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

Phase 3

Withdrawn

• Conditions: Tuberculosis, Pulmonary
• Interventions: Drug: 6EHRZLfx; Drug: 6EH³RZ; Drug: 6EHR³Z

• Registration Number: NCT03862248
• Lead Sponsor: Institute of Tropical Medicine, Belgium

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-02-04
• Study First Submitted QC: 2019-03-01
• Study First Posted: 2019-03-05
• Study Start: 2019-09-30
• Status Verified: 2020-01
• Last Update Submitted: 2020-01-16
• Last Update Posted: 2020-01-21
• Primary Completion: 2022-10-01
• Study Completion: 2022-10-01

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
World Health Organisation (WHO) regimen	6EHRZLfx	WHO levofloxacin-strengthened regimen (6EHRZLfx)
High-Dose Isoniazid	6EH³RZ	New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg
High-Dose Rifampicin	6EHR³Z	New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 with acquired resistance	18 months (6-month treatment + 12-month follow-up period)	proportion of participants with acquired resistance, by treatment regimen
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
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.
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, ...).

Trial Locations

Locations (1)

Damien Foundation; 🇧🇩 Dhaka, Bangladesh