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

Overview

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 Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 1, 2022

Interventions

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

Arms, Groups and Cohorts

  • Experimental: High-Dose Isoniazid
    • New high-dose isoniazid retreatment regimen (6EH³RZ) – H 15mg/kg
  • Experimental: High-Dose Rifampicin
    • New high-dose rifampicin retreatment regimen (6EHR³Z) – R 30mg/kg
  • Active Comparator: World Health Organisation (WHO) regimen
    • WHO levofloxacin-strengthened regimen (6EHRZLfx)

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • Frequency of resistance to the different drug components at screening.
    • Time Frame: 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
    • Time Frame: 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
  • Programmatic effectiveness (i.e proportion of participants with relapse-free cure)
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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 relapse-free cure
    • Time Frame: 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
    • Time Frame: 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.
  • Proportion of participants with acquired resistance
    • Time Frame: 18 months (6-month treatment + 12-month follow-up period)
    • proportion of participants with acquired resistance, by treatment regimen
  • Identify predictors of programmatic effectiveness (including treatment regimen, resistance profile, presence of cavities, the grading of the smear, …)
    • Time Frame: 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, …).

Participating in This Clinical Trial

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.

Gender Eligibility: All

participant eligibility is based on self-representation of gender identity

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Institute of Tropical Medicine, Belgium
  • Collaborator
    • Damien Foundation
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Tom Decroo, MD, Principal Investigator, Insitute of Tropical Medicine Antwerp

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