<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/NCT02231229</url>
  </required_header>
  <id_info>
    <org_study_id>P120130 AOM12317</org_study_id>
    <secondary_id>IDRCB2013-A01406-39</secondary_id>
    <nct_id>NCT02231229</nct_id>
  </id_info>
  <brief_title>Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation</brief_title>
  <acronym>FAST-TB</acronym>
  <official_title>Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation: a National Multicenter Randomized Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      French guidelines currently recommend to initiate a 4-drug containing regimen associating&#xD;
      isoniazid (INH or H), rifampicin (RIFor RMP or R), pyrazinamide (PZA or Z) and ethambutol&#xD;
      (EMB or E) pending the results of drug susceptibility testing (DST). The rationale behind&#xD;
      routine use of EMB is to prevent the emergence of resistance to rifampicin (RMP), in case of&#xD;
      primary resistance to INH. Hence, early detection of resistance to INH and RIF using&#xD;
      molecular testing in Mycobacterium tuberculosis could allow early adaptation of&#xD;
      antituberculosis treatment: i) start with a 3-drug containing regimen (i.e. INH, RIF, and&#xD;
      PZA); ii) early enforcement of treatment when resistance is suspected, pending in depth&#xD;
      susceptibility testings.&#xD;
&#xD;
      the duration of treatment is 6 months or 12 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The impact of rapid detection of resistance with PCR has been poorly evaluated in low-endemic&#xD;
      countries. In France, primary resistance to isoniazid and rifampicin were estimated at,&#xD;
      respectively, 5.2%, and 1.2 %. Based on these estimates, French guidelines currently&#xD;
      recommends to initiate a 4-drug containing regimen associating isoniazid (INH or H),&#xD;
      rifampicin (RIFor RMP or R), pyrazinamide (PZA or Z) and ethambutol (EMB or E) pending the&#xD;
      results of drug susceptibility testing (DST). The rationale behind routine use of EMB is to&#xD;
      prevent the emergence of resistance to rifampicin (RMP), in case of primary resistance to&#xD;
      INH. Hence, early detection of resistance to INH and RIF using molecular testing in&#xD;
      Mycobacterium tuberculosis could allow early adaptation of antituberculosis treatment: i)&#xD;
      start with a 3-drug containing regimen (i.e. INH, RIF, and PZA), in patients with fully&#xD;
      susceptible isolates (currently 95% of cases); ii) early enforcement of treatment when&#xD;
      resistance is suspected, pending in depth susceptibility testings. GenoType ®MTB DR plus&#xD;
      sensitivity for RIF and INH resistance detection has been estimated at 100% and 83%,&#xD;
      respectively.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 23, 2014</start_date>
  <completion_date type="Actual">February 18, 2020</completion_date>
  <primary_completion_date type="Actual">July 4, 2018</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients with treatment success at the end of TB treatment</measure>
    <time_frame>6 or 12 months after enrollment</time_frame>
    <description>TB treatment success (cure certain or probable cure) at the end of TB treatment&#xD;
cure certain: negative sputum cultures or negative sputum direct examination in a patient who has completed treatment and have never filled the definition of treatment failure.&#xD;
probable cure: clinical and radiological improvement of symptoms associated with tuberculosis in a patient who has completed treatment and have never filled the definition of treatment failure.&#xD;
completed treatment: patients who took more than 80% of prescribed treatment.&#xD;
clinical improvement: improvement in overall score of Teeter AND no weight loss&#xD;
radiological improvement: between baseline and end of treatment&#xD;
failure: if Positive sputum culture after 5 months of treatment, death during treatment whatever the cause, treatment interrupted for more than two months, decision of the clinician to change TB treatment because of the suspicion of failure after 5 months of TB treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with relapse</measure>
    <time_frame>within 12 months after the end of TB treatment</time_frame>
    <description>positive culture of respiratory sample after TB treatment and after having had negative cultures during treatment or decision by the clinician to restart treatment because of suspicion of relapse</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with failure</measure>
    <time_frame>6 or 12 months after enrollment</time_frame>
    <description>proportion of patients with treatment changes or discontinuations including the proportion of subjects stopping strategy and treatment assigned at randomization, and the delay between the stop and inclusion.&#xD;
Will not be considered modifications or discontinuations:&#xD;
adaptation of treatment on the results of susceptibility testing in the conventional arm (adaptations following the susceptibility in the PCR arm will therefore be considered as a modification).&#xD;
switching to bitherapy in the 2 arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Capillary drug concentration, for each of the prescribed treatment in hair segments</measure>
    <time_frame>at 2 and 6 months</time_frame>
    <description>measure of drug concentrations in hair segments, for each of the prescribed treatment, in order to estimate treatment observance and if drug hair concentrations are associated with therapy success or toxicity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments</measure>
    <time_frame>6 months or at the latest 12 months after enrollment</time_frame>
    <description>comparison between the 2 arms of incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Direct medical costs associated with each strategy</measure>
    <time_frame>within 18 or at the latest 12 months after enrolment</time_frame>
    <description>comparison of direct medical costs induced by PCR strategy and by conventional strategy</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">204</enrollment>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>PCR-based strategy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PCR-based strategy: after testing for isoniazid and rifampin resistance using a molecular testing with PCR (GenoType ®MTB DR plus), patients will receive HRZ combination therapy (INH , RIF, PZA) if no resistance is detected</description>
  </arm_group>
  <arm_group>
    <arm_group_label>conventional therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Conventional therapy: based on the standard of care in France: initiation of the standard 4 drug regimen INH, RIF, PZA, and EMB, until drug susceptibility testing (DST) results are available.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>PCR-based strategy</intervention_name>
    <description>Treatment based on the results of detection of resistance to isoniazid and rifampicin using PCR (GenoType ® Mycobacterium Tuberculosis Drug Resistance (MTBDR)plus 2.0) in a smear positive patient with pulmonary tuberculosis: initiation of a 3 drug combination (isoniazid (H / INH); rifampicin (R /RIF); pyrazinamide (Z / PZA)) if no resistance is detected and treatment based on suspected resistance in case of INH and/or RIF resistant strain.</description>
    <arm_group_label>PCR-based strategy</arm_group_label>
    <other_name>HRZ combination therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>conventional therapy</intervention_name>
    <description>Initiation of a standard 4 drug combination (isoniazid (H / INH); rifampicin (R /RIF); pyrazinamide (Z / PZA); ethambutol (EMB or E)) until the results of DST are available.</description>
    <arm_group_label>conventional therapy</arm_group_label>
    <other_name>4 drug combination (HRZE)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients&#xD;
&#xD;
          -  with active pulmonary tuberculosis (TB) and positive respiratory samples on&#xD;
             microscopic examination for acid-fast bacilli (AFB+,) who are eligible for a standard&#xD;
             TB treatment with a 4 drug combination&#xD;
&#xD;
          -  PCR (Genotype MTBDR Plus v2.0, Hain Lifescience) result available within the first 7&#xD;
             days of tuberculosis treatment.&#xD;
&#xD;
          -  who are seeking care in France (metropolitan or overseas) and accept a follow-up of 18&#xD;
             to 24 months after inclusion.&#xD;
&#xD;
          -  who have had a prior clinical examination&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Refusal to participate in the study&#xD;
&#xD;
          -  Prior history of TB treatment&#xD;
&#xD;
          -  For women of child bearing age, pregnancy, willing to become pregnant or breastfeeding&#xD;
&#xD;
          -  Patient without healthcare insurance (French social security)&#xD;
&#xD;
          -  Patient participating in another clinical trial&#xD;
&#xD;
          -  Any condition that might compromise, in the investigator's opinion, patient's&#xD;
             compliance with the protocol.&#xD;
&#xD;
          -  Results of cultures available at enrollment&#xD;
&#xD;
          -  No HIV testing available within the last 3 months prior to inclusion in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>84 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yazdan Yazdanpanah, MD-PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bichat Claude Bernard Hospital</name>
      <address>
        <city>Paris</city>
        <zip>75018</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bichat hospital</name>
      <address>
        <city>Paris</city>
        <zip>75018</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>July 3, 2014</study_first_submitted>
  <study_first_submitted_qc>September 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 4, 2014</study_first_posted>
  <last_update_submitted>March 17, 2020</last_update_submitted>
  <last_update_submitted_qc>March 17, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pulmonary tuberculosis</keyword>
  <keyword>Mycobacterium tuberculosis (MTB)</keyword>
  <keyword>Drug Resistance (DR)</keyword>
  <keyword>Isoniazid (INH or H)</keyword>
  <keyword>Rifampicin (RIF or RMP or R)</keyword>
  <keyword>Pyrazinamide (PZA or Z)</keyword>
  <keyword>Ethambutol (EMB or E)</keyword>
  <keyword>Fast-TB</keyword>
  <keyword>Isoniazid, Rifampicin, Pyrazinamide (HRZ)</keyword>
  <keyword>Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE)</keyword>
  <keyword>drug susceptibility testing (DST)</keyword>
  <keyword>Acid-Fast Bacilli (AFB+)</keyword>
  <keyword>Polymerase Chain Reaction (PCR)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT02231229
org study id: P120130 AOM12317
secondary id: IDRCB2013-A01406-39
nct id: NCT02231229
lead sponsor: 
has dmc: No
French guidelines currently recommend to initiate a 4-drug containing regimen associating
      isoniazid (INH or H), rifampicin (RIFor RMP or R), pyrazinamide (PZA or Z) and ethambutol
      (EMB or E) pending the results of drug susceptibility testing (DST). The rationale behind
      routine use of EMB is to prevent the emergence of resistance to rifampicin (RMP), in case of
      primary resistance to INH. Hence, early detection of resistance to INH and RIF using
      molecular testing in Mycobacterium tuberculosis could allow early adaptation of
      antituberculosis treatment: i) start with a 3-drug containing regimen (i.e. INH, RIF, and
      PZA); ii) early enforcement of treatment when resistance is suspected, pending in depth
      susceptibility testings.

      the duration of treatment is 6 months or 12 months.
The impact of rapid detection of resistance with PCR has been poorly evaluated in low-endemic
      countries. In France, primary resistance to isoniazid and rifampicin were estimated at,
      respectively, 5.2%, and 1.2 %. Based on these estimates, French guidelines currently
      recommends to initiate a 4-drug containing regimen associating isoniazid (INH or H),
      rifampicin (RIFor RMP or R), pyrazinamide (PZA or Z) and ethambutol (EMB or E) pending the
      results of drug susceptibility testing (DST). The rationale behind routine use of EMB is to
      prevent the emergence of resistance to rifampicin (RMP), in case of primary resistance to
      INH. Hence, early detection of resistance to INH and RIF using molecular testing in
      Mycobacterium tuberculosis could allow early adaptation of antituberculosis treatment: i)
      start with a 3-drug containing regimen (i.e. INH, RIF, and PZA), in patients with fully
      susceptible isolates (currently 95% of cases); ii) early enforcement of treatment when
      resistance is suspected, pending in depth susceptibility testings. GenoType ®MTB DR plus
      sensitivity for RIF and INH resistance detection has been estimated at 100% and 83%,
      respectively.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of patients with treatment success at the end of TB treatment
time frame: 6 or 12 months after enrollment
description: TB treatment success (cure certain or probable cure) at the end of TB treatment
cure certain: negative sputum cultures or negative sputum direct examination in a patient who has completed treatment and have never filled the definition of treatment failure.
probable cure: clinical and radiological improvement of symptoms associated with tuberculosis in a patient who has completed treatment and have never filled the definition of treatment failure.
completed treatment: patients who took more than 80% of prescribed treatment.
clinical improvement: improvement in overall score of Teeter AND no weight loss
radiological improvement: between baseline and end of treatment
failure: if Positive sputum culture after 5 months of treatment, death during treatment whatever the cause, treatment interrupted for more than two months, decision of the clinician to change TB treatment because of the suspicion of failure after 5 months of TB treatment
measure: Proportion of patients with relapse
time frame: within 12 months after the end of TB treatment
description: positive culture of respiratory sample after TB treatment and after having had negative cultures during treatment or decision by the clinician to restart treatment because of suspicion of relapse
measure: Proportion of patients with failure
time frame: 6 or 12 months after enrollment
description: proportion of patients with treatment changes or discontinuations including the proportion of subjects stopping strategy and treatment assigned at randomization, and the delay between the stop and inclusion.
Will not be considered modifications or discontinuations:
adaptation of treatment on the results of susceptibility testing in the conventional arm (adaptations following the susceptibility in the PCR arm will therefore be considered as a modification).
switching to bitherapy in the 2 arms.
measure: Capillary drug concentration, for each of the prescribed treatment in hair segments
time frame: at 2 and 6 months
description: measure of drug concentrations in hair segments, for each of the prescribed treatment, in order to estimate treatment observance and if drug hair concentrations are associated with therapy success or toxicity
measure: Incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments
time frame: 6 months or at the latest 12 months after enrollment
description: comparison between the 2 arms of incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments
measure: Direct medical costs associated with each strategy
time frame: within 18 or at the latest 12 months after enrolment
description: comparison of direct medical costs induced by PCR strategy and by conventional strategy
arm group label: PCR-based strategy
arm group type: Experimental
description: PCR-based strategy: after testing for isoniazid and rifampin resistance using a molecular testing with PCR (GenoType ®MTB DR plus), patients will receive HRZ combination therapy (INH , RIF, PZA) if no resistance is detected
arm group label: conventional therapy
arm group type: Active Comparator
description: Conventional therapy: based on the standard of care in France: initiation of the standard 4 drug regimen INH, RIF, PZA, and EMB, until drug susceptibility testing (DST) results are available.
intervention type: Other
intervention name: PCR-based strategy
description: Treatment based on the results of detection of resistance to isoniazid and rifampicin using PCR (GenoType ® Mycobacterium Tuberculosis Drug Resistance (MTBDR)plus 2.0) in a smear positive patient with pulmonary tuberculosis: initiation of a 3 drug combination (isoniazid (H / INH); rifampicin (R /RIF); pyrazinamide (Z / PZA)) if no resistance is detected and treatment based on suspected resistance in case of INH and/or RIF resistant strain.
arm group label: PCR-based strategy
other name: HRZ combination therapy
intervention type: Drug
intervention name: conventional therapy
description: Initiation of a standard 4 drug combination (isoniazid (H / INH); rifampicin (R /RIF); pyrazinamide (Z / PZA); ethambutol (EMB or E)) until the results of DST are available.
arm group label: conventional therapy
other name: 4 drug combination (HRZE)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 84 Years
healthy volunteers: No
last name: Yazdan Yazdanpanah, MD-PHD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Tuberculosis
sharing ipd: Undecided