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

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ClinicalTrials.gov Identifier: NCT03474198
Recruitment Status : Recruiting
First Posted : March 22, 2018
Last Update Posted : April 19, 2019
Sponsor:
Collaborators:
National University Hospital, Singapore
Singapore Clinical Research Institute (SCRI)
Information provided by (Responsible Party):
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


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 Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This 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 : March 21, 2018
Estimated Primary Completion Date : March 12, 2022
Estimated Study Completion Date : March 12, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

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




Primary Outcome Measures :
  1. Unsatisfactory clinical outcome at week 96 after randomisation [ Time Frame: 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 :
  1. Acceptability of the strategy using trial-specific questionnaire [ Time Frame: 96 weeks ]
    7-item trial-specific questionnaire

  2. Total days on TB drug treatment [ Time Frame: 96 weeks ]
  3. Time off work or study due to illness/treatment [ Time Frame: 96 weeks ]
  4. Total Quality of life using MOS-HIV questionnaire [ Time Frame: 96 weeks ]
    MOS-HIV questionnaire

  5. Respiratory disability at week 96 [ Time Frame: 96 weeks ]
  6. Total Grade 3 or 4 clinical adverse events [ Time Frame: 96 weeks ]
  7. Total serious adverse events [ Time Frame: 96 weeks ]
  8. Death [ Time Frame: 96 weeks ]
  9. Adherence to TB medication [ Time Frame: Either during first 8 weeks or at any time during period when TB treatment is prescribed ]
  10. Treatment default [ Time Frame: Either during first 8 weeks or at any time during period when TB treatment is prescribed ]
  11. Acquired drug resistance by week 96 [ Time Frame: 96 weeks ]
  12. Community transmission risk [ Time Frame: 96 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03474198


Contacts
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Contact: Christopher Cousins, Project Leader 65 6601 5371 mdccdc@nus.edu.sg
Contact: Nicholas Paton, Chief Investigator 65 6601 5371 nick_paton@nuhs.edu.sg

Locations
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Indonesia
Universitas Padjadjaran Recruiting
Bandung, Indonesia
Persahbahatan Hospital Recruiting
Jakarta, Indonesia
Wahidin Sudirohusodo Hospital Recruiting
Makassar, Indonesia
Saiful Anwar Hospital Recruiting
Malang, Indonesia
Soetomo General Hospital Recruiting
Surabaya, Indonesia
Philippines
Perpetual Succour Hospital Recruiting
Cebu, Philippines
De La Salle Health Sciences Institute Recruiting
Manila, Philippines
Lung Center Philippines Recruiting
Manila, Philippines
Philippines Tuberculosis Society Incorporated (PTSI) Not yet recruiting
Manila, Philippines
Tropical Disease Foundation Recruiting
Manila, Philippines
Quezon Institute Recruiting
Quezon City, Philippines
Singapore
National University Hospital Not yet recruiting
Singapore, Singapore
Thailand
King Chulalongkorn Memorial Hospital Recruiting
Bangkok, Thailand
Central Chest Institute of Thailand Recruiting
Nonthaburi, Thailand
Sponsors and Collaborators
University College, London
National University Hospital, Singapore
Singapore Clinical Research Institute (SCRI)
Investigators
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Study Director: Nicholas Paton National University Hospital, Singapore

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03474198     History of Changes
Other Study ID Numbers: TRUNCATE-TB
First Posted: March 22, 2018    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Levofloxacin
Ofloxacin
Rifampin
Isoniazid
Linezolid
Pyrazinamide
Ethambutol
Rifapentine
Clofazimine
Bedaquiline
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors