Alternative Antibiotics for Syphilis

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 - Master protocol registered. Initial regimen: linezolid 600 mg once daily for 5 days.

Oct 2022 - Recruitment to the once-daily 5-day regimen was discontinued due to futility in the prespecified interim analysis.

02 Feb 2023 - Major protocol amended to evaluate linezolid 600 mg twice daily for 10 days (RCT2). Sample size recalculated using revised efficacy assumptions (observed BPG efficacy >95% instead of 90%). Primary endpoint and overall statistical design unchanged.

17 Oct 2023 - Added UK participation and additional recruiting sites. 2024-2025 - Administrative and operational revisions Current protocol - This record reflects the final master protocol for the evaluation of linezolid 600 mg twice daily for 10 days.

Inclusion criteria

• Age 18 years or older at baseline visit.
• Primary, secondary or early latent syphilis diagnosis based on SEIMC/IUSTI Guidelines*

• Primary syphilis is defined as typical ulcer (chancre) and one of the following: detection of T.p. by Polymerase chain reaction (PCR), positive darkfield examination (DFE) or positive serological test (RPR≥1:4) for syphilis.
• Secondary syphilis is defined based on typical clinical symptoms with positive treponemal and non-treponemal tests (RPR≥1:4).
• Early latent syphilis is defined as positive serological treponemal and non-treponemal tests (RPR≥1:4) with no clinical evidence of infection, with a previous negative syphilis serology,or a four-fold increase in RPR titer of a non-treponemal test within the past 12 months.Serological tests for syphilis performed within 10 days prior to study inclusion visit willbe acceptable for enrollment.
• Signature of written informed consent.
• Ability to comply with the requirements of the study protocol.
• If women of childbearing potential, use of a highly effective method of contraception (abstinence,hormonal contraception, intra-uterine device [IUD], or anatomical sterility in self or partner)committed during 1 week after last IMP administration.
• If men, use of condom during heterosexual intercourse and use of a highly effective method ofcontraception (abstinence, hormonal contraception, intra-uterine device [IUD], or anatomical sterilityin self or partner) in female partner committed during 1 week after last IMP administration.

• For inclusion purposes, positive point of care tests (POCT) will be accepted in selected patients without previous syphilis history and negative serological tests for syphilis during the last 12 months (Syphilis rapid diagnostic test [RDT] or Chembio DPP syphilis screen & confirm assay [DPP]), or with a previous history of syphilis and negative non-treponemal tests during the last 12 months (DPP). Further confirmation by the methods described in a), b) or c) will be necessary. Participants whose diagnosis is not confirmed will be excluded from the efficacy analyses.

Exclusion criteria

• Known allergy to any of the IMPs and/or excipients, particularly known hypersensitivity to penicillin, cephalosporins or other beta-lactam agents and/or allergy to soya or peanut.
• Lactose or galactose intolerance or glucose-galactose malabsorbtion.
• Diagnosis criteria of symptomatic neurosyphilis.
• Pregnant or breastfeeding women.
• Current treatment with any drugs likely to interact with the study medication (see Appendix 6).
• Have taken any antibiotics with potential activity against syphilis (e.g. beta lactams, cephalosporines, macrolides, tetracyclines) within 1 week prior to randomization.
• Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, incapacitating psycho-affective disturbance, acute confusional state.
• Renal function impairment requiring hemodialysis.
• Symptomatic concomitant STI (i.e., gonococcus, chlamydia, lymphogranuloma venereum, Mycoplasma genitalium) or other infection disease requiring antibiotic treatment potentially active against syphilis.
• Having received treatment for the early syphilis recently diagnosed (In the previous 6 months)