient with smear positive tuberculosis who is capable to give informed consent&#xD;
             will be offered to be included in the trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any patient under 18 or who is unable to give informed consent will be excluded from&#xD;
             this trial. Any patient who is unable to give a sputum sample.&#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_contact>
    <last_name>Catherine Cosgrove, MBBS</last_name>
    <phone>+44 (0)2087252379</phone>
    <email>ccosgrov@sgul.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>St George's NHS Healthcare Trust</name>
      <address>
        <city>London</city>
        <zip>SW180RE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Catherine Cosgrove, PhD MBBS</last_name>
      <phone>+44(0)2087252379</phone>
      <email>ccosgrov@sgul.ac.uk</email>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>September 12, 2014</study_first_submitted>
  <study_first_submitted_qc>September 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 19, 2014</study_first_posted>
  <last_update_submitted>September 17, 2014</last_update_submitted>
  <last_update_submitted_qc>September 17, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 19, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>TB</keyword>
  <keyword>Tuberculosis</keyword>
  <keyword>MDR TB</keyword>
  <keyword>Drug resistant TB</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_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/NCT02245347
org study id: 12.LO.1694
nct id: NCT02245347
lead sponsor: 
has dmc: No
Drug resistant tuberculosis is a growing problem world wide. The current methods for
      diagnosis are time consuming and may delay diagnosis and treatment for many weeks. In this
      study the investigators wish to take sputum samples from patients to see if the investigators
      can validate a molecular DNA based process for prompt identification of drug resistant
      tuberculosis. The investigators wish to extract and amplify DNA from drug resistant
      tuberculosis and identify genes within it that confer resistance.
Drug resistant M. tuberculosis is an increasing problem in the United Kingdom and abroad. In
      the United Kingdom (UK) as a whole the number of isolates that were shown to be resistant to
      at least one of the first line drugs was nearly 400, with the total number of isolates
      approaching 5000. A total of 9040 cases were reported in the UK in 2009 and of these 6.9%
      demonstrated resistance to at least one first line drug(1). In certain populations the
      incidence of drug resistance is higher: in London, homeless patients, those who have been in
      prison and those from certain countries abroad, particularly Eastern Europe.

      The difficulty of drug resistant tuberculosis is that the treatment duration, cost and
      complexity is increased. Typically the patient will be on treatment for 18 months or more and
      the Health Protection Agency (HPA) has estimated the cost of this as being upto £50000.

      Current diagnosis rests on the culture of the M. tuberculosis and drug sensitivity testing.
      This can take six or eight weeks, meaning that patients may be on ineffective therapy for
      some time, leading to further transmission and deterioration of the patient's clinical
      condition. In this study the investigators would hope to develop a new test to improve and
      expedite the diagnosis of multi- drug resistant or MDR TB.

      The predominant mechanism by which resistance occurs in M. tuberculosis is by the development
      and selection of mutants containing single nucleotide polymorphisms (SNP's)(2). Present
      commercial assays enable only a common subset (5-10) of the (900+) documented resistance
      mutations to be detected (www.tbdreamdb.com). It is highly likely that many more exist
      particularly in regions of the genome that may modulate sensitivity or resistance. This
      complexity is compounded by the requirement to treat TB with cocktails of antibiotics even
      for fully drug sensitive M.tuberculosis for which treatment consists of isoniazid (H),
      rifampicin (R), pyrazinamide (Z) and ethambutol (E). Multidrug resistant (MDR) and
      extensively drug resistant (XDR) TB cases are treated with second line drugs such as
      moxifloxacin, amikacin, capreomycin, para-aminosalicylic acid (PAS), thiocetazone and others
      for which genotypic markers of resistance are not tested. Such complex treatment combinations
      increase the need to screen multiple gene targets with the imperative to treat immediately
      with correct combinations of antibiotics.

      The large number of mutations makes exhaustive detection of all known SNP's impossible with
      existing diagnostic procedures. Whole genome sequencing offers the potential to interrogate
      the genome of clinical isolates of M. tuberculosis for all known mutations and from this to
      infer an antimicrobial sensitivity pattern.

      The extensive cost of treating and managing MDR cases(3) could potentially be reduced by
      obtaining a rapid genomic resistance profile early within the patients treatment. Cost
      benefit analysis of immediate whole genome sequencing (WGS) on all TB cases would be highly
      beneficial financially as well as clinically. The investigators propose to conduct a limited
      pilot study to assess the potential to acquire whole genome sequence directly from sputum
      specimens, early in a patient's treatment and to retrospectively define the potential impact
      of the availability of this data on patient care. This proposal will thus provide an evidence
      base for WGS to be developed into a routine diagnostic test/process with medical potential
      both at local National Health Service (NHS) level and globally so as to improve care pathways
      for MDR and XDR TB.
observational model: Case-Only
time perspective: Prospective
measure: Identification and sequencing of mycobacterial DNA from sputum samples
time frame: within 24 hours of sample collection
description: To see if mycobacterial DNA can be identified and sequenced from sputum and if the results correlate with the Microtiter Plate Methods done phenotypically in the standard manner.
arm group label: Patients with expected MDR TB
Sputum samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Catherine Cosgrove, MBBS
phone: +44 (0)2087252379
email: ccosgrov@sgul.ac.uk
facility: 
status: Recruiting
contact: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Tuberculosis