Novel Triple-dose Tuberculosis Retreatment Regimens: How to Overcome Resistance Without Creating More
Trial Snapshot
- Phase
- Phase 3
- Status
- Withdrawn
- Sponsor
- Locations
- 1
- Primary Endpoint
- Bacteriological effectiveness (proportion of relapse-free cure excluding deaths and lost-to-follow-up)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Sex
- All
- Accepts 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.
Arms & Interventions
High-Dose Isoniazid
New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg
Intervention: 6EH³RZ (Drug)
High-Dose Rifampicin
New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg
Intervention: 6EHR³Z (Drug)
World Health Organisation (WHO) regimen
WHO levofloxacin-strengthened regimen (6EHRZLfx)
Intervention: 6EHRZLfx (Drug)
Outcomes
Primary Outcomes
Bacteriological effectiveness (proportion of relapse-free cure excluding deaths and lost-to-follow-up)
Time Frame: 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 Outcomes
- Programmatic effectiveness (i.e proportion of participants with relapse-free cure)(18 months (6-month treatment + 12-month follow-up period))
- Number of SAEs and study-specific adverse events of the different retreatment regimens(up to month 6)
- Negative predictive value of two-week FDA(2 weeks after start of treatment)
- Proportion of participants with acquired resistance(18 months (6-month treatment + 12-month follow-up period))
- Frequency of resistance to the different drug components at screening.(At screening (day 0))
- Identify predictors of bacteriological effectiveness(18 months (6-month treatment + 12-month follow-up period))
- Proportion of participants relapse-free cure(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(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, …)(18 months (6-month treatment + 12-month follow-up period))