Alternative Antibiotics for Syphilis

Overview

The Trep-AB clinical trial will test the efficacy of an investigational neuropenetrative drug, Linezolid (LZD), compared to standard treatment, Benzathine penicillin G (BPG), for early syphilis in humans. The overarching idea of the work proposed herein is to investigate the use of LZD to treat syphilis, conducting a randomized controlled clinical trial to evaluate this new indication of a known antibacterial agent.

The syphilis epidemic is rampant around the world, and therapeutic options are restricted to an antibiotic, intramuscular (IM) benzathine penicillin G (BPG), which does not efficiently cross the blood-brain barrier. Treponema pallidum (T.p.), the bacteria that causes syphilis, invades the central nervous system (CNS) in 40% of patients, usually without symptoms. The prognostic implications of CNS invasion are the potential for severe neurologic complications, and treatment failure due to sequestered bacteria in the CNS. When indicated, the only way to identify and treat neurosyphilis is by lumbar puncture to examine the cerebrospinal fluid (CSF), followed by intravenous (IV) Benzyl penicillin therapy. The invetigators have carried out in silico studies showing that oxazolidinones are potentially active against T.p., are neuropenetrative and can be administered orally. The invetigators have carried out preclinical studies using an in vitro culture system for T.p. and the use of the syphilis animal model with rabbits to test different antibiotics. The invetigators have confirmed that LZD was the best compound that could go on to be tested in clinical trials to treat syphilis. The Trep-AB clinical trial will test the non-inferiority of an investigational neuropenetrative drug, LZD, compared to standard treatment BPG, for early syphilis in humans conducting a randomized controlled clinical. Primary objective is to demonstrate the non-inferiority of LZD treatment compared with standard BPG treatment to cure patients with early syphilis. Seconday objective is to isolate T.p. strains in clinical samples to subtype DNA from patients at baseline and during recurrence or treatment failure. PROTOCOL HISTORY 05 Oct 2021 - Initial registration. The Trep-AB master protocol was registered as a two-arm, open-label, randomised non-inferiority trial comparing linezolid 600 mg once daily for 5 days with BPG for early syphilis. The planned recruitment target was 360 participants (180 per treatment group). Oct 2022 - Prespecified interim analysis. After 59 participants had been enrolled in the pre-interim phase, recruitment to the linezolid 600 mg once-daily for 5 days regimen was discontinued because the prespecified futility criterion was met. 02 Feb 2023 - Major protocol amendment. * Following the interim analysis, the protocol was amended to evaluate an optimised linezolid regimen of 600 mg twice daily for 10 days, marking the transition from the pre-interim to the post-interim phase of the trial. The amended regimen replaced the discontinued 600 mg once-daily for 5 days regimen; the two linezolid regimens were not evaluated concurrently. * The eligibility criteria, BPG comparator, primary endpoint, non-inferiority objective, and overall statistical framework remained unchanged. * The sample size for the post-interim phase was recalculated using revised efficacy assumptions observed in pre-interim phase (95% vs 90%), resulting in a recruitment target of 165 participants, instead of 360. Registry update following the amendment. When the registry was updated to reflect the major protocol amendment, the optimised linezolid regimen was added to the existing record without clearly indicating that it replaced the discontinued regimen. Consequently, the registry could be interpreted as describing a three-arm study comprising BPG and both linezolid regimens, although no three-arm comparison was conducted. Similarly, the registered total sample size of 224 represented the 59 participants enrolled during the pre-interim phase plus the planned 165 participants for the post-interim phase; it was not the target sample size for a single three-arm or pooled comparison. 17 Oct 2023 - Added UK participation and additional recruiting sites. 2024-2025 - Subsequent amendments addressed sdministrative and operational aspects of the study without changing the primary endpoint or statistical framework. Current registry record. The registry has been updated to clarify the sequential structure of the trial. The pre-interim phase evaluated linezolid 600 mg once daily for 5 days and was discontinued for futility; the post-interim phase evaluated linezolid 600 mg twice daily for 10 days in newly randomised participants. The present report concerns the post-interim phase only. The two phases were not concurrent, and participants from the pre-interim phase are not included in the primary efficacy analysis reported here.