Novel Triple-dose Tuberculosis Retreatment Regimens: How to Overcome Resistance Without Creating More

Study Overview
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Brief Summary
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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.

Official Title
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Novel Triple-dose Tuberculosis Retreatment Regimens: How to Overcome Resistance Without Creating More

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: 6EH³RZ
* Drug: 6EHR³Z
* Drug: 6EHRZLfx


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-Dose Isoniazid<br>New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg | Drug: 6EH³RZ<br>* New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg<br>|
| Experimental: High-Dose Rifampicin<br>New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg | Drug: 6EHR³Z<br>* New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg<br>|
| Active Comparator: World Health Organisation (WHO) regimen<br>WHO levofloxacin-strengthened regimen (6EHRZLfx) | Drug: 6EHRZLfx<br>* WHO levofloxacin-strengthened regimen (6EHRZLfx)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 18 months (6-month treatment + 12-month follow-up period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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. | 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. | 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. | 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. | 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. | 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 | 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, …). | 18 months (6-month treatment + 12-month follow-up period) |