TriDoRe: Novel Triple-dose Tuberculosis Retreatment Regimens: How to Overcome Resistance Without Creating More
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: High-Dose Isoniazid New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg |
Drug: 6EH³RZ
New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg
|
| Experimental: High-Dose Rifampicin New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg |
Drug: 6EHR³Z
New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg
|
| Active Comparator: World Health Organisation (WHO) regimen WHO levofloxacin-strengthened regimen (6EHRZLfx) |
Drug: 6EHRZLfx
WHO levofloxacin-strengthened regimen (6EHRZLfx)
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
- 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.
- 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.
- 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, …).
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Damien Foundation | Dhaka | Bangladesh |
Sponsors and Collaborators
- Institute of Tropical Medicine, Belgium
- Damien Foundation
Investigators
- Principal Investigator: Tom Decroo, MD, Insitute of Tropical Medicine Antwerp
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TriDoRe