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

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

Study Overview

• Status: Completed
• Conditions: Tuberculosis, Pulmonary
• Intervention / Treatment: Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Rifampicin; Drug: Linezolid; Drug: Clofazimine; Drug: Rifapentine; Drug: Levofloxacin; Drug: Bedaquiline

• Study Type: Interventional
• Enrollment (Actual): 675
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• India
  • New Delhi, India
    • National Institute of TB and Respiratory Diseases
• Indonesia
  • Bandung, Indonesia
    • Universitas Padjadjaran
  • Jakarta, Indonesia
    • Persahbahatan Hospital
  • Makassar, Indonesia
    • Wahidin Sudirohusodo Hospital
  • Malang, Indonesia
    • Saiful Anwar Hospital
  • Surabaya, Indonesia
    • Soetomo General Hospital
• Philippines
  • Cebu, Philippines
    • Perpetual Succour Hospital
  • Manila, Philippines
    • De La Salle Health Sciences Institute
  • Manila, Philippines
    • Lung Center Philippines
  • Manila, Philippines
    • Philippines Tuberculosis Society Incorporated (PTSI)
  • Manila, Philippines
    • Tropical Disease Foundation
  • Quezon City, Philippines
    • Quezon Institute
• Singapore
  • Singapore, Singapore
    • National University Hospital
• Thailand
  • Bangkok, Thailand
    • King Chulalongkorn Memorial Hospital
  • Nonthaburi, Thailand
    • Central Chest Institute of Thailand
• Uganda
  • Kampala, Uganda
    • Infectious Diseases Institute
  • Kampala, Uganda
    • Joint Clinical Research Centre
  • Mbarara, Uganda
    • Joint Clinical Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard TB Management Strategy; Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only	Drug: Rifampicin; 10mg/kg; Drug: Isoniazid; 5mg/kg; Drug: Pyrazinamide; 25mg/kg; Drug: Ethambutol; 15mg/kg; Drug: Rifampicin; 35mg/kg
Experimental: 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	Drug: Rifampicin; 10mg/kg; Drug: Isoniazid; 5mg/kg; Drug: Pyrazinamide; 25mg/kg; Drug: Ethambutol; 15mg/kg; Drug: Rifampicin; 35mg/kg; Drug: Linezolid; 600mg
Experimental: 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	Drug: Rifampicin; 10mg/kg; Drug: Isoniazid; 5mg/kg; Drug: Pyrazinamide; 25mg/kg; Drug: Ethambutol; 15mg/kg; Drug: Rifampicin; 35mg/kg; Drug: Clofazimine; 200mg
Experimental: 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	Drug: Isoniazid; 5mg/kg; Drug: Pyrazinamide; 25mg/kg; Drug: Linezolid; 600mg; Drug: Rifapentine; 1200mg; Drug: Levofloxacin; 1000mg
Experimental: 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	Drug: Isoniazid; 5mg/kg; Drug: Pyrazinamide; 25mg/kg; Drug: Ethambutol; 15mg/kg; Drug: Linezolid; 600mg; Drug: Bedaquiline; 400mg once daily for 2 weeks then 200mg 3x a week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of the strategy using trial-specific questionnaire	7-item 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	MOS-HIV questionnaire	96 weeks
Respiratory disability at week 96		96 weeks
Total Grade 3 or 4 clinical adverse events		96 weeks
Total serious adverse events		96 weeks
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

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: National University Hospital, Singapore; Singapore Clinical Research Institute (SCRI)
• Investigators: Study Director: Nicholas Paton, National University Hospital, Singapore

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2018
• Primary Completion (Actual): January 20, 2022
• Study Completion (Actual): January 20, 2022

Study Registration Dates

• First Submitted: March 12, 2018
• First Submitted That Met QC Criteria: March 21, 2018
• First Posted (Actual): March 22, 2018

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Fatty Acid Synthesis Inhibitors; Linezolid; Rifapentine; Rifampin; Levofloxacin; Bedaquiline; Isoniazid; Pyrazinamide; Ethambutol; Clofazimine
• Other Study ID Numbers: TRUNCATE-TB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No