Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis
Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis
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
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

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