Optimization of the TB Treatment Regimen Cascade
Condition: Tuberculosis, Pulmonary
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: double rimfampicin; Standard TB treatment
Intervention description: Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained; Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 701.0
Sex: All
Minimum age: 15 Years
Healthy volunteers: No
Keywords: Bangladesh; Rimfapicin

Summary:

      - Hypothesis: Double dose rifampicin together with earlier monitoring of sputum conversion
      using vital staining reduces unfavorable outcome of Cat. 1 first-line TB treatment without
      excess serious toxicity, and allows early switch to specific treatment of MDR-TB without
      using Cat. 2 retreatment regimen

      - General study design: This open label, randomised clinical trial is intended as a pilot
      study on the efficacy and safety of high-dose rifampicin and feasibility and added value of
      auramine and/or FDA vital staining sputum smear after 2 weeks of intensive treatment phase.
      If this proof-of-concept study provides substantial indication of benefit without indication
      of excess toxicity, the data from the study will be used to design a larger scale,
      cluster-randomized study. The aim of this cluster randomised study would be to provide
      definite proof of the benefit of the intervention on adverse treatment outcomes and lack of
      excess toxicity associated with high dose rifampicin. In addition, the cluster-randomized
      study would provide a more precise assessment of the suppression and prevention of (acquired)
      resistance endpoints.

      An interim analysis is thus planned at the time the last recruited patient finishes
      treatment, i.e. about 9 months after the end of recruitment. It will focus on assessment of
      drug toxicity versus suggested benefits of the intervention. This analysis will be primarily
      performed for the go/no-go decision and design considerations for the cluster-randomized
      trial. The decision on proceeding to the cluster randomized study will be based on the
      absence of excess toxicity, a trend toward a reduction of unfavourable outcomes (excluding
      relapse), and possible favourable effects on initially present low-resistance mutations /
      mutations acquired during treatment. It will also allow to adapt the design of the larger
      study particularly regarding the algorithm for resistance screening, and whether or not
      treatment shortening could be justified with rapid initial conversion.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosed with smear-positive pulmonary TB

          -  15 years or older

          -  Able and willing to provide written informed consent

        Exclusion Criteria:

          -  contacts of MDR-TB patients and other MDR-TB suspects diagnosed with resistance on
             rapid DST for rifampicin performed prior to start of treatment according to NTP
             guidelines

          -  smear-negative pulmonary and extra-pulmonary TB cases

          -  patients in need of hospitalization because of very bad general condition or
             complications

          -  patients with clinically active liver disease, for the study defined as jaundice
             confirmed by a local Medical Officer (Government)

          -  any known HIV-positive patient (although none are expected)

          -  any patient with known hepatitis B or C infection

          -  pregnant women; in addition, patients in the intervention arm who become pregnant
             during treatment will be switched to the control arm