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NCT Number: NCT02231229

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

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.

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Key information

Conditions

Tuberculosis Actinomycetales Infections Bacterial Infections Bacterial Infections and Mycoses Gram-Positive Bacterial Infections Infections Lung Diseases Mycobacterium Infections Respiratory Tract Diseases Respiratory Tract Infections Sclerotylosis Tuberculosis, Pulmonary

Age range

18 year–84 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Bichat Claude Bernard Hospital, Paris, France

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

PCR-based strategy

Other

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.

Other names: HRZ combination therapy

Conventional therapy

Drug

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.

Other names: 4 drug combination (HRZE)

Primary outcomes

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

    Time frame: 6 or 12 months after enrollment

    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 outcomes

  1. Proportion of patients with relapse

    Time frame: within 12 months after the end of TB treatment

    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

  2. Proportion of patients with failure

    Time frame: 6 or 12 months after enrollment

    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.

  3. Capillary drug concentration, for each of the prescribed treatment in hair segments

    Time frame: at 2 and 6 months

    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

  4. 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

    comparison between the 2 arms of incidence and nature of grade 3 or grade 4 adverse events related or not to TB treatments

  5. Direct medical costs associated with each strategy

    Time frame: within 18 or at the latest 12 months after enrolment

    comparison of direct medical costs induced by PCR strategy and by conventional strategy

Sponsors and collaborators

Lead sponsor

Assistance Publique - Hôpitaux de Paris

Other

Registry information

Official study title

Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation: a National Multicenter Randomized Clinical Trial

Acronym: FAST-TB

Important dates

Study start
2014
Primary completion
2018
Study completion
2020
First posted
Sep 4, 2014
Registry last updated
Mar 18, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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