Clinical trial NCT05534750: Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis (TEDITUB)
Official title: Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Tuberculosis
Multidrug Resistant Tuberculosis
Keywords: Tuberculosis
Multidrug Resistant
Linezolid
Tedizolid
Pyrazinamide
Rifampicin
Isionazid
Ethambutol
Early Bactericidal Activity
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2022-09-09
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years old and \<75 years old
* Woman on childbearing age should be on effective contraception during the duration of the study and up to 6 months after treatment; a mechanical contraception (use of condom) will be strongly recommended
* Male (effective contraception must be used during duration of the study and up to 3 months after treatment)
* Patient with a first infection with Mycobacterium tuberculosis of pulmonary localization suspected by the presence of a clinical pulmonary symptomatology, a chest X-ray or an abnormal chest computed tomography, and the positive microscopic examination of a sputum (AFB +, presence of AFB) with confirmation of tuberculosis by a genotypic test demonstrating no resistance to rifampicin, without clinical signs of extra-thoracic involvement
* State medical assistance application being processed ( If patient does not benefit from social security),
* Signature of informed consent

Exclusion Criteria:

* Resistance to one of the anti-tuberculosis drugs used detected by a genotypic test in accordance with the recommendations of the High Council of Public Health of 2015;
* History of anti-tuberculosis treatment (patients with a documented negative genotypic test for isoniazid and rifampicin resistance may be included)
* History of treatment in the previous two years with one of the antibiotics evaluated in this trial lasting more than one month;
* Absolute contraindication to the use of at least one of the test molecules (isoniazid, rifampicin, ethambutol, pyrazinamide, linezolid, tedizolid);
* Tuberculosis having, in the opinion of the investigator, severity criteria not allowing to wait 7 days before starting standard treatment (oxygenorequirement, severe immunosuppression, extra-pulmonary involvement, any sign of severity requiring treatment in intensive care unit);
* HIV-infected patient receiving protease inhibitors whose antiviral treatment cannot be changed and therefore cannot receive rifampicin; or any other drug contraindicated with one of the study treatments (the list of contraindicated drugs is detailed in the following non-inclusion criteria).
* Neoplastic pathology during treatment with chemo and / or radiotherapy;
* Decompensated cirrhosis;
* Pregnancy, desire to become pregnant, breast-feeding (for women of childbearing potential, contraception should be used for the duration of the study and up to 6 months after treatment, mechanical contraception will be strongly recommended and up to 3 months after treatment);
* Protected adults (under guardianship, curatorship) and under safeguard of justice
* Significant laboratory abnormalities (hemoglobin \<9g / dl, polynuclear neutrophils \<500 / mm3, platelets \<50,000 / mm3, creatinine clearance \<30ml / min, ASAT or ALAT\> 3N, and total bilirubin\> 3N)
* Hyperuricaemia
* Porphyria
* Optic neuritis or peripheral neuropathy
* BMI≤ 16 kg/m2
* Participation in other interventional research
* Current treatment with one or more medications contraindicated in combination with linezolid: Linezolid should not be used in patients treated with monoamine oxidase A or B inhibitors (for example: phenelzine, isocarboxacid, selegiline, moclobemide) or who received one of these products in the previous two weeks
* Current treatment with one or more medications contraindicated in combination with quadritherapy:
* Combination with bictegravir, cobicistat, daclatasvir, dasabuvir, delamanid, grazoprevir/elbasvir, protease inhibitors boosted by ritonavir, isavuconazole, ledipasvir, lurasidone, midostaurin, ombitasvir/paritaprevir, praziquantel, rilpivirine, sofosbuvir, velpatasvir, voriconazole, voxilaprevir
* Gastrointestinal topicals, antacids and adsorbents and salts and aluminum hydroxides

Primary outcomes:
measure: Assessment of the early bactericidal activity (EBA) of tedizolid (200mg / day) at the end of the first 2 days of treatment (D3).
timeFrame: Day 3
Secondary outcomes:
measure: Evaluation of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8
timeFrame: Day 8
measure: Comparison of the early bactericidal activity (EBA) of tedizolid between Day 1 and Day 3
timeFrame: Day 3
measure: Comparison of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8
timeFrame: Day 8
measure: Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 1 and Day 3
timeFrame: Day 3
measure: Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 3 and Day 8
timeFrame: Day 8
measure: Tedizolid pharmacokinetics'measurement
timeFrame: 24hours
measure: Evaluation of Tedizolid's tolerance on hemoglobin
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on polynuclear neutrophils
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on platelets
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on creatinine clearance
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on AST/ALT
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on bilirubin
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on dress syndrome
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on optic neuropathy
timeFrame: 30 days
measure: Evaluation of Tedizolid's tolerance on peripheral neuropathy
timeFrame: 30 days
Other outcomes:
Locations:
city: Paris
country: France
facility: Bacteriology department- Hôpital Saint-Antoine
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Nicolas VEZIRIS, PU-PH
role: PRINCIPAL_INVESTIGATOR
References: