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Trial registered on ANZCTR


Registration number
ACTRN12624000654550
Ethics application status
Approved
Date submitted
23/03/2024
Date registered
21/05/2024
Date last updated
21/05/2024
Date data sharing statement initially provided
21/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the effectiveness of a fluoroquinolone-based treatment of isoniazid-resistant tuberculosis: The FLIRT Trial
Scientific title
The FLIRT Trial: A phase III, international, multi-centre, double-blind randomised controlled trial to evaluate the effectiveness of fluoroquinolone-based therapy versus placebo for isoniazid-resistant tuberculosis
Secondary ID [1] 311806 0
Nil known
Universal Trial Number (UTN)
Trial acronym
FLIRT Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
isoniazid-resistant tuberculosis 333325 0
Mycobacterium tuberculosis 333326 0
Condition category
Condition code
Infection 330013 330013 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
26 weeks of oral treatment, comprising
(a) an 'intensive phase’ of eight weeks of daily oral levofloxacin (L), rifampicin (R), pyrazinamide (Z) and ethambutol (E) tablets, 2LRZE, followed by
(b) a ‘continuation phase’ of eighteen weeks of daily oral levofloxacin and rifampicin (4LR) tablets plus a daily placebo tablet (in place of pyrazinamide and ethambutol).

The dosing will be as follows:
Levofloxacin 250mg tablets, 25 – 35kg 2 tablets (500mg); 36 – 55kg 3 tablets (750mg); 56kg and above 4 tablets (1000mg)

Rifampicin tablets or syrup
up to 35kg: syrup 10mg/kg; 36-55kg: 450mg; 56kg and over: 600mg

Pyrazinamide tablets
up to 35kg: 20-25mg/kg; 36-55kg: 1000mg; 56kg-75kg: 1500mg; 76kg and above: 2000mg

Ethambutol tablets
up to 35kg: 15mg/kg; 36-55kg: 800mg; 56-75kg: 1200mg; 76kg and above: 1600mg

Placebo tablets for pyrazinamide and ethambutol (during the continuation phase, weeks 9-26) will contain the same components as the active drug, without the active drug component.

Pyrazinamide Placebo includes: Maize Starch
Ethambutol Placebo: Dicalcium Phosphate, Colloidal silicon dioxide, Gelatin
Levofloxacin Placebo: Core tablet: Maize Starch, Microcrystalline Cellulose
Intervention code [1] 328253 0
Treatment: Drugs
Comparator / control treatment
A 26-week daily course of oral rifampicin, pyrazinamide and ethambutol plus a placebo (in place of levofloxacin).

The dosing will be as follows:
Rifampicin tablets or syrup
up to 35kg: syrup 10mg/kg; 36-55kg: 450mg; 56kg and over: 600mg

Pyrazinamide tablets
up to 35kg: 20-25mg/kg; 36-55kg: 1000mg; 56kg-75kg: 1500mg; 76kg and above: 2000mg

Ethambutol tablets
up to 35kg: 15mg/kg; 36-55kg: 800mg; 56-75kg: 1200mg; 76kg and above: 1600mg

Placebo tablets will contain the same components as the active drug, without the active drug component.

Pyrazinamide Placebo includes: Maize Starch
Ethambutol Placebo: Dicalcium Phosphate, Colloidal silicon dioxide, Gelatin
Levofloxacin Placebo: Core tablet: Maize Starch, Microcrystalline Cellulose
Control group
Placebo

Outcomes
Primary outcome [1] 337766 0
Sustained treatment success
Timepoint [1] 337766 0
18 months post baseline
Secondary outcome [1] 433222 0
Grade 3, 4 and 5 treatment-related adverse events that result in the permanent discontinuation of the study drug, and are considered possibly or probably related to one of the study drugs
Timepoint [1] 433222 0
From baseline up to 28 days after the last dose of the study regimen
Secondary outcome [2] 433223 0
Sputum culture conversion at 2 months converted to negative; or not able to produce an expectorated sample at 2 months
Timepoint [2] 433223 0
2 months post baseline
Secondary outcome [3] 433224 0
Death
Timepoint [3] 433224 0
18 months post baseline
Secondary outcome [4] 433225 0
Treatment failure
Timepoint [4] 433225 0
To the end of treatment
Secondary outcome [5] 433228 0
Acquired antibiotic resistance
Timepoint [5] 433228 0
18 months post-baseline
Secondary outcome [6] 433229 0
Cost-effectiveness
Timepoint [6] 433229 0
18 months post-baseline
Secondary outcome [7] 433230 0
Non-inferiority of the intervention (fluoroquinolone-containing) regimen compared to the comparator regimen
Timepoint [7] 433230 0
18 months post-baseline
Secondary outcome [8] 433232 0
The proportion of sustained treatment success in the modified Intention to Treat (mITT) population, excluding individuals with ethambutol and/or pyrazinamide resistance at baseline
Timepoint [8] 433232 0
18 months post-baseline
Secondary outcome [9] 433233 0
Patient reported outcomes will be include health-related quality of life score measured using the EQ-5D-5L questionnaire.
Timepoint [9] 433233 0
Start of treatment and 6 months post-baseline
Secondary outcome [10] 435131 0
Tolerability of medication
Timepoint [10] 435131 0
Start of treatment and 6 months post-baseline

Eligibility
Key inclusion criteria
• aged at least 10 years
• Isoniazid-resistant (INH-R), rifampicin-susceptible (RIF-S) and fluoroquinolone susceptible (FQ-S) pulmonary TB, defined as those having sputum that is:
(i) culture-positive (confirmed M. tuberculosis positive on antigenic testing), with or without a positive smear; OR
(ii) positive on molecular testing for M. tuberculosis;
AND
(iii) Having molecular and/or phenotypic drug susceptibility testing that is*
(b) negative for RIF-R and
(c) positive for INH-R; and
(d) negative for FQ-R

Footnotes:
*Individuals with a discrepant phenotypic and genotypic test for INH-R (i.e. negative for INH-resistance despite a genotypic drug susceptibility test (DST) that shows INH-R) will be sent to receive standard treatment according to local guidelines, in which case they will be excluded from the modified intention to treat analysis. FQ: fluoroquinolones.

*Patients with pulmonary tuberculosis (TB) will be eligible for inclusion if they have TB that also involves the central nervous system (CNS), pleura, bones, joints, miliary TB and pericardial TB, on account of good tissue penetration of levofloxacin into these spaces. If extrapulmonary TB is present, the patient must also have pulmonary TB
Minimum age
10 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Treatment for TB for >14 days in the current episode on date of randomisation for patients diagnosed with isoniazid resistance (INH-R) using molecular testing (such as GeneXpert or Hain testing), OR treatment >28 days for patients diagnosed with INH-R using only phenotypic (culture-based) drug susceptibility testing.
• Documented prior diagnosis with rifampicin-resistant (RR)/ multidrug-resistant (MDR) TB
• Severe communication difficulty, as assessed by the study doctor
• Unable to take oral medications
• Known allergy to FQ antibiotics, or history of severe tendinopathy related to fluoroquinolones
• FQ use for a total of >10 days in the previous 120 days
• Unable to recognise changes in vision, due to severe visual impairment or dementia
• Currently taking another medication reported to increase the cardiac QTc interval (e.g. amiodarone, sotalol, disopyramide, quinidine, procainamide, terfenadine) and having a QTc of more than or equal to 450ms
• Susceptibility to isoniazid on phenotypic drug-susceptibility testing on isolates collected at baseline.
• RIF contraindicated due to drug interactions that are considered too difficult to manage by the healthcare worker, or due to a history of hypersensitivity to RIF, rifapentine or rifabutin.
• Kidney tests show end stage kidney disease (eGFR <20mL/min/1.73m2)
• Laboratory tests done up to 14 days before the date of randomisation:
o serum or plasma alanine aminotransferase (ALT) more than three times the upper limit of normal
o serum or plasma total bilirubin more than 2.5 times the upper limit of normal

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment using a centralised computer-generated randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated randomization sequence, stratified by study site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
920
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment outside Australia
Country [1] 26214 0
Viet Nam
State/province [1] 26214 0
Country [2] 26215 0
Canada
State/province [2] 26215 0
Quebec, Vancouver

Funding & Sponsors
Funding source category [1] 316143 0
Government body
Name [1] 316143 0
National Health and Medical Research Council (NHMRC)
Country [1] 316143 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Country
Australia
Secondary sponsor category [1] 318319 0
University
Name [1] 318319 0
McGill University
Address [1] 318319 0
Country [1] 318319 0
Canada

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314967 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 314967 0
https://www.slhd.nsw.gov.au/rpa/research/
Ethics committee country [1] 314967 0
Australia
Date submitted for ethics approval [1] 314967 0
25/10/2022
Approval date [1] 314967 0
23/12/2022
Ethics approval number [1] 314967 0
Ethics committee name [2] 314968 0
Ministry of Health Ethics Committee
Ethics committee address [2] 314968 0
Vietnam Ministry of Health, Ministry of Health Ethics Committee, 138A, Giang Vo Street, Ba Ðinh District, Ha Noi, Vietnam.
Ethics committee country [2] 314968 0
Viet Nam
Date submitted for ethics approval [2] 314968 0
26/07/2023
Approval date [2] 314968 0
12/04/2024
Ethics approval number [2] 314968 0
88/CN-HDDD
Ethics committee name [3] 314969 0
Can Tho Lung Hospital Institutional Review Board
Ethics committee address [3] 314969 0
Ms Nguyen Pham Cam Tu, Ethics Committee, Can Tho Hospital for Tuberculosis Lung Disease, QL91, Phuoc Thoi, O Mon, Can Tho, Vietnam.
Ethics committee country [3] 314969 0
Viet Nam
Date submitted for ethics approval [3] 314969 0
14/06/2023
Approval date [3] 314969 0
29/03/2024
Ethics approval number [3] 314969 0
Ethics committee name [4] 314970 0
National Lung Hospital
Ethics committee address [4] 314970 0
Mr. Nguyen Do Phan, Ethics Committee, National Lung Hospital, 463 Hoang Hoa Tham Street, Ba Dinh, Hanoi, Vietnam.
Ethics committee country [4] 314970 0
Viet Nam
Date submitted for ethics approval [4] 314970 0
05/01/2023
Approval date [4] 314970 0
28/03/2024
Ethics approval number [4] 314970 0
Ethics committee name [5] 314971 0
Hanoi Lung Hospital
Ethics committee address [5] 314971 0
Hoang Van Huan, Hanoi Lung Hospital Ethics Committee, 44 Thanh Nhan Street, THanh Nhan, Hai Ba Trung, Hanoi, Vietnam.
Ethics committee country [5] 314971 0
Viet Nam
Date submitted for ethics approval [5] 314971 0
26/06/2023
Approval date [5] 314971 0
10/07/2023
Ethics approval number [5] 314971 0

Summary
Brief summary
Tuberculosis (TB) kills over 1.4 million people each year and has been the top infectious cause of death worldwide since 2015. Drug resistance is a major driver of prolonged morbidity and mortality, contributing to poor outcomes and allowing ongoing transmission of this airborne infection. Drug-resistant TB is caused by Mycobacterium tuberculosis that is resistant to at least one of the four first-line antibiotics used in combination to treat TB (isoniazid [INH], rifampicin [RIF], pyrazinamide [PZA] or ethambutol [EMB]). No trials of INH-resistant (INH-R) TB have been performed since the availability of later-generation fluoroquinolones (FQs), one of the best-tolerated and most effective group of antibiotics against TB. Safer and more effective regimens are needed. WHO called for treatment trials for INH-R TB, yet none are planned based upon our review of trial registries.

The study hypothesis is that six months of an antibiotic treatment that includes a fluoroquinolone antibiotic will improve treatment outcomes for patients with isoniazid-resitsant tuberculosis. The research question to be addressed by this trial is: “What is the effectiveness and safety of a 6-month fluoroquinolone-containing intervention regimen, with 2 months of pyrazinamide, in comparison to that of a control regimen not containing a fluoroquinolone for treatment of isoniazid-resistant fluoroquinolone resistant tuberculosis?”
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 133282 0
Prof Greg J. Fox
Address 133282 0
Level 2, Medical Foundation Building K25A, 90-92 Parramatta Road, The University of Sydney, NSW 2006
Country 133282 0
Australia
Phone 133282 0
+61 290363121
Fax 133282 0
Email 133282 0
[email protected]
Contact person for public queries
Name 133283 0
Greg J. Fox
Address 133283 0
Level 2, Medical Foundation Building K25A, 90-92 Parramatta Road, The University of Sydney, NSW 2006
Country 133283 0
Australia
Phone 133283 0
+61 290363121
Fax 133283 0
Email 133283 0
[email protected]
Contact person for scientific queries
Name 133284 0
Greg J. Fox
Address 133284 0
Level 2, Medical Foundation Building K25A, 90-92 Parramatta Road, The University of Sydney, NSW 2006
Country 133284 0
Australia
Phone 133284 0
+61 290363121
Fax 133284 0
Email 133284 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.