Evaluation of Early Bactericidal Activity of Tedizolid Phosphate and Linezolid in Patients with Suspected Pulmonary Mycobacterium Tuberculosis Infection

The primary objective of this study is the **assessment** of the early bactericidal activity (EBA) of tedizolid (200 mg/day) at the end of the first two days of treatment (D3) in patients with a first suspected infection with **Mycobacterium tuberculosis** in the lungs. This evaluation is clinically relevant as it aims to determine the efficacy of tedizolid in reducing the bacterial load in the early phase of treatment, which is crucial for improving patient outcomes and potentially shortening the duration of therapy.

Secondary objectives include:

• Evaluation of the early bactericidal activity (EBA) of tedizolid between Day 3 and Day 8.
• Comparison of the EBA of tedizolid and linezolid between Day 1 and Day 3 and between Day 3 and Day 8.
• Comparison of the EBA of tedizolid and quadruple therapy between Day 1 and Day 3 and between Day 3 and Day 8.
• Measurement of tedizolid pharmacokinetics.
• Evaluation of tedizolid's tolerance.

These secondary objectives aim to provide a comprehensive understanding of tedizolid's efficacy, pharmacokinetics, and safety profile compared to other treatments, which is essential for optimizing therapeutic strategies against **Mycobacterium tuberculosis**.

The clinical trial involves participants with a **first suspected infection with Mycobacterium tuberculosis** in the lungs. The study population includes both male and female subjects, aged 18 to 74 years. Participants are required to be in general good health, with no clinical signs of extra-thoracic involvement, and must have a positive microscopic examination of sputum confirming tuberculosis without resistance to rifampicin. The trial does not include a vulnerable population. Participants are expected to adhere to effective contraception during the study and for a specified period after treatment. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the early bactericidal activity of **tedizolid** and **linezolid** against **Mycobacterium tuberculosis** in patients with a first suspected pulmonary infection. This is a randomized, double-blind, controlled trial with a primary objective to assess the early bactericidal activity (EBA) of tedizolid at a dose of 200 mg per day by the end of the first two days of treatment. The trial is expected to run from April 2023 to May 2026, with participant involvement lasting up to 7 days of treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, effective contraception use, and confirmation of tuberculosis without resistance to **rifampicin**. The primary endpoint will be measured by the reduction in colony-forming units (CFU) of M. tuberculosis in sputum samples between Day 1 and Day 3. Secondary endpoints include comparisons of the bactericidal activity of tedizolid to linezolid and standard quadruple therapy, as well as assessments of tedizolid's toxicity at Day 7 and Day 30.

Study visits will include follow-up assessments on Day 3 and Day 8 to evaluate the bactericidal activity and monitor any adverse events. The end-of-study visit will occur at the conclusion of the treatment period, with additional follow-up for toxicity assessment. Participants may be terminated early from the study if they experience significant adverse events or fail to adhere to the study protocol. The trial will ensure that all procedures are conducted in accordance with ethical standards and regulatory requirements.

The clinical trial involves the administration of **Linezolid**, an experimental medication, in the form of a coated tablet. The active substance, linezolid, is of chemical origin. The maximum daily dose is 1200 mg, with a total maximum dose of 8400 mg over a treatment period of 7 days. The medication is administered orally, and participant compliance is monitored throughout the trial.

**Tedizolid Phosphate** is another experimental medication used in the trial, provided as a film-coated tablet. The active substance, tedizolid phosphate, is also of chemical origin. The maximum daily dose is 200 mg, with a total maximum dose of 1400 mg over a 7-day treatment period. This medication is administered orally, and modifications to the secondary packaging have been made to meet research needs.

In addition to the experimental medications, the trial includes non-experimental treatments such as **Pyrazinamide**, administered orally. The active substance is of chemical origin, with a maximum daily dose of 25 mg/kg and a total maximum dose of 25 mg/kg over 7 days.

**Isoniazid** is also used as a non-experimental treatment, administered orally. The active substance is chemically derived, with a maximum daily dose of 5 mg/kg and a total maximum dose of 5 mg/kg over the treatment period.

**Ethambutol** is included in the trial as a non-experimental treatment, administered orally. The active substance is of chemical origin, with a maximum daily dose of 20 mg/kg and a total maximum dose of 20 mg/kg over 7 days.

The trial also involves the administration of a combination treatment containing **Isoniazid, Pyrazinamide, and Rifampicin**. This combination is administered orally, with a maximum daily dose of 6 units and a total maximum dose of 42 units over the treatment period.

Lastly, **Rifampicin** is used as a non-experimental treatment, administered orally. The active substance is chemically derived, with a maximum daily dose of 10 mg/kg and a total maximum dose of 10 mg/kg over 7 days.

The efficacy of the clinical trial evaluating the early bactericidal activity of tedizolid and linezolid against **Mycobacterium tuberculosis** will be assessed using both primary and secondary endpoints. The primary endpoint involves the measurement of early bactericidal activity (EBA) from Day 1 to Day 3, calculated as EABD1D3 = (log10 number of CFU of M. tuberculosis on medium 7H11/mL of sputum on Day 1) - (log10 number of CFU of M. tuberculosis on medium 7H11/mL of sputum on Day 3) / 2. Secondary endpoints include the measurement of EBA from Day 3 to Day 8, calculated as EBAD3D8 = (log10 number of CFU of M. tuberculosis on medium 7H11/mL of sputum on Day 3) - (log10 number of CFU of M. tuberculosis on medium 7H11/mL of sputum on Day 8) / 5. Additionally, comparisons will be made between the early bactericidal activity of tedizolid 200 mg/day and linezolid 1200 mg/day, as well as with standard quadruple therapy, over the same time periods.

Further assessments include the time to positivity of cultures in liquid medium, with specific measurements such as ABPJ1J3L = (time to positivity of culture of sample at Day 3) - (time to positivity of culture of sample at Day 1) / 2, and bactericidal activity in liquid medium between Day 3 and Day 8 (ABPJ3J8L). These parameters will be compared between tedizolid and linezolid, as well as with standard four-therapy treatment. The total and free concentration of tedizolid will be measured at multiple time points (0, 1, 3, 5, and 24 hours), and the area under the curve (AUC) will be calculated. Toxicity of tedizolid will be assessed at Day 7 and Day 30, with adverse events leading to premature discontinuation of treatment being documented.