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

Tuberculosis, Pulmonary Clinical Trial

— TriDoRe  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03862248
• Other study ID #: TriDoRe
• Status: Withdrawn
• Phase: Phase 3
• Start date: September 30, 2019
• Est. completion date: October 1, 2022

Study information

• Verified date: January 2020
• Source: Institute of Tropical Medicine, Belgium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: October 1, 2022
• Est. primary completion date: October 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• 6EH³RZ
New high-dose isoniazid retreatment regimen (6EH³RZ) - H 15mg/kg
• 6EHR³Z
New high-dose rifampicin retreatment regimen (6EHR³Z) - R 30mg/kg
• 6EHRZLfx
WHO levofloxacin-strengthened regimen (6EHRZLfx)

Locations

Country	Name	City	State
Bangladesh	Damien Foundation	Dhaka

Sponsors (2)

Lead Sponsor	Collaborator
Institute of Tropical Medicine, Belgium	Damien Foundation

Country where clinical trial is conducted

Bangladesh, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)