None listed
Conditions
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?”
Interventions
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
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
Sponsors
The University of Sydney
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
10 Years to No maximum
Healthy volunteers
No
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
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
Outcome results
None listed