Clinical trial NCT03474198: Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis
Official title: Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Tuberculosis, Pulmonary
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: National University Hospital, Singapore
name: Singapore Clinical Research Institute (SCRI)
First posted: 2018-03-22
Enrollment: 675
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study uses a multi-arm, multi-stage (MAMS) parallel study design
Primary purpose: TREATMENT

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


Eligibility 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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Primary outcomes:
measure: Unsatisfactory clinical outcome at week 96 after randomisation
timeFrame: 96 weeks
Secondary outcomes:
measure: Acceptability of the strategy using trial-specific questionnaire
timeFrame: 96 weeks
measure: Total days on TB drug treatment
timeFrame: 96 weeks
measure: Time off work or study due to illness/treatment
timeFrame: 96 weeks
measure: Total Quality of life using MOS-HIV questionnaire
timeFrame: 96 weeks
measure: Respiratory disability at week 96
timeFrame: 96 weeks
measure: Total Grade 3 or 4 clinical adverse events
timeFrame: 96 weeks
measure: Total serious adverse events
timeFrame: 96 weeks
measure: Death
timeFrame: 96 weeks
measure: Adherence to TB medication
timeFrame: Either during first 8 weeks or at any time during period when TB treatment is prescribed
measure: Treatment default
timeFrame: Either during first 8 weeks or at any time during period when TB treatment is prescribed
measure: Acquired drug resistance by week 96
timeFrame: 96 weeks
measure: Community transmission risk
timeFrame: 96 weeks
Other outcomes:
Locations:
city: New Delhi
country: India
facility: National Institute of TB and Respiratory Diseases
city: Bandung
country: Indonesia
facility: Universitas Padjadjaran
city: Jakarta
country: Indonesia
facility: Persahbahatan Hospital
city: Makassar
country: Indonesia
facility: Wahidin Sudirohusodo Hospital
city: Malang
country: Indonesia
facility: Saiful Anwar Hospital
city: Surabaya
country: Indonesia
facility: Soetomo General Hospital
city: Cebu
country: Philippines
facility: Perpetual Succour Hospital
city: Manila
country: Philippines
facility: De La Salle Health Sciences Institute
city: Manila
country: Philippines
facility: Lung Center Philippines
city: Manila
country: Philippines
facility: Philippines Tuberculosis Society Incorporated (PTSI)
city: Manila
country: Philippines
facility: Tropical Disease Foundation
city: Quezon City
country: Philippines
facility: Quezon Institute
city: Singapore
country: Singapore
facility: National University Hospital
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Nonthaburi
country: Thailand
facility: Central Chest Institute of Thailand
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre
city: Mbarara
country: Uganda
facility: Joint Clinical Research Centre
Study officials:
affiliation: National University Hospital, Singapore
name: Nicholas Paton
role: STUDY_DIRECTOR
References:
citation: 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.