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

Primary Purpose

Tuberculosis, Multidrug Resistant Tuberculosis

Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Tedizolid arm (SIVEXTRO®)
Linezolid arm (ZYVOXID®)
Standard quadruple therapy arm
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring Tuberculosis, Multidrug Resistant, Linezolid, Tedizolid, Pyrazinamide, Rifampicin, Isionazid, Ethambutol, Early Bactericidal Activity

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥ 18 years old and <75 years old
  • 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:

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;
  • 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; mechanical contraception will be strongly recommended);
  • 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

Sites / Locations

  • Bacteriology department- Hôpital Saint-AntoineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Tedizolid arm

Linezolid arm

Standard quadruple therapy arm

Arm Description

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 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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
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
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
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
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
Tedizolid pharmacokinetics'measurement
To measure the total and free concentration of tedizolid measured at 0, 1, 3, 5 and 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
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
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
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
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
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
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.
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
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

Full Information

First Posted
July 22, 2022
Last Updated
October 4, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT05534750
Brief Title
Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis (TEDITUB)
Acronym
TEDITUB
Official Title
Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 20, 2023 (Actual)
Primary Completion Date
April 2025 (Anticipated)
Study Completion Date
May 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Multidrug Resistant Tuberculosis
Keywords
Tuberculosis, Multidrug Resistant, Linezolid, Tedizolid, Pyrazinamide, Rifampicin, Isionazid, Ethambutol, Early Bactericidal Activity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Tedizolid arm
Arm Type
Experimental
Arm Description
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.
Arm Title
Linezolid arm
Arm Type
Experimental
Arm Description
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.
Arm Title
Standard quadruple therapy arm
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Tedizolid arm (SIVEXTRO®)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Linezolid arm (ZYVOXID®)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Standard quadruple therapy arm
Intervention Description
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.
Primary Outcome Measure Information:
Title
Assessment of the early bactericidal activity (EBA) of tedizolid (200mg / day) at the end of the first 2 days of treatment (D3).
Description
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
Secondary Outcome Measure Information:
Title
Evaluation of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8
Description
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
Title
Comparison of the early bactericidal activity (EBA) of tedizolid between Day 1 and Day 3
Description
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
Title
Comparison of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8
Description
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
Title
Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 1 and Day 3
Description
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
Title
Comparison of the early bactericidal activity of tedizolid 200 mg / day to that of standard quadruple therapy between Day 3 and Day 8
Description
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
Title
Tedizolid pharmacokinetics'measurement
Description
To measure the total and free concentration of tedizolid measured at 0, 1, 3, 5 and 24hours
Time Frame
24hours
Title
Evaluation of Tedizolid's tolerance on hemoglobin
Description
Rate of patients with hemoglobin <9, g / dl, which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on polynuclear neutrophils
Description
Rate of patients with polynuclear neutrophils <500 / mm3, which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on platelets
Description
Rate of patients with platelets <30,000 / mm3 which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on creatinine clearance
Description
Rate of patients with creatinine clearance <30ml / min which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on AST/ALT
Description
Rate of patients with AST or ALT> 5N which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on bilirubin
Description
Rate of patients with total bilirubin> 5N which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on dress syndrome
Description
Rate of patients with dress syndrome which will lead to premature discontinuation of the administration of the treatment.
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on optic neuropathy
Description
Rate of patients with optic neuropathy which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days
Title
Evaluation of Tedizolid's tolerance on peripheral neuropathy
Description
Rate of patients with rapidly progressive peripheral neuropathy, which will lead to premature discontinuation of the administration of the treatment
Time Frame
30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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; 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nicolas VEZIRIS, PU-PH
Phone
01 49 28 30 41
Email
nicolas.veziris@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Ruxandra CALIN, MD
Phone
01 56 01 74 12
Email
ruxandra.calin@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicolas VEZIRIS, PU-PH
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Bacteriology department- Hôpital Saint-Antoine
City
Paris
ZIP/Postal Code
75012
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicolas VEZIRIS, PU-PH
Phone
01 49 28 30 41
Email
nicolas.veziris@aphp.fr
First Name & Middle Initial & Last Name & Degree
Ruxandra CALIN, MD
Phone
01 56 01 74 12
Email
ruxandra.calin@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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