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Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation (FAST-TB)

Primary Purpose

Tuberculosis

Status
Completed
Phase
Phase 4
Locations
France
Study Type
Interventional
Intervention
PCR-based strategy
conventional therapy
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring Pulmonary tuberculosis, Mycobacterium tuberculosis (MTB), Drug Resistance (DR), Isoniazid (INH or H), Rifampicin (RIF or RMP or R), Pyrazinamide (PZA or Z), Ethambutol (EMB or E), Fast-TB, Isoniazid, Rifampicin, Pyrazinamide (HRZ), Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE), drug susceptibility testing (DST), Acid-Fast Bacilli (AFB+), Polymerase Chain Reaction (PCR)

Eligibility Criteria

18 Years - 84 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult patients
  • with active pulmonary tuberculosis (TB) and positive respiratory samples on microscopic examination for acid-fast bacilli (AFB+,) who are eligible for a standard TB treatment with a 4 drug combination
  • PCR (Genotype MTBDR Plus v2.0, Hain Lifescience) result available within the first 7 days of tuberculosis treatment.
  • who are seeking care in France (metropolitan or overseas) and accept a follow-up of 18 to 24 months after inclusion.
  • who have had a prior clinical examination

Exclusion Criteria:

  • Refusal to participate in the study
  • Prior history of TB treatment
  • For women of child bearing age, pregnancy, willing to become pregnant or breastfeeding
  • Patient without healthcare insurance (French social security)
  • Patient participating in another clinical trial
  • Any condition that might compromise, in the investigator's opinion, patient's compliance with the protocol.
  • Results of cultures available at enrollment
  • No HIV testing available within the last 3 months prior to inclusion in the study.

Sites / Locations

  • Bichat Claude Bernard Hospital
  • Bichat hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

PCR-based strategy

conventional therapy

Arm 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

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.

Outcomes

Primary Outcome Measures

Proportion of patients with treatment success at the end of TB treatment
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

Secondary Outcome Measures

Proportion of patients with relapse
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
Proportion of patients with failure
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.
Capillary drug concentration, for each of the prescribed treatment in hair segments
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
Incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments
comparison between the 2 arms of incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments
Direct medical costs associated with each strategy
comparison of direct medical costs induced by PCR strategy and by conventional strategy

Full Information

First Posted
July 3, 2014
Last Updated
March 17, 2020
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT02231229
Brief Title
Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation
Acronym
FAST-TB
Official Title
Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation: a National Multicenter Randomized Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
July 23, 2014 (Actual)
Primary Completion Date
July 4, 2018 (Actual)
Study Completion Date
February 18, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis
Keywords
Pulmonary tuberculosis, Mycobacterium tuberculosis (MTB), Drug Resistance (DR), Isoniazid (INH or H), Rifampicin (RIF or RMP or R), Pyrazinamide (PZA or Z), Ethambutol (EMB or E), Fast-TB, Isoniazid, Rifampicin, Pyrazinamide (HRZ), Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE), drug susceptibility testing (DST), Acid-Fast Bacilli (AFB+), Polymerase Chain Reaction (PCR)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
204 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PCR-based strategy
Arm Type
Experimental
Arm 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 Title
conventional therapy
Arm Type
Active Comparator
Arm 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(s)
PCR-based strategy
Other Intervention Name(s)
HRZ combination therapy
Intervention 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.
Intervention Type
Drug
Intervention Name(s)
conventional therapy
Other Intervention Name(s)
4 drug combination (HRZE)
Intervention 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.
Primary Outcome Measure Information:
Title
Proportion of patients with treatment success at the end of TB treatment
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
Time Frame
6 or 12 months after enrollment
Secondary Outcome Measure Information:
Title
Proportion of patients with relapse
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
Time Frame
within 12 months after the end of TB treatment
Title
Proportion of patients with failure
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.
Time Frame
6 or 12 months after enrollment
Title
Capillary drug concentration, for each of the prescribed treatment in hair segments
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
Time Frame
at 2 and 6 months
Title
Incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments
Description
comparison between the 2 arms of 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
Title
Direct medical costs associated with each strategy
Description
comparison of direct medical costs induced by PCR strategy and by conventional strategy
Time Frame
within 18 or at the latest 12 months after enrolment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
84 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult patients with active pulmonary tuberculosis (TB) and positive respiratory samples on microscopic examination for acid-fast bacilli (AFB+,) who are eligible for a standard TB treatment with a 4 drug combination PCR (Genotype MTBDR Plus v2.0, Hain Lifescience) result available within the first 7 days of tuberculosis treatment. who are seeking care in France (metropolitan or overseas) and accept a follow-up of 18 to 24 months after inclusion. who have had a prior clinical examination Exclusion Criteria: Refusal to participate in the study Prior history of TB treatment For women of child bearing age, pregnancy, willing to become pregnant or breastfeeding Patient without healthcare insurance (French social security) Patient participating in another clinical trial Any condition that might compromise, in the investigator's opinion, patient's compliance with the protocol. Results of cultures available at enrollment No HIV testing available within the last 3 months prior to inclusion in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yazdan Yazdanpanah, MD-PHD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Bichat Claude Bernard Hospital
City
Paris
ZIP/Postal Code
75018
Country
France
Facility Name
Bichat hospital
City
Paris
ZIP/Postal Code
75018
Country
France

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation

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