The objective of this work is to measure the early bactericidal activity of tedizolid, to compare it with the bactericidal activity of linezolid (reference molecule for the treatment of multidrug-resistant tuberculosis) and with that of standard quadruple therapy (reference treatment of drug susceptible tuberculosis).
This is a Phase 2, prospective, randomized, open-label controlled trial in 3 parallel groups comparing tedizolid with 2 standard treatments: linezolid (oxazolidinone whose anti-tuberculosis activity has already been demonstrated) and standard treatment for tuberculosis (quadruple therapy: isoniazid, rifampicin, ethambutol, pyrazinamide ). The objective is to measure the early bactericidal activity of tedizolid, to compare it with the bactericidal activity of linezolid and with that of standard quadruple therapy. Design: A multicentric, open-label, randomized clinical trial Sample size : 60 patients, 20 in each group Treatments groups: * Tedizolid arm: * Tedizolid (SIVEXTRO®), * 200 mg film-coated tablet * Dosage of 1 tablet per day to be taken in the morning for 7 days (taken with or without meals). * Linezolid arm (ZYVOXID®): * Linezolid arm (ZYVOXID®) * 600 mg film-coated tablet * Dosage of 2 tablets per day to be taken in the morning for 7 days (taken with or without meals). * Standard quadruple therapy arm: * Isoniazid (RIMIFON®) Tablets 50 or 200 mg Dosage 3 to 5mg / kg / day for 7 days to be taken in the morning on an empty stomach. * Rifampicin, dosage 10mg / kg / day for 7 days to be taken in the morning on an empty stomach. * Ethambutol 15-20mg / kg / day for 7 days to be taken in the morning on an empty stomach. * Pyrazinamide 20-25mg / kg / day for 7 days to be taken in the morning on an empty stomach. Treatment duration : 7 days Assessement: After signing the consent, patients will be randomized, a sputum sample will be taken before the first drug intake. Then, patients will be treated for 7 days depending on the randomization group (tedizolid, linezolid or standard quadruple therapy). Daily, a sputum of at least 2 mL will be withdrawn from the patients for 7 days. A consultation with blood test will be carried out on D30, date of the patient's end of participation. No interim analysis is planned. Analysis will be performed at the end of the study after data review and freezing of database.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Patients will be taken 1 tablet per day of 200 mg film-coated of Tedizolid (SIVEXTRO®), in the morning for 7 days. Then, the early bactericidal activity will be measured and compared to the other arms.
Patients will be taken 2 tablets per day of 600 mg film-coated of Linezolid (ZYVOXID®) in the morning for 7 days. Then, the early bactericidal activity will be measured and compared to the other arms.
Patients will be taken : ISONIAZIDE : o A dosage of 5mg / kg / day for 7 days (to be taken in the morning on an empty stomach) of Isoniazid (RIMIFON®) RIFAMPICINE : o A dosage of 10mg / kg / day for 7 days (to be taken in the morning on an empty stomach) ETHAMBUTOL : o A dosage of 15-20mg / kg / day for 7 days (to be taken in the morning on an empty stomach) of Ethambutol PYRAZAMIDE : o A dosage of 20-25mg / kg / day for 7 days (to be taken in the morning on an empty stomach) of Pyrazinamide Then, the early bactericidal activity will be measured and compared to the other arms.
Bacteriology department- Hôpital Saint-Antoine
Paris, France
RECRUITINGAssessment of the early bactericidal activity (EBA) of tedizolid (200mg / day) at the end of the first 2 days of treatment (D3).
The measurement will be done as follow: EABD1D3= (log10 number of CFU (CFU= colony forming unit) of M. tuberculosis on medium 7H11/mL of sputum on D1) - (log10number of CFU of M. tuberculosis on medium 7H11/mL of sputum on D3)/2.
Time frame: Day 3
Evaluation of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8
The measurement will be done as follow: EBAD3D8= (log10 number of CFU (CFU=colony forming unit) of M. tuberculosis on medium 7H11/mL of sputum on D3) - ( log10 number of CFU of M. tuberculosis on medium 7H11/mL of sputum at D8)/5
Time frame: Day 8
Comparison of the early bactericidal activity (EBA) of tedizolid between Day 1 and Day 3
Compare the early bactericidal activity of tedizolid 200 mg / day to that of linezolid 1200 mg / day between Day 1 and Day 3
Time frame: Day 3
Comparison of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8
Compare the early bactericidal activity of tedizolid 200 mg / day to that of linezolid 1200 mg / day between Day 1 and Day 3 and between Day 3 and Day 8
Time frame: Day 8
Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 1 and Day 3
Compare the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 1 and Day 3
Time frame: Day 3
Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 3 and Day 8
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Purpose
TREATMENT
Masking
NONE
Enrollment
60
Compare the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 3 and Day 8
Time frame: Day 8
Tedizolid pharmacokinetics'measurement
To measure the total and free concentration of tedizolid measured at 0, 1, 3, 5 and 24hours
Time frame: 24hours
Evaluation of Tedizolid's tolerance on hemoglobin
Rate of patients with hemoglobin \<9, g / dl, which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days
Evaluation of Tedizolid's tolerance on polynuclear neutrophils
Rate of patients with polynuclear neutrophils \<500 / mm3, which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days
Evaluation of Tedizolid's tolerance on platelets
Rate of patients with platelets \<30,000 / mm3 which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days
Evaluation of Tedizolid's tolerance on creatinine clearance
Rate of patients with creatinine clearance \<30ml / min which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days
Evaluation of Tedizolid's tolerance on AST/ALT
Rate of patients with AST or ALT\> 5N which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days
Evaluation of Tedizolid's tolerance on bilirubin
Rate of patients with total bilirubin\> 5N which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days
Evaluation of Tedizolid's tolerance on dress syndrome
Rate of patients with dress syndrome which will lead to premature discontinuation of the administration of the treatment.
Time frame: 30 days
Evaluation of Tedizolid's tolerance on optic neuropathy
Rate of patients with optic neuropathy which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days
Evaluation of Tedizolid's tolerance on peripheral neuropathy
Rate of patients with rapidly progressive peripheral neuropathy, which will lead to premature discontinuation of the administration of the treatment
Time frame: 30 days