Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis (TEDITUB) (TEDITUB)

Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis

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).

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis; Multidrug Resistant Tuberculosis
• Intervention / Treatment: Drug: Tedizolid arm (SIVEXTRO®); Drug: Linezolid arm (ZYVOXID®); Drug: Standard quadruple therapy arm

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ruxandra CALIN, MD; Phone Number: 01 56 01 74 12; Email: ruxandra.calin@aphp.fr
• Study Contact Backup: Name: Nicolas VEZIRIS, PU-PH; Phone Number: 01 49 28 30 41; Email: nicolas.veziris@aphp.fr

Study Locations

• France
  • Paris, France, 75012
    • Recruiting
    • Bacteriology department- Hôpital Saint-Antoine
    • Contact: Ruxandra CALIN, MD; Phone Number: 01 56 01 74 12; Email: ruxandra.calin@aphp.fr
    • Contact: Nicolas VEZIRIS, PU-PH; Phone Number: 01 49 28 30 41; Email: nicolas.veziris@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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;
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tedizolid arm; 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.	Drug: Tedizolid arm (SIVEXTRO®); 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.
Experimental: Linezolid arm; 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.	Drug: Linezolid arm (ZYVOXID®); 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.
Active Comparator: Standard quadruple therapy arm; Patients will be taken : ISONIAZIDE : o A dosage of 3 to 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.	Drug: Standard quadruple therapy arm; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment 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.	Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	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	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	Compare the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 3 and Day 8	Day 8
Tedizolid pharmacokinetics'measurement	To measure the total and free concentration of tedizolid measured at 0, 1, 3, 5 and 24hours	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	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	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	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	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	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	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.	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	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	30 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Nicolas VEZIRIS, PU-PH, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2023
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: July 22, 2022
• First Submitted That Met QC Criteria: September 6, 2022
• First Posted (Actual): September 9, 2022

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 4, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Tuberculosis; Ethambutol; Tedizolid; Early Bactericidal Activity; Linezolid; Rifampicin; Pyrazinamide; Multidrug Resistant; Isionazid
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Linezolid; Tedizolid; Tedizolid phosphate
• Other Study ID Numbers: APHP210084

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No