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

NCT03474198 | Completed Phase 2 DMC

• 1 other identifier: TRUNCATE-TB
• Study Type: interventional
• Target: 675
• Locations: 6 countries
• Sites: 18

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

Outcome Measures

Primary Outcomes (1)

• Unsatisfactory clinical outcome at week 96 after randomisation

  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

  96 weeks

Secondary Outcomes (12)

• Acceptability of the strategy using trial-specific questionnaire

  96 weeks

• 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

• Respiratory disability at week 96

  96 weeks

Study Arms (5)

Standard TB Management Strategy

ACTIVE COMPARATOR

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

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol

TRUNCATE-TB Management Strategy using Regimen B

EXPERIMENTAL

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

Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Linezolid; Drug: Rifampicin

TRUNCATE-TB Management Strategy using Regimen C

EXPERIMENTAL

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

Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Clofazimine; Drug: Rifampicin

TRUNCATE-TB Management Strategy using Regimen D

EXPERIMENTAL

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

Drug: Isoniazid; Drug: Pyrazinamide; Drug: Linezolid; Drug: Rifapentine; Drug: Levofloxacin

TRUNCATE-TB Management Strategy using Regimen E

EXPERIMENTAL

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

Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Linezolid; Drug: Bedaquiline

Interventions

Rifampicin DRUG

10mg/kg

Standard TB Management Strategy

Isoniazid DRUG

5mg/kg

Standard TB Management Strategy; TRUNCATE-TB Management Strategy using Regimen B; TRUNCATE-TB Management Strategy using Regimen C; TRUNCATE-TB Management Strategy using Regimen D; TRUNCATE-TB Management Strategy using Regimen E

Pyrazinamide DRUG

25mg/kg

Standard TB Management Strategy; TRUNCATE-TB Management Strategy using Regimen B; TRUNCATE-TB Management Strategy using Regimen C; TRUNCATE-TB Management Strategy using Regimen D; TRUNCATE-TB Management Strategy using Regimen E

Ethambutol DRUG

15mg/kg

Standard TB Management Strategy; TRUNCATE-TB Management Strategy using Regimen B; TRUNCATE-TB Management Strategy using Regimen C; TRUNCATE-TB Management Strategy using Regimen E

Linezolid DRUG

600mg

TRUNCATE-TB Management Strategy using Regimen B; TRUNCATE-TB Management Strategy using Regimen D; TRUNCATE-TB Management Strategy using Regimen E

Clofazimine DRUG

200mg

TRUNCATE-TB Management Strategy using Regimen C

Rifapentine DRUG

1200mg

TRUNCATE-TB Management Strategy using Regimen D

Levofloxacin DRUG

1000mg

TRUNCATE-TB Management Strategy using Regimen D

Bedaquiline DRUG

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

TRUNCATE-TB Management Strategy using Regimen E

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• History of myocardial infarction, congestive cardiac failure, cardiac arrhythmias or any known congenital cardiac problems
• History of severe chronic lung disease with symptom score of ≥3 on MRC breathlessness scale
• History of seizures
• Current tendinitis or history of tendinopathy associated with fluoroquinolone use
• Symptomatic peripheral neuropathy causing greater than minimal interference with usual social and functional activities

Sponsors & Collaborators

• University College, London: lead
• National University Hospital, Singapore: collaborator
• Singapore Clinical Research Institute (SCRI): collaborator

Study Sites (18)

National Institute of TB and Respiratory Diseases

New Delhi, India

Location

Universitas Padjadjaran

Bandung, Indonesia

Location

Persahbahatan Hospital

Jakarta, Indonesia

Location

Wahidin Sudirohusodo Hospital

Makassar, Indonesia

Location

Saiful Anwar Hospital

Malang, Indonesia

Location

Soetomo General Hospital

Surabaya, Indonesia

Location

Perpetual Succour Hospital

Cebu, Philippines

Location

De La Salle Health Sciences Institute

Manila, Philippines

Location

Lung Center Philippines

Manila, Philippines

Location

Philippines Tuberculosis Society Incorporated (PTSI)

Manila, Philippines

Location

Tropical Disease Foundation

Manila, Philippines

Location

Quezon Institute

Quezon City, Philippines

Location

National University Hospital

Singapore, Singapore

Location

King Chulalongkorn Memorial Hospital

Bangkok, Thailand

Location

Central Chest Institute of Thailand

Nonthaburi, Thailand

Location

Infectious Diseases Institute

Kampala, Uganda

Location

Joint Clinical Research Centre

Kampala, Uganda

Location

Joint Clinical Research Centre

Mbarara, Uganda

Location

Related Publications (3)

• 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.

  PMID: 40414233 DERIVED

• 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.

  PMID: 36808186 DERIVED

• 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.

  PMID: 30102705 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Linezolid; Clofazimine; rifapentine; Levofloxacin; bedaquiline

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines; Acetamides; Amides; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Phenazines; Heterocyclic Compounds, 3-Ring; Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring

Study Officials

• Nicholas Paton

  National University Hospital, Singapore

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study uses a multi-arm, multi-stage (MAMS) parallel study design

Study Record Dates

• First Submitted: March 12, 2018
• First Posted: March 22, 2018
• Study Start: March 21, 2018
• Primary Completion: January 20, 2022
• Study Completion: January 20, 2022
• Last Updated: August 14, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1); PH (6); TH (2); UG (3); IN (1); ID (5)