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

NCT ID: NCT03474198

Last Updated: 2023-08-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 675 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-21
• Study Completion Date: 2022-01-20

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

Conditions

Tuberculosis, Pulmonary

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard TB Management Strategy

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

Group Type: ACTIVE_COMPARATOR

Rifampicin

Intervention Type: DRUG

10mg/kg

Isoniazid

Intervention Type: DRUG

5mg/kg

Pyrazinamide

Intervention Type: DRUG

25mg/kg

Ethambutol

Intervention Type: DRUG

15mg/kg

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

Group Type: EXPERIMENTAL

Isoniazid

Intervention Type: DRUG

5mg/kg

Pyrazinamide

Intervention Type: DRUG

25mg/kg

Ethambutol

Intervention Type: DRUG

15mg/kg

Linezolid

Intervention Type: DRUG

600mg

Rifampicin

Intervention Type: DRUG

35mg/kg

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

Group Type: EXPERIMENTAL

Isoniazid

Intervention Type: DRUG

5mg/kg

Pyrazinamide

Intervention Type: DRUG

25mg/kg

Ethambutol

Intervention Type: DRUG

15mg/kg

Clofazimine

Intervention Type: DRUG

200mg

Rifampicin

Intervention Type: DRUG

35mg/kg

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

Group Type: EXPERIMENTAL

Isoniazid

Intervention Type: DRUG

5mg/kg

Pyrazinamide

Intervention Type: DRUG

25mg/kg

Linezolid

Intervention Type: DRUG

600mg

Rifapentine

Intervention Type: DRUG

1200mg

Levofloxacin

Intervention Type: DRUG

1000mg

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

Group Type: EXPERIMENTAL

Isoniazid

Intervention Type: DRUG

5mg/kg

Pyrazinamide

Intervention Type: DRUG

25mg/kg

Ethambutol

Intervention Type: DRUG

15mg/kg

Linezolid

Intervention Type: DRUG

600mg

Bedaquiline

Intervention Type: DRUG

400mg once daily for 2 weeks then 200mg 3x a week

Interventions

Rifampicin

10mg/kg

Intervention Type: DRUG

Isoniazid

5mg/kg

Intervention Type: DRUG

Pyrazinamide

25mg/kg

Intervention Type: DRUG

Ethambutol

15mg/kg

Intervention Type: DRUG

Linezolid

600mg

Intervention Type: DRUG

Clofazimine

200mg

Intervention Type: DRUG

Rifapentine

1200mg

Intervention Type: DRUG

Levofloxacin

1000mg

Intervention Type: DRUG

Bedaquiline

400mg once daily for 2 weeks then 200mg 3x a week

Intervention Type: DRUG

Rifampicin

35mg/kg

Intervention Type: DRUG

Eligibility Criteria

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

-

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National University Hospital, Singapore

OTHER

Sponsor Role: collaborator

Singapore Clinical Research Institute (SCRI)

UNKNOWN

Sponsor Role: collaborator

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicholas Paton

Role: STUDY_DIRECTOR

National University Hospital, Singapore

Locations

National Institute of TB and Respiratory Diseases

New Delhi, , India

Universitas Padjadjaran

Bandung, , Indonesia

Persahbahatan Hospital

Jakarta, , Indonesia

Wahidin Sudirohusodo Hospital

Makassar, , Indonesia

Saiful Anwar Hospital

Malang, , Indonesia

Soetomo General Hospital

Surabaya, , Indonesia

Perpetual Succour Hospital

Cebu, , Philippines

De La Salle Health Sciences Institute

Manila, , Philippines

Lung Center Philippines

Manila, , Philippines

Philippines Tuberculosis Society Incorporated (PTSI)

Manila, , Philippines

Tropical Disease Foundation

Manila, , Philippines

Quezon Institute

Quezon City, , Philippines

National University Hospital

Singapore, , Singapore

King Chulalongkorn Memorial Hospital

Bangkok, , Thailand

Central Chest Institute of Thailand

Nonthaburi, , Thailand

Infectious Diseases Institute

Kampala, , Uganda

Joint Clinical Research Centre

Kampala, , Uganda

Joint Clinical Research Centre

Mbarara, , Uganda

Countries

India; Indonesia; Philippines; Singapore; Thailand; Uganda

References

Paton NI, Cousins C, Sari IP, Burhan E, Ng NK, Dalay VB, Suresh C, Kusmiati T, Chew KL, Balanag VM, Lu Q, Ruslami R, Djaharuddin I, Sugiri JJR, Veto RS, Sekaggya-Wiltshire C, Avihingsanon A, Saini JK, Papineni P, Nunn AJ, Crook AM; TRUNCATE-TB Trial Team. Efficacy and safety of 8-week regimens for the treatment of rifampicin-susceptible pulmonary tuberculosis (TRUNCATE-TB): a prespecified exploratory analysis of a multi-arm, multi-stage, open-label, randomised controlled trial. Lancet Infect Dis. 2025 Oct;25(10):1084-1096. doi: 10.1016/S1473-3099(25)00151-3. Epub 2025 May 22.

Reference Type: DERIVED

PMID: 40414233 (View on PubMed)

Paton NI, Cousins C, Suresh C, Burhan E, Chew KL, Dalay VB, Lu Q, Kusmiati T, Balanag VM, Lee SL, Ruslami R, Pokharkar Y, Djaharuddin I, Sugiri JJR, Veto RS, Sekaggya-Wiltshire C, Avihingsanon A, Sarin R, Papineni P, Nunn AJ, Crook AM; TRUNCATE-TB Trial Team. Treatment Strategy for Rifampin-Susceptible Tuberculosis. N Engl J Med. 2023 Mar 9;388(10):873-887. doi: 10.1056/NEJMoa2212537. Epub 2023 Feb 20.

Reference Type: DERIVED

PMID: 36808186 (View on PubMed)

Converse PJ, Almeida DV, Tasneen R, Saini V, Tyagi S, Ammerman NC, Li SY, Anders NM, Rudek MA, Grosset JH, Nuermberger EL. Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer. PLoS Negl Trop Dis. 2018 Aug 13;12(8):e0006728. doi: 10.1371/journal.pntd.0006728. eCollection 2018 Aug.

Reference Type: DERIVED

PMID: 30102705 (View on PubMed)

Other Identifiers

TRUNCATE-TB

Identifier Type: -

Identifier Source: org_study_id