Tuberculosis, Pulmonary
Conditions
Brief summary
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.
Interventions
DRUG6EH³RZ
New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg
DRUG6EHR³Z
New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg
DRUG6EHRZLfx
WHO levofloxacin-strengthened regimen (6EHRZLfx)
Sponsors
Damien Foundation
Institute of Tropical Medicine, Belgium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* All newly registered patients with smear-positive recurrent pulmonary TB * Adults as well as children (no age limit) * Able and willing to provide written informed consent
Exclusion criteria
* Patients transferred to a health facility not supported by Damien Foundation will be excluded. This includes patients diagnosed with HIV/TB-coinfection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bacteriological effectiveness (proportion of relapse-free cure excluding deaths and lost-to-follow-up) | 18 months (6-month treatment + 12-month follow-up period) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Identify predictors of bacteriological effectiveness | 18 months (6-month treatment + 12-month follow-up period) | Identify predictors (including treatment regimen, resistance profile, presence of cavities, the grading of the smear, …) of bacteriological effectiveness |
| Programmatic effectiveness (i.e proportion of participants with relapse-free cure) | 18 months (6-month treatment + 12-month follow-up period) | Compare the programmatic effectiveness of the 3 different regimens. Relapse-free cure is based on sputum smear and culture-result. |
| Number of SAEs and study-specific adverse events of the different retreatment regimens | up to month 6 | Compare the safety (SAEs and study-specific adverse events ) of the different retreatment regimens. |
| Negative predictive value of two-week FDA | 2 weeks after start of treatment | 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. |
| Frequency of resistance to the different drug components at screening. | At screening (day 0) | Determine the initial resistance profile to the different drug components (Isoniazid, Rifampicin, Pyrazinamide and Levofloxacin) for the entire cohort of patients with recurrent TB |
| 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 | 18 months (6-month treatment + 12-month follow-up period) | Estimate the clinical relevance of different proportions of mutant subpopulations (heteroresistance), by regimen studied in the trial. |
| Proportion of participants with acquired resistance | 18 months (6-month treatment + 12-month follow-up period) | proportion of participants with acquired resistance, by treatment regimen |
| Identify predictors of programmatic effectiveness (including treatment regimen, resistance profile, presence of cavities, the grading of the smear, …) | 18 months (6-month treatment + 12-month follow-up period) | Identify predictors (including treatment regimen, resistance profile, presence of cavities, the grading of the smear, …). |
| Proportion of participants relapse-free cure | 18 months (6-month treatment + 12-month follow-up period) | 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. |
Countries
Bangladesh
Outcome results
None listed