Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis
Overview
- Phase
- Phase 2
- Intervention
- Rifampicin
- Conditions
- Tuberculosis, Pulmonary
- Sponsor
- University College, London
- Enrollment
- 675
- Locations
- 17
- Primary Endpoint
- Unsatisfactory clinical outcome at week 96 after randomisation
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The current standard management strategy for drug-sensitive pulmonary tuberculosis (TB) is to treat with multiple drugs for 6 months, although patients often fail to adhere to the long treatment, leading to poor clinical outcomes including drug resistance, which is expensive and difficult to treat.
The TRUNCATE-TB trial evaluates an alternative strategy (the TRUNCATE-TB Management Strategy) comprising treatment for 2 months (8 weeks, extended to 12 weeks if inadequate clinical response) with a regimen predicted to have enhanced sterilising activity ("boosted regimen") and monitoring closely after treatment cessation. Those who relapse (predicted to be always drug sensitive and likely to occur early) will be retreated with a standard 6 month regimen.
The trial is a randomized, open-label, multi-arm, multi-stage (MAMS) trial to test the hypothesis that the TRUNCATE-TB Management Strategy is non-inferior to the standard management strategy in terms of longer-term outcomes (clinical status at 96 weeks). If non-inferiority is demonstrated then the advantages/disadvantages of implementing the strategy will be explored in secondary outcomes (from patient and programme perspective).
The trial will evaluate the TRUNCATE-TB Management Strategy with 4 potential boosted regimens (180 per arm, total 900 with the standard TB management strategy arm). The boosted regimens include new drugs (licensed drugs, repurposed from other indications) and optimized doses of standard drugs, selected based on consideration of maximal sterilising effect, absence of drug-drug interactions, as well as safety and tolerability over a period of 2 months
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age 18 to 65 years
- •Clinical symptoms consistent with pulmonary TB and/or evidence of pulmonary TB on chest X-ray (CXR)
- •Sputum GeneXpert test positive
- •Willing to comply with the study visits and procedures
- •Resident at a fixed address
- •Willing to have directly observed therapy
- •Willing and able to provide written informed consent
Exclusion Criteria
- •Taken more than 10 daily doses of standard anti-TB medication or fluoroquinolones during the 3 months prior to randomisation
- •Previous active TB disease for which treatment was given prior to the current episode
- •Known or suspected extra-pulmonary TB
- •Severe clinical pulmonary TB
- •Sputum smear 3+ on microscopy\*
- •Cavity size \> 4cm on screening CXR\*
- •Presence of rifampicin resistance on GeneXpert test
- •Poorly-controlled diabetes that, in the opinion of the investigator, is unlikely to be controlled with available management strategies
- •Active malignancy requiring systemic chemotherapy or radiotherapy
- •Known Hepatitis B surface antigen positive and/or HCV antibody positive, unless liver function tests consistently within normal range for at least 2 years
Arms & Interventions
Standard TB Management Strategy
Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only
Intervention: Rifampicin
Standard TB Management Strategy
Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only
Intervention: Isoniazid
Standard TB Management Strategy
Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only
Intervention: Pyrazinamide
Standard TB Management Strategy
Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only
Intervention: Ethambutol
TRUNCATE-TB Management Strategy using Regimen B
TRUNCATE-TB Management Strategy: 8 weeks\* of initial treatment using Regimen B; close monitoring after treatment completion; treatment of relapse with 24 weeks of standard treatment. \*If persistent symptoms and positive smear at week 8, extend to 12 weeks of treatment using Regimen B; if persistent symptoms and positive smear at week 12, switch to standard treatment regimen and extend to 24 weeks of treatment. Regimen B: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, linezolid
Intervention: Isoniazid
TRUNCATE-TB Management Strategy using Regimen B
TRUNCATE-TB Management Strategy: 8 weeks\* of initial treatment using Regimen B; close monitoring after treatment completion; treatment of relapse with 24 weeks of standard treatment. \*If persistent symptoms and positive smear at week 8, extend to 12 weeks of treatment using Regimen B; if persistent symptoms and positive smear at week 12, switch to standard treatment regimen and extend to 24 weeks of treatment. Regimen B: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, linezolid
Intervention: Pyrazinamide
TRUNCATE-TB Management Strategy using Regimen B
TRUNCATE-TB Management Strategy: 8 weeks\* of initial treatment using Regimen B; close monitoring after treatment completion; treatment of relapse with 24 weeks of standard treatment. \*If persistent symptoms and positive smear at week 8, extend to 12 weeks of treatment using Regimen B; if persistent symptoms and positive smear at week 12, switch to standard treatment regimen and extend to 24 weeks of treatment. Regimen B: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, linezolid
Intervention: Ethambutol
TRUNCATE-TB Management Strategy using Regimen B
TRUNCATE-TB Management Strategy: 8 weeks\* of initial treatment using Regimen B; close monitoring after treatment completion; treatment of relapse with 24 weeks of standard treatment. \*If persistent symptoms and positive smear at week 8, extend to 12 weeks of treatment using Regimen B; if persistent symptoms and positive smear at week 12, switch to standard treatment regimen and extend to 24 weeks of treatment. Regimen B: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, linezolid
Intervention: Linezolid
TRUNCATE-TB Management Strategy using Regimen B
TRUNCATE-TB Management Strategy: 8 weeks\* of initial treatment using Regimen B; close monitoring after treatment completion; treatment of relapse with 24 weeks of standard treatment. \*If persistent symptoms and positive smear at week 8, extend to 12 weeks of treatment using Regimen B; if persistent symptoms and positive smear at week 12, switch to standard treatment regimen and extend to 24 weeks of treatment. Regimen B: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, linezolid
Intervention: Rifampicin
TRUNCATE-TB Management Strategy using Regimen C
TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine
Intervention: Isoniazid
TRUNCATE-TB Management Strategy using Regimen C
TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine
Intervention: Pyrazinamide
TRUNCATE-TB Management Strategy using Regimen C
TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine
Intervention: Ethambutol
TRUNCATE-TB Management Strategy using Regimen C
TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine
Intervention: Clofazimine
TRUNCATE-TB Management Strategy using Regimen C
TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine
Intervention: Rifampicin
TRUNCATE-TB Management Strategy using Regimen D
TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin
Intervention: Isoniazid
TRUNCATE-TB Management Strategy using Regimen D
TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin
Intervention: Pyrazinamide
TRUNCATE-TB Management Strategy using Regimen D
TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin
Intervention: Linezolid
TRUNCATE-TB Management Strategy using Regimen D
TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin
Intervention: Rifapentine
TRUNCATE-TB Management Strategy using Regimen D
TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin
Intervention: Levofloxacin
TRUNCATE-TB Management Strategy using Regimen E
TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline
Intervention: Isoniazid
TRUNCATE-TB Management Strategy using Regimen E
TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline
Intervention: Pyrazinamide
TRUNCATE-TB Management Strategy using Regimen E
TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline
Intervention: Ethambutol
TRUNCATE-TB Management Strategy using Regimen E
TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline
Intervention: Linezolid
TRUNCATE-TB Management Strategy using Regimen E
TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline
Intervention: Bedaquiline
Outcomes
Primary Outcomes
Unsatisfactory clinical outcome at week 96 after randomisation
Time Frame: 96 weeks
As defined by ongoing requirement for TB treatment at week 96 OR ongoing TB disease activity at week 96 (clinical, microbiological and/or imaging evidence) OR death before week 96
Secondary Outcomes
- Time off work or study due to illness/treatment(96 weeks)
- Treatment default(Either during first 8 weeks or at any time during period when TB treatment is prescribed)
- Acceptability of the strategy using trial-specific questionnaire(96 weeks)
- Total Quality of life using MOS-HIV questionnaire(96 weeks)
- Respiratory disability at week 96(96 weeks)
- Total serious adverse events(96 weeks)
- Community transmission risk(96 weeks)
- Total days on TB drug treatment(96 weeks)
- Total Grade 3 or 4 clinical adverse events(96 weeks)
- Acquired drug resistance by week 96(96 weeks)
- Death(96 weeks)
- Adherence to TB medication(Either during first 8 weeks or at any time during period when TB treatment is prescribed)