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

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 Overview

• Status: Withdrawn
• Conditions: Tuberculosis, Pulmonary
• Intervention / Treatment: Drug: 6EH³RZ; Drug: 6EHR³Z; Drug: 6EHRZLfx

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh
    • Damien Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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)

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Institute of Tropical Medicine, Belgium
• Collaborators: Damien Foundation
• Investigators: Principal Investigator: Tom Decroo, MD, Insitute of Tropical Medicine Antwerp

Study record dates

Study Major Dates

• Study Start (Anticipated): September 30, 2019
• Primary Completion (Anticipated): October 1, 2022
• Study Completion (Anticipated): October 1, 2022

Study Registration Dates

• First Submitted: February 4, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 5, 2019

Study Record Updates

• Last Update Posted (Actual): January 21, 2020
• Last Update Submitted That Met QC Criteria: January 16, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary
• Other Study ID Numbers: TriDoRe

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No