Evaluation of Linezolid Versus Benzathine Benzylpenicillin in the Treatment of Early Syphilis: A Non-Inferiority Clinical Trial

The primary objective of this study is to demonstrate the **non-inferiority** of **linezolid (LZD)** treatment compared with standard **benzathine benzylpenicillin (BPG)** treatment in curing patients with early **syphilis**. Establishing the non-inferiority of LZD is clinically relevant as it could provide an effective oral alternative to the standard intramuscular BPG, potentially improving patient compliance and accessibility to treatment.

Secondary objectives include:

• To isolate **Treponema pallidum** strains in clinical samples to subtype DNA from patients at baseline and during recurrence or treatment failure, complementing the primary objective.
• To identify mutations in **penicillin-binding proteins** that could be linked to a possible penicillin resistance phenotype in cases of recurrence or treatment failure, further complementing the primary objective.
• To assess the safety of LZD treatment compared with standard BPG treatment in patients with early syphilis.
• To assess **RPR titer** variation within 2 weeks after the start of treatment for primary syphilis.

The clinical trial involves a total of **50 participants** diagnosed with **syphilis**, specifically targeting individuals with primary, secondary, or early latent stages of the disease. The study population includes both male and female subjects aged 18 years or older, ensuring a broad representation of adults. Participants were selected based on their ability to comply with the study protocol and the requirement to provide written informed consent. The trial does not include a vulnerable population. Lifestyle considerations such as the use of effective contraception methods are required for both men and women of childbearing potential during and shortly after the trial period. The selection criteria ensure that participants are capable of adhering to the study's demands, thereby maintaining the integrity and reliability of the trial outcomes.

The clinical trial is designed to evaluate the **non-inferiority** of linezolid (LZD) treatment compared to the standard benzathine benzylpenicillin (BPG) treatment in curing patients with early **syphilis**. This is a randomized, double-blind, controlled trial with an estimated duration from October 14, 2021, to December 1, 2025. Participants will be randomly assigned to receive either the test product, linezolid, administered orally, or the comparator product, benzathine benzylpenicillin, administered intramuscularly. The trial aims to assess both clinical and serological cure rates, as well as the recurrence of infection through molecular methods.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening visit, will confirm eligibility based on criteria such as age, diagnosis of primary, secondary, or early latent syphilis, and the ability to comply with the study protocol. Participants must provide written informed consent and, if applicable, commit to using effective contraception methods. Follow-up visits will occur at specified intervals to assess clinical and serological outcomes, with primary endpoints including the healing of syphilis lesions and a decline in RPR titer. Secondary endpoints involve genomic assessments of Treponema pallidum strains and the evaluation of adverse events related to the treatments.

The expected length of participant involvement is up to 48 weeks, with the treatment period for linezolid lasting a maximum of 14 days and for benzathine benzylpenicillin up to 1 day. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or the occurrence of significant adverse events. The end-of-study visit will finalize data collection and ensure the well-being of participants. This trial is conducted under rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of two **antibiotic** treatments for patients with early **syphilis**. The experimental medication, **Linezolid**, is administered orally. It is provided in a pharmaceutical form identified as PHF00101MIG. The maximum daily dose of Linezolid is 1200 mg, with a total maximum dose of 16800 mg over a treatment period of 14 days. The active substance in Linezolid is chemically derived and is classified under the ATC code J01XX08. Participant compliance with the dosing schedule will be monitored throughout the trial.

The comparator treatment in this study is **Benzathine Benzylpenicillin**, which is administered intramuscularly. This medication is provided in a pharmaceutical form identified as PHF00243MIG. The maximum daily and total dose for Benzathine Benzylpenicillin is 1200000 IU, administered over a single day. The active substances in this treatment include **Lidocaine Hydrochloride Monohydrate** and Benzathine Benzylpenicillin, both of which are chemically derived. The ATC classification for Benzathine Benzylpenicillin is J01CE08. The administration of this treatment will be closely monitored to ensure adherence to the dosing regimen.

Efficacy in the clinical trial titled "Oral and Neuro-Penetrative Alternative Antibiotics for Patients with Syphilis" will be assessed using several primary and secondary endpoints. The primary endpoints include the measurement of clinical cure, defined by the healing of primary syphilis lesions within 2 weeks and secondary syphilis lesions within 6 weeks from the start of treatment. Additionally, serological cure will be evaluated by a four-fold decline in the Rapid Plasma Reagin (RPR) titer or seroreversion at 12, 24, and 48 weeks from treatment initiation. Molecular cure will be assessed by detecting the recurrence of **Treponema pallidum** DNA to determine relapse or reinfection within 48 weeks from treatment start.

Secondary endpoints involve the assessment of **T. pallidum** strains using genomic molecular methods in various samples, including ulcer or mucosal lesion swabs, plasma, oral swabs/saliva, skin punch biopsies, ear lobe scrapings, and cerebrospinal fluid (CSF) from selected patients. Comparative genomics will be conducted to identify mutations associated with resistance phenotypes. The trial will also evaluate the proportion of patients experiencing adverse events related to Linezolid (LZD) treatment compared to standard Benzathine Benzylpenicillin (BPG) treatment. Additionally, changes in RPR titer at week 2 from treatment start will be monitored. These assessments will be conducted at specified timepoints to ensure comprehensive evaluation of the treatment's efficacy.