Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis (TRUNCATE-TB)

University College London (UCL)

Status and phase: Completed; Phase 3; Phase 2

Conditions: Tuberculosis, Pulmonary

Treatments: Drug: Pyrazinamide; Drug: Ethambutol; Drug: Bedaquiline; Drug: Levofloxacin; Drug: Rifapentine; Drug: Linezolid; Drug: Isoniazid; Drug: Clofazimine; Drug: Rifampicin

Study type: Interventional

Funder types: Other

Identifiers

NCT03474198

TRUNCATE-TB

Details and patient eligibility

About

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

Enrollment: 675 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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675 participants in 5 patient groups

Standard TB Management Strategy

Active Comparator group

Description:

Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only

Treatment:

Drug: Ethambutol

Drug: Rifampicin

Drug: Rifampicin

Drug: Isoniazid

Drug: Pyrazinamide

TRUNCATE-TB Management Strategy using Regimen B

Experimental group

Description:

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

Treatment:

Drug: Ethambutol

Drug: Linezolid

Drug: Rifampicin

Drug: Rifampicin

Drug: Isoniazid

Drug: Pyrazinamide

TRUNCATE-TB Management Strategy using Regimen C

Experimental group

Description:

TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine

Treatment:

Drug: Ethambutol

Drug: Rifampicin

Drug: Rifampicin

Drug: Isoniazid

Drug: Clofazimine

Drug: Pyrazinamide

TRUNCATE-TB Management Strategy using Regimen D

Experimental group

Description:

TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin

Treatment:

Drug: Rifapentine

Drug: Levofloxacin

Drug: Linezolid

Drug: Isoniazid

Drug: Pyrazinamide

TRUNCATE-TB Management Strategy using Regimen E

Experimental group

Description:

TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline

Treatment:

Drug: Ethambutol

Drug: Bedaquiline

Drug: Linezolid

Drug: Isoniazid

Drug: Pyrazinamide