Tuberculosis, Pulmonary
Conditions
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
Interventions
DRUGRifampicin
10mg/kg
DRUGIsoniazid
5mg/kg
DRUGPyrazinamide
25mg/kg
DRUGEthambutol
15mg/kg
DRUGLinezolid
600mg
DRUGClofazimine
200mg
DRUGRifapentine
1200mg
DRUGLevofloxacin
1000mg
DRUGBedaquiline
400mg once daily for 2 weeks then 200mg 3x a week
Sponsors
National University Hospital, Singapore
Singapore Clinical Research Institute (SCRI)
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study uses a multi-arm, multi-stage (MAMS) parallel study design
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18 to 65 years 2. Clinical symptoms consistent with pulmonary TB and/or evidence of pulmonary TB on chest X-ray (CXR) 3. Sputum GeneXpert test positive 4. Willing to comply with the study visits and procedures 5. Resident at a fixed address 6. Willing to have directly observed therapy 7. Willing and able to provide written informed consent
Exclusion criteria
1. Taken more than 10 daily doses of standard anti-TB medication or fluoroquinolones during the 3 months prior to randomisation 2. Previous active TB disease for which treatment was given prior to the current episode 3. Known or suspected extra-pulmonary TB 4. Severe clinical pulmonary TB 5. Sputum smear 3+ on microscopy\* 6. Cavity size \> 4cm on screening CXR\* 7. Presence of rifampicin resistance on GeneXpert test 8. Poorly-controlled diabetes that, in the opinion of the investigator, is unlikely to be controlled with available management strategies 9. Active malignancy requiring systemic chemotherapy or radiotherapy 10. Known Hepatitis B surface antigen positive and/or HCV antibody positive, unless liver function tests consistently within normal range for at least 2 years 11. History of myocardial infarction, congestive cardiac failure, cardiac arrhythmias or any known congenital cardiac problems 12. History of severe chronic lung disease with symptom score of ≥3 on MRC breathlessness scale 13. History of seizures 14. Current tendinitis or history of tendinopathy associated with fluoroquinolone use 15. Symptomatic peripheral neuropathy causing greater than minimal interference with usual social and functional activities 16. Current alcohol or drug abuse 17. Women who are currently pregnant or breast-feeding 18. Women of childbearing potential unwilling or unable to use appropriate effective contraception for the first 6 months of the trial 19. Known allergy to one or more of the study drugs 20. Taking a concomitant medication that has a known or predicted interaction with any of the study drugs to which the patient might be randomised, or is known to prolong the QTc interval 21. Taking any immunosuppressive drugs or use of systemic corticosteroids for more than 2 weeks prior to screening 22. Colour blindness detected by Ishihara test 23.12-lead ECG at screening shows QTc greater than 450ms and/or any other clinically-significant abnormality such as arrhythmia or ischaemia 24.Any of the following laboratory parameters at screening: * Absolute neutrophil \<1000 cells/mL, haemoglobin \<7.0 g/dL, OR platelet count \<50,000 cells/mm3 * Creatinine clearance of \<60ml/min (calculated using Cockcroft-Gault equation) * ALT greater than 3 times the upper limit of normal * Uncorrected serum potassium \<3.5 mmol/L 25.HIV antibody positive at screening\* 26.Any other significant condition (e.g. psychiatric illness, chronic diarrhoeal disease), that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial or lead to poor compliance with study visits and protocol requirements 27.Participation in other clinical intervention trial or research protocol Note: \*Criteria may be modified in later stages of the trial \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Unsatisfactory clinical outcome at week 96 after randomisation | 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
| Measure | Time frame | Description |
|---|---|---|
| Total days on TB drug treatment | 96 weeks | — |
| Time off work or study due to illness/treatment | 96 weeks | — |
| Total Quality of life using MOS-HIV questionnaire | 96 weeks | MOS-HIV questionnaire |
| Respiratory disability at week 96 | 96 weeks | — |
| Total Grade 3 or 4 clinical adverse events | 96 weeks | — |
| Acceptability of the strategy using trial-specific questionnaire | 96 weeks | 7-item trial-specific questionnaire |
| Death | 96 weeks | — |
| Adherence to TB medication | Either during first 8 weeks or at any time during period when TB treatment is prescribed | — |
| Treatment default | Either during first 8 weeks or at any time during period when TB treatment is prescribed | — |
| Acquired drug resistance by week 96 | 96 weeks | — |
| Community transmission risk | 96 weeks | — |
| Total serious adverse events | 96 weeks | — |
Countries
India, Indonesia, Philippines, Singapore, Thailand, Uganda
Outcome results
None listed