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

Tuberculosis, Pulmonary Clinical Trial

— TRUNCATE-TB  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03474198
• Other study ID #: TRUNCATE-TB
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: March 21, 2018
• Est. completion date: January 20, 2022

Study information

• Verified date: August 2023
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 675
• Est. completion date: January 20, 2022
• Est. primary completion date: January 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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 -

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• Rifampicin
10mg/kg
• Isoniazid
5mg/kg
• Pyrazinamide
25mg/kg
• Ethambutol
15mg/kg
• Linezolid
600mg
• Clofazimine
200mg
• Rifapentine
1200mg
• Levofloxacin
1000mg
• Bedaquiline
400mg once daily for 2 weeks then 200mg 3x a week
• Rifampicin
35mg/kg

Locations

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

Sponsors (3)

Lead Sponsor	Collaborator
University College, London	National University Hospital, Singapore, Singapore Clinical Research Institute (SCRI)

Countries where clinical trial is conducted

India,  Indonesia,  Philippines,  Singapore,  Thailand,  Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Acceptability of the strategy using trial-specific questionnaire	7-item trial-specific questionnaire	96 weeks
Secondary	Total days on TB drug treatment		96 weeks
Secondary	Time off work or study due to illness/treatment		96 weeks
Secondary	Total Quality of life using MOS-HIV questionnaire	MOS-HIV questionnaire	96 weeks
Secondary	Respiratory disability at week 96		96 weeks
Secondary	Total Grade 3 or 4 clinical adverse events		96 weeks
Secondary	Total serious adverse events		96 weeks
Secondary	Death		96 weeks
Secondary	Adherence to TB medication		Either during first 8 weeks or at any time during period when TB treatment is prescribed
Secondary	Treatment default		Either during first 8 weeks or at any time during period when TB treatment is prescribed
Secondary	Acquired drug resistance by week 96		96 weeks
Secondary	Community transmission risk		96 weeks