Drug-resistance is a major challenge for tuberculosis (TB) care programs. The new WHO guideline recommends adding levofloxacin in previously treated patients with isoniazid-resistant rifampicin-susceptible TB. The investigators believe that such a retreatment regimen may result in acquired resistance to fluoroquinolone, the core drug of multidrug-resistant TB (MDR-TB) regimen, and thus threaten the effectiveness of the fluoroquinolone-based MDR-TB treatment regimen. Therefore the investigators propose to study if regimens strengthened by using high-dose first-line drugs, either a triple dose of isoniazid or a triple dose of rifampicin, are non-inferior to the WHO recommended levofloxacin-strengthened regimen. If one of both high-dose regimens would be non-inferior, it could replace the levofloxacin-strengthened regimen.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Damien Foundation
Dhaka, Bangladesh
Bacteriological effectiveness (proportion of relapse-free cure excluding deaths and lost-to-follow-up)
To study if the bacteriological effectiveness of two high-dose regimens is non-inferior to the WHO recommended levofloxacin-strengthened regimen in patients with rifampicin-susceptible recurrent TB. Relapse-free cure is based on sputum smear and culture-result.
Time frame: 18 months (6-month treatment + 12-month follow-up period)
Frequency of resistance to the different drug components at screening.
Determine the initial resistance profile to the different drug components (Isoniazid, Rifampicin, Pyrazinamide and Levofloxacin) for the entire cohort of patients with recurrent TB
Time frame: At screening (day 0)
Identify predictors of bacteriological effectiveness
Identify predictors (including treatment regimen, resistance profile, presence of cavities, the grading of the smear, …) of bacteriological effectiveness
Time frame: 18 months (6-month treatment + 12-month follow-up period)
Programmatic effectiveness (i.e proportion of participants with relapse-free cure)
Compare the programmatic effectiveness of the 3 different regimens. Relapse-free cure is based on sputum smear and culture-result.
Time frame: 18 months (6-month treatment + 12-month follow-up period)
Number of SAEs and study-specific adverse events of the different retreatment regimens
Compare the safety (SAEs and study-specific adverse events ) of the different retreatment regimens.
Time frame: up to month 6
Negative predictive value of two-week FDA
Evaluate a novel application of fluorescein diacetate vital staining fluorescence microscopy (FDA) at 0 and 2 weeks of treatment, to estimate its utility as screening test for initial resistance to rifampicin, and identify predictors for FDA reduction at 2 weeks. The negative predictive value of two-week FDA showing no lack of 10-fold reduction of viable bacilli at two weeks.
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Time frame: 2 weeks after start of treatment
Proportion of participants relapse-free cure
To estimate the proportion of relapse-free cure among patients with FDA conversion to zero at 2 weeks, by regimen.The proportion (95% confidence interval) relapse-free cure among those who converted on the two-week FDA, by regimen.
Time frame: 18 months (6-month treatment + 12-month follow-up period)
Difference (95% confidence interval) in bacteriological effectiveness (susceptible to both rifampicin and isoniazid vs heteroresistance to rifampicin and/or isoniazid).(heteroresistance), by regimen studied in the trial
Estimate the clinical relevance of different proportions of mutant subpopulations (heteroresistance), by regimen studied in the trial.
Time frame: 18 months (6-month treatment + 12-month follow-up period)
Proportion of participants with acquired resistance
proportion of participants with acquired resistance, by treatment regimen
Time frame: 18 months (6-month treatment + 12-month follow-up period)
Identify predictors of programmatic effectiveness (including treatment regimen, resistance profile, presence of cavities, the grading of the smear, …)
Identify predictors (including treatment regimen, resistance profile, presence of cavities, the grading of the smear, …).
Time frame: 18 months (6-month treatment + 12-month follow-up period)