<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/NCT03303963</url>
  </required_header>
  <id_info>
    <org_study_id>DRIA2014-326</org_study_id>
    <nct_id>NCT03303963</nct_id>
  </id_info>
  <brief_title>DIAgnostics for Multidrug Resistant Tuberculosis in Africa</brief_title>
  <acronym>DIAMA</acronym>
  <official_title>Culture Free Diagnosis and Follow-up of Multidrug Resistant Tuberculosis Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dissou AFFOLABI</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rwanda Biomedical Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Tuberculosis Reference Laboratory Bamenda</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Jimma University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Service de Pneumophtisiologie, Hôpital Ignace Deen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of the Sciences, Techniques and Technologies of Bamako</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Damien Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cheikh Anta Diop University, Senegal</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institute of Tropical Medicine, Belgium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>World Health Organization</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>London School of Hygiene and Tropical Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Genoscreen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Laboratoire de Référence des Mycobactéries</source>
  <oversight_info>
    <has_dmc>No</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>
      Recent advances in molecular diagnostics of tuberculosis, especially the GeneXpert&#xD;
      Mycobacterium tuberculosis/Rifampicin test have reduced the time to diagnose Rifampicin&#xD;
      Resistant Tuberculosis (RR-TB) but only rifampicin resistance is diagnosed, leading to&#xD;
      presumptive diagnosis of resistance to isoniazid and maybe other drugs. Thus in low and&#xD;
      middle income countries, most drug sensitivity testing relies on phenotypic drug resistance&#xD;
      testing, which takes up to 4 months. In addition, currently, culture on monthly sputum&#xD;
      samples is recommended by the World Health Organization for follow-up of Rifampicin Resistant&#xD;
      Tuberculosis patients under treatment. Unfortunately, culture is often not locally available&#xD;
      and samples need to be transported from field to culture laboratories. The associated&#xD;
      transport delays lead to high rates of contamination and false negative culture, particularly&#xD;
      in laboratories in low resource settings. Many gaps for the diagnosis and management of RR-TB&#xD;
      patients still need to be addressed and the DIAMA project (DIAgnostics for Multidrug&#xD;
      resistant tuberculosis in Africa) study aims to address some of them.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The proposed DIAMA (DIAgnostics for Multidrug resistant tuberculosis in Africa) study aims to&#xD;
      address current gaps in the diagnosis and management of patients with Multi-Drug-Resistant&#xD;
      (MDR) tuberculosis. Building on existing networks and research collaborations previously&#xD;
      funded by the European &amp; Developing Countries Clinical Trials Partnership (EDCTP), this&#xD;
      project involved partners in West, Central, and East Africa. It aims to evaluate and&#xD;
      implement rapid and accurate molecular tests for several anti Tuberculosis drugs, to replace&#xD;
      the current dependency on phenotypic drug resistance testing, which takes up to 4 months and&#xD;
      is technically so demanding that few laboratories can perform it correctly.&#xD;
&#xD;
      The project builds on the continuous surveillance of Tuberculosis retreatment patients for&#xD;
      rifampicin resistance. Two African partners (Benin and Rwanda) with advanced molecular&#xD;
      laboratories are establishing reference laboratories for the 'Deeplex' assay, a novel&#xD;
      multiplex deep sequencing-based drug resistance diagnostic platform that simultaneously&#xD;
      provides sequence information of genes that confer resistance to several key anti&#xD;
      tuberculosis drugs. Partners are recruiting all patients with rifampicin resistant&#xD;
      Tuberculosis, and a subset of those with rifampicin sensitive Tuberculosis. In a first phase,&#xD;
      sputum will be shipped for the Deeplex assay, for comparison against phenotypic DST, the&#xD;
      reference method for detecting resistance to 1st and 2nd line drugs. In addition, since Whole&#xD;
      Genome Sequencing is the &quot;reference&quot; of molecular tests, Deeplex assay will also be validated&#xD;
      again this test. In a second phase, Cepheid 2nd line Xpert and Molbio Truenat test, two&#xD;
      'lower tech' tests at the last stages of laboratory validations, will also be validated. The&#xD;
      Cepheid Xpert 2nd line cartridge can be implemented in existing Xpert machines used for the&#xD;
      Xpert MTB/Rif assays. These tests will be compared versus the Deeplex assay and versus WGS&#xD;
&#xD;
      Using the latest advances in DataTocare software developed by one of the project partners,&#xD;
      molecular results will be communicated in real time to the National Tuberculosis Programmes,&#xD;
      so that Multi Drug Resistant Tuberculosis patients can swiftly start appropriate treatment.&#xD;
      The added-value of this system will be evaluated as a pilot study in some sites.&#xD;
&#xD;
      Lastly, once patients have initiated MDR treatment, they will be monitored for treatment&#xD;
      success by faster alternative approaches to the WHO recommended monthly cultures: serial&#xD;
      sputum samples will have Fluorescein DiAcetate (FDA) vital stain microscopy, measurement of&#xD;
      the bacterial load using the Xpert MTB/Rif as well as precursor of ribosomal RNA measurement&#xD;
      (pre-rRNA).&#xD;
&#xD;
      Together, these advances are expected to dramatically improve the currently dismal prognosis&#xD;
      of MDR-TB in health systems in resource-poor settings.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 4, 2017</start_date>
  <completion_date type="Actual">November 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Validation of Deeplex test</measure>
    <time_frame>4 years</time_frame>
    <description>Concordance between phenotypic Drug Susceptibility Test, WGS and Deeplex results</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Validation of GeneXpert 2nd line</measure>
    <time_frame>4 years</time_frame>
    <description>Concordance between WGS, Deeplex results and GeneXpert 2nd line results</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Validation of MolBio TrueNat for INH, FQ and BDQ</measure>
    <time_frame>4 years</time_frame>
    <description>Concordance between WGS, Deeplex results and MolBioTrueNat results</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Validation of FDA microscopy</measure>
    <time_frame>4 years</time_frame>
    <description>Concordance between Culture results and FDA microscopy results</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Validation of GeneXpert Ct value</measure>
    <time_frame>4 years</time_frame>
    <description>Concordance between Culture results and GeneXpert Ct value results</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Estimation of proportion of additional resistance in patients resistant to Rifampicin</measure>
    <time_frame>4 years</time_frame>
    <description>Evaluation to be done with the Deeplex test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of the association of specific mutations against some drugs with programmatic treatment outcome</measure>
    <time_frame>4 years</time_frame>
    <description>Evaluation to be done with the Deeplex test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of the add value of Connectivity system in the management of Multi Drug Resistant-Tuberculosis patients</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation to be done with Data2Care connectivity system</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">3356</enrollment>
  <condition>Tuberculosis, Multidrug-Resistant</condition>
  <arm_group>
    <arm_group_label>Rifampicin resistant and susceptible patients</arm_group_label>
    <description>Study 1: Patients detected positive by the GeneXpert Mycobacterium tuberculosis/Rifampicin (susceptible and resistant to rifampicin)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rifampicin resistant patients</arm_group_label>
    <description>Study 2: Follow up of the rifampicin resistant patients included in the study 1 during their treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line</intervention_name>
    <description>Improvement of the diagnosis of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to diagnose Tuberculosis resistance to 1st and 2nd line drugs through novel molecular multiplex assays (Study 1) by:&#xD;
Validating the Deeplex test and establish a network for shipment of sputum samples in ethanol to regional reference laboratories (Study 1 - phase 1)&#xD;
Validating the Molbio Truenat test as a point of care test (Study 1 - phase 2)&#xD;
Validating the Cepheid GeneXpert 2nd line cartridge at the district level (Study 1 -phase2)</description>
    <arm_group_label>Rifampicin resistant and susceptible patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis</intervention_name>
    <description>Improvement of the management of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to set up alternative culture-free approaches for the monitoring of patients' response to Multi Drug Resistant-Tuberculosis treatment (Study 2), with:&#xD;
FDA microscopy&#xD;
Measurement of bacterial load by following Cycle threshold (Ct) values in GeneXpert Mycobacterium tuberculosis/Rifampicin&#xD;
Measurement of pre-rRNA synthesis</description>
    <arm_group_label>Rifampicin resistant patients</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Sputum.&#xD;
&#xD;
      At the enrolment, three samples (spot-overnight-spot) will be collected for the comparison of&#xD;
      phenotypic results against molecular results.&#xD;
&#xD;
      During the treatment, two monthly samples (overnight-spot) will be collected for the&#xD;
      comparison of culture result against FDA Microscopy and GeneXpert Ct values.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Two multi center observational studies will be conducted:&#xD;
&#xD;
        Study 1: Cross sectional study for Tuberculosis(TB) cases aged ≥ 15 (all Rifampicin&#xD;
        resistant (RR) ones (new cases or retreatment patients) and equal number of Rifampicin&#xD;
        sensitive retreatment patients from the same country) with comparison of TB resistance&#xD;
        diagnostic test performance at baseline. There are 2 phases in this project; phase 1 is the&#xD;
        comparison of Deeplex results against the phenotypic results and WGS (Gold standard), phase&#xD;
        2 is the comparison of MolBio TrueNat and GeneXpert 2nd generation results against Deeplex&#xD;
        and WGS (gold standard).&#xD;
&#xD;
        Study 2: Cohort study of RR-TB patients (recruited in Study 1) under treatment with&#xD;
        comparison of the performance of FDA and GeneXpert compared to solid culture&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Being ≥ 15 year old&#xD;
&#xD;
          -  Having a positive test on GeneXpert (M. tuberculosis) with or without resistance&#xD;
             detected to rifampicin&#xD;
&#xD;
          -  Willing and able to provide written informed consent, or for minors: assent from and&#xD;
             consent from a legal representative&#xD;
&#xD;
        Exclusion Criteria: None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dissou AFFOLABI, MD, MSc, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Laboratoire de Référence des Mycobactéries</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institute of Tropical Medecine</name>
      <address>
        <city>Antwerp</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou</name>
      <address>
        <city>Cotonou</city>
        <state>Atlantique/Littoral</state>
        <zip>01BP321</zip>
        <country>Benin</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Tuberculosis Reference Laboratory Bamenda</name>
      <address>
        <city>Bamenda</city>
        <country>Cameroon</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut National de Recherche Biomédicale (INRB)</name>
      <address>
        <city>Kinshasa</city>
        <country>Congo, The Democratic Republic of the</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jimma University</name>
      <address>
        <city>Jīma</city>
        <country>Ethiopia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Service de Pneumophtisiologie, Hôpital Ignace Deen, Conakry</name>
      <address>
        <city>Conakry</city>
        <country>Guinea</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Université des Sciences, des Techniques et des Technologies de Bamako, SEREFO</name>
      <address>
        <city>Bamako</city>
        <country>Mali</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Damien Fundation</name>
      <address>
        <city>Ibadan</city>
        <country>Nigeria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rwanda Biomedical Center (RBC)</name>
      <address>
        <city>Kigali</city>
        <country>Rwanda</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Université Cheick Anta Diop (UCAD)</name>
      <address>
        <city>Dakar</city>
        <country>Senegal</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Benin</country>
    <country>Cameroon</country>
    <country>Congo, The Democratic Republic of the</country>
    <country>Ethiopia</country>
    <country>Guinea</country>
    <country>Mali</country>
    <country>Nigeria</country>
    <country>Rwanda</country>
    <country>Senegal</country>
  </location_countries>
  <reference>
    <citation>Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010 Sep 9;363(11):1005-15. doi: 10.1056/NEJMoa0907847. Epub 2010 Sep 1.</citation>
    <PMID>20825313</PMID>
  </reference>
  <results_reference>
    <citation>Bastos ML, Hussain H, Weyer K, Garcia-Garcia L, Leimane V, Leung CC, Narita M, Pena JM, Ponce-de-Leon A, Seung KJ, Shean K, Sifuentes-Osornio J, Van der Walt M, Van der Werf TS, Yew WW, Menzies D; Collaborative Group for Meta-analysis of Individual Patient Data in MDR-TB. Treatment outcomes of patients with multidrug-resistant and extensively drug-resistant tuberculosis according to drug susceptibility testing to first- and second-line drugs: an individual patient data meta-analysis. Clin Infect Dis. 2014 Nov 15;59(10):1364-74. doi: 10.1093/cid/ciu619. Epub 2014 Aug 5.</citation>
    <PMID>25097082</PMID>
  </results_reference>
  <results_reference>
    <citation>Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, Rieder HL. Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis. 2014 Oct;18(10):1180-7. doi: 10.5588/ijtld.14.0100.</citation>
    <PMID>25216831</PMID>
  </results_reference>
  <results_reference>
    <citation>Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, Hanki Y, Van Deun A. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis. 2014 Oct;18(10):1188-94. doi: 10.5588/ijtld.13.0075.</citation>
    <PMID>25216832</PMID>
  </results_reference>
  <results_reference>
    <citation>Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, Rieder HL. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684-92. doi: 10.1164/rccm.201001-0077OC. Epub 2010 May 4.</citation>
    <PMID>20442432</PMID>
  </results_reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 24, 2017</study_first_submitted>
  <study_first_submitted_qc>October 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 6, 2017</study_first_posted>
  <last_update_submitted>March 13, 2023</last_update_submitted>
  <last_update_submitted_qc>March 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Laboratoire de Référence des Mycobactéries</investigator_affiliation>
    <investigator_full_name>Dissou AFFOLABI</investigator_full_name>
    <investigator_title>Professor (Deputy Head of the Laboratory)</investigator_title>
  </responsible_party>
  <keyword>culture-free</keyword>
  <keyword>tuberculosis</keyword>
  <keyword>multidrug resistant</keyword>
  <keyword>diagnosis</keyword>
  <keyword>follow-up</keyword>
  <keyword>africa</keyword>
  <keyword>molecular tools</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>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 21, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/63/NCT03303963/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03303963
org study id: DRIA2014-326
nct id: NCT03303963
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
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collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Recent advances in molecular diagnostics of tuberculosis, especially the GeneXpert
      Mycobacterium tuberculosis/Rifampicin test have reduced the time to diagnose Rifampicin
      Resistant Tuberculosis (RR-TB) but only rifampicin resistance is diagnosed, leading to
      presumptive diagnosis of resistance to isoniazid and maybe other drugs. Thus in low and
      middle income countries, most drug sensitivity testing relies on phenotypic drug resistance
      testing, which takes up to 4 months. In addition, currently, culture on monthly sputum
      samples is recommended by the World Health Organization for follow-up of Rifampicin Resistant
      Tuberculosis patients under treatment. Unfortunately, culture is often not locally available
      and samples need to be transported from field to culture laboratories. The associated
      transport delays lead to high rates of contamination and false negative culture, particularly
      in laboratories in low resource settings. Many gaps for the diagnosis and management of RR-TB
      patients still need to be addressed and the DIAMA project (DIAgnostics for Multidrug
      resistant tuberculosis in Africa) study aims to address some of them.
The proposed DIAMA (DIAgnostics for Multidrug resistant tuberculosis in Africa) study aims to
      address current gaps in the diagnosis and management of patients with Multi-Drug-Resistant
      (MDR) tuberculosis. Building on existing networks and research collaborations previously
      funded by the European & Developing Countries Clinical Trials Partnership (EDCTP), this
      project involved partners in West, Central, and East Africa. It aims to evaluate and
      implement rapid and accurate molecular tests for several anti Tuberculosis drugs, to replace
      the current dependency on phenotypic drug resistance testing, which takes up to 4 months and
      is technically so demanding that few laboratories can perform it correctly.

      The project builds on the continuous surveillance of Tuberculosis retreatment patients for
      rifampicin resistance. Two African partners (Benin and Rwanda) with advanced molecular
      laboratories are establishing reference laboratories for the 'Deeplex' assay, a novel
      multiplex deep sequencing-based drug resistance diagnostic platform that simultaneously
      provides sequence information of genes that confer resistance to several key anti
      tuberculosis drugs. Partners are recruiting all patients with rifampicin resistant
      Tuberculosis, and a subset of those with rifampicin sensitive Tuberculosis. In a first phase,
      sputum will be shipped for the Deeplex assay, for comparison against phenotypic DST, the
      reference method for detecting resistance to 1st and 2nd line drugs. In addition, since Whole
      Genome Sequencing is the "reference" of molecular tests, Deeplex assay will also be validated
      again this test. In a second phase, Cepheid 2nd line Xpert and Molbio Truenat test, two
      'lower tech' tests at the last stages of laboratory validations, will also be validated. The
      Cepheid Xpert 2nd line cartridge can be implemented in existing Xpert machines used for the
      Xpert MTB/Rif assays. These tests will be compared versus the Deeplex assay and versus WGS

      Using the latest advances in DataTocare software developed by one of the project partners,
      molecular results will be communicated in real time to the National Tuberculosis Programmes,
      so that Multi Drug Resistant Tuberculosis patients can swiftly start appropriate treatment.
      The added-value of this system will be evaluated as a pilot study in some sites.

      Lastly, once patients have initiated MDR treatment, they will be monitored for treatment
      success by faster alternative approaches to the WHO recommended monthly cultures: serial
      sputum samples will have Fluorescein DiAcetate (FDA) vital stain microscopy, measurement of
      the bacterial load using the Xpert MTB/Rif as well as precursor of ribosomal RNA measurement
      (pre-rRNA).

      Together, these advances are expected to dramatically improve the currently dismal prognosis
      of MDR-TB in health systems in resource-poor settings.
observational model: Cohort
time perspective: Prospective
measure: Validation of Deeplex test
time frame: 4 years
description: Concordance between phenotypic Drug Susceptibility Test, WGS and Deeplex results
measure: Validation of GeneXpert 2nd line
time frame: 4 years
description: Concordance between WGS, Deeplex results and GeneXpert 2nd line results
measure: Validation of MolBio TrueNat for INH, FQ and BDQ
time frame: 4 years
description: Concordance between WGS, Deeplex results and MolBioTrueNat results
measure: Validation of FDA microscopy
time frame: 4 years
description: Concordance between Culture results and FDA microscopy results
measure: Validation of GeneXpert Ct value
time frame: 4 years
description: Concordance between Culture results and GeneXpert Ct value results
measure: Estimation of proportion of additional resistance in patients resistant to Rifampicin
time frame: 4 years
description: Evaluation to be done with the Deeplex test
measure: Measurement of the association of specific mutations against some drugs with programmatic treatment outcome
time frame: 4 years
description: Evaluation to be done with the Deeplex test
measure: Evaluation of the add value of Connectivity system in the management of Multi Drug Resistant-Tuberculosis patients
time frame: 2 years
description: Evaluation to be done with Data2Care connectivity system
arm group label: Rifampicin resistant and susceptible patients
description: Study 1: Patients detected positive by the GeneXpert Mycobacterium tuberculosis/Rifampicin (susceptible and resistant to rifampicin)
arm group label: Rifampicin resistant patients
description: Study 2: Follow up of the rifampicin resistant patients included in the study 1 during their treatment
intervention type: Diagnostic Test
intervention name: Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line
description: Improvement of the diagnosis of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to diagnose Tuberculosis resistance to 1st and 2nd line drugs through novel molecular multiplex assays (Study 1) by:
Validating the Deeplex test and establish a network for shipment of sputum samples in ethanol to regional reference laboratories (Study 1 - phase 1)
Validating the Molbio Truenat test as a point of care test (Study 1 - phase 2)
Validating the Cepheid GeneXpert 2nd line cartridge at the district level (Study 1 -phase2)
arm group label: Rifampicin resistant and susceptible patients
intervention type: Diagnostic Test
intervention name: Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis
description: Improvement of the management of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to set up alternative culture-free approaches for the monitoring of patients' response to Multi Drug Resistant-Tuberculosis treatment (Study 2), with:
FDA microscopy
Measurement of bacterial load by following Cycle threshold (Ct) values in GeneXpert Mycobacterium tuberculosis/Rifampicin
Measurement of pre-rRNA synthesis
arm group label: Rifampicin resistant patients
Sputum.

      At the enrolment, three samples (spot-overnight-spot) will be collected for the comparison of
      phenotypic results against molecular results.

      During the treatment, two monthly samples (overnight-spot) will be collected for the
      comparison of culture result against FDA Microscopy and GeneXpert Ct values.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 15 Years
maximum age: N/A
healthy volunteers: No
last name: Dissou AFFOLABI, MD, MSc, PhD
role: Principal Investigator
affiliation: Laboratoire de Référence des Mycobactéries
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country: Belgium
country: Benin
country: Cameroon
country: Congo, The Democratic Republic of the
country: Ethiopia
country: Guinea
country: Mali
country: Nigeria
country: Rwanda
country: Senegal
citation: Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010 Sep 9;363(11):1005-15. doi: 10.1056/NEJMoa0907847. Epub 2010 Sep 1.
PMID: 20825313
citation: Bastos ML, Hussain H, Weyer K, Garcia-Garcia L, Leimane V, Leung CC, Narita M, Pena JM, Ponce-de-Leon A, Seung KJ, Shean K, Sifuentes-Osornio J, Van der Walt M, Van der Werf TS, Yew WW, Menzies D; Collaborative Group for Meta-analysis of Individual Patient Data in MDR-TB. Treatment outcomes of patients with multidrug-resistant and extensively drug-resistant tuberculosis according to drug susceptibility testing to first- and second-line drugs: an individual patient data meta-analysis. Clin Infect Dis. 2014 Nov 15;59(10):1364-74. doi: 10.1093/cid/ciu619. Epub 2014 Aug 5.
PMID: 25097082
citation: Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, Rieder HL. Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis. 2014 Oct;18(10):1180-7. doi: 10.5588/ijtld.14.0100.
PMID: 25216831
citation: Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, Hanki Y, Van Deun A. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis. 2014 Oct;18(10):1188-94. doi: 10.5588/ijtld.13.0075.
PMID: 25216832
citation: Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, Rieder HL. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684-92. doi: 10.1164/rccm.201001-0077OC. Epub 2010 May 4.
PMID: 20442432
responsible party type: Sponsor-Investigator
investigator affiliation: Laboratoire de Référence des Mycobactéries
investigator full name: Dissou AFFOLABI
investigator title: Professor (Deputy Head of the Laboratory)
mesh term: Tuberculosis
mesh term: Tuberculosis, Multidrug-Resistant
sharing ipd: Undecided
provided document: 