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

Sponsor

University College, London (Other)

Overall Status

Unknown status

CT.gov ID

NCT03474198

Collaborator

National University Hospital, Singapore (Other), Singapore Clinical Research Institute (SCRI) (Other)

900

Enrollment

Locations

Arms

47.7

Anticipated Duration (Months)

64.3

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis, Pulmonary	Drug: Rifampicin Drug: Isoniazid Drug: Pyrazinamide Drug: Ethambutol Drug: Linezolid Drug: Clofazimine Drug: Rifapentine Drug: Levofloxacin Drug: Bedaquiline Drug: Rifampicin	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

900 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This study uses a multi-arm, multi-stage (MAMS) parallel study designThis study uses a multi-arm, multi-stage (MAMS) parallel study design

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 21, 2018

Anticipated Primary Completion Date :

Mar 12, 2022

Anticipated Study Completion Date :

Mar 12, 2022

Arms and Interventions

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
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: Isoniazid 5mg/kg Drug: Pyrazinamide 25mg/kg Drug: Ethambutol 15mg/kg Drug: Linezolid 600mg Drug: Rifampicin 35mg/kg
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: Isoniazid 5mg/kg Drug: Pyrazinamide 25mg/kg Drug: Ethambutol 15mg/kg Drug: Clofazimine 200mg Drug: Rifampicin 35mg/kg
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

Outcome Measures

Primary Outcome Measures

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

Acceptability of the strategy using trial-specific questionnaire [96 weeks]
7-item trial-specific questionnaire
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]
MOS-HIV questionnaire
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	Country
1	Universitas Padjadjaran	Bandung	Indonesia
2	Persahbahatan Hospital	Jakarta	Indonesia
3	Wahidin Sudirohusodo Hospital	Makassar	Indonesia
4	Saiful Anwar Hospital	Malang	Indonesia
5	Soetomo General Hospital	Surabaya	Indonesia
6	Perpetual Succour Hospital	Cebu	Philippines
7	De La Salle Health Sciences Institute	Manila	Philippines
8	Lung Center Philippines	Manila	Philippines
9	Philippines Tuberculosis Society Incorporated (PTSI)	Manila	Philippines
10	Tropical Disease Foundation	Manila	Philippines
11	Quezon Institute	Quezon City	Philippines
12	National University Hospital	Singapore	Singapore
13	King Chulalongkorn Memorial Hospital	Bangkok	Thailand
14	Central Chest Institute of Thailand	Nonthaburi	Thailand