Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis
- Conditions
- Tuberculosis, Pulmonary
- Interventions
- Registration Number
- NCT03474198
- Lead Sponsor
- University College, London
- 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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 675
- 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
- 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
- Current alcohol or drug abuse
- Women who are currently pregnant or breast-feeding
- Women of childbearing potential unwilling or unable to use appropriate effective contraception for the first 6 months of the trial
- Known allergy to one or more of the study drugs
- 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
- Taking any immunosuppressive drugs or use of systemic corticosteroids for more than 2 weeks prior to screening
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard TB Management Strategy Ethambutol Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only Standard TB Management Strategy Isoniazid Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only Standard TB Management Strategy Rifampicin Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only Standard TB Management Strategy Pyrazinamide Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid only TRUNCATE-TB Management Strategy using Regimen B Isoniazid 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 TRUNCATE-TB Management Strategy using Regimen B Pyrazinamide 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 TRUNCATE-TB Management Strategy using Regimen B Rifampicin 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 TRUNCATE-TB Management Strategy using Regimen B Ethambutol 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 TRUNCATE-TB Management Strategy using Regimen B Linezolid 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 TRUNCATE-TB Management Strategy using Regimen C Isoniazid TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine TRUNCATE-TB Management Strategy using Regimen C Clofazimine TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine TRUNCATE-TB Management Strategy using Regimen C Pyrazinamide TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine TRUNCATE-TB Management Strategy using Regimen C Ethambutol TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine TRUNCATE-TB Management Strategy using Regimen C Rifampicin TRUNCATE-TB Management Strategy as described above, using Regimen C in place of B. Regimen C: Rifampicin (35mg/kg), isoniazid, pyrazinamide, ethambutol, clofazimine TRUNCATE-TB Management Strategy using Regimen D Isoniazid TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin TRUNCATE-TB Management Strategy using Regimen D Pyrazinamide TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin TRUNCATE-TB Management Strategy using Regimen D Rifapentine TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin TRUNCATE-TB Management Strategy using Regimen D Linezolid TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin TRUNCATE-TB Management Strategy using Regimen D Levofloxacin TRUNCATE-TB Management Strategy as described above, using Regimen D in place of B. Regimen D: Rifapentine, isoniazid, pyrazinamide, linezolid, levofloxacin TRUNCATE-TB Management Strategy using Regimen E Pyrazinamide TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline TRUNCATE-TB Management Strategy using Regimen E Ethambutol TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline TRUNCATE-TB Management Strategy using Regimen E Isoniazid TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline TRUNCATE-TB Management Strategy using Regimen E Linezolid TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline TRUNCATE-TB Management Strategy using Regimen E Bedaquiline TRUNCATE-TB Management Strategy as described above, using Regimen E in place of B. Regimen E: Isoniazid, pyrazinamide, ethambutol, linezolid, bedaquiline
- Primary Outcome Measures
Name Time Method Unsatisfactory clinical outcome at week 96 after randomisation 96 weeks 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
- Secondary Outcome Measures
Name Time Method Treatment default Either during first 8 weeks or at any time during period when TB treatment is prescribed Acceptability of the strategy using trial-specific questionnaire 96 weeks 7-item trial-specific questionnaire
Total Quality of life using MOS-HIV questionnaire 96 weeks MOS-HIV questionnaire
Respiratory disability at week 96 96 weeks Total serious adverse events 96 weeks Community transmission risk 96 weeks Total days on TB drug treatment 96 weeks Total Grade 3 or 4 clinical adverse events 96 weeks Acquired drug resistance by week 96 96 weeks Time off work or study due to illness/treatment 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
Trial Locations
- Locations (17)
Saiful Anwar Hospital
🇮🇩Malang, Indonesia
Joint Clinical Research Centre
🇺🇬Mbarara, Uganda
Infectious Diseases Institute
🇺🇬Kampala, Uganda
National Institute of TB and Respiratory Diseases
🇮🇳New Delhi, India
King Chulalongkorn Memorial Hospital
🇹🇭Bangkok, Thailand
National University Hospital
🇸🇬Singapore, Singapore
Philippines Tuberculosis Society Incorporated (PTSI)
🇵🇭Manila, Philippines
Tropical Disease Foundation
🇵🇭Manila, Philippines
Perpetual Succour Hospital
🇵🇭Cebu, Philippines
De La Salle Health Sciences Institute
🇵🇭Manila, Philippines
Lung Center Philippines
🇵🇭Manila, Philippines
Persahbahatan Hospital
🇮🇩Jakarta, Indonesia
Universitas Padjadjaran
🇮🇩Bandung, Indonesia
Wahidin Sudirohusodo Hospital
🇮🇩Makassar, Indonesia
Soetomo General Hospital
🇮🇩Surabaya, Indonesia
Quezon Institute
🇵🇭Quezon City, Philippines
Central Chest Institute of Thailand
🇹🇭Nonthaburi, Thailand