Alternative Antibiotics for Syphilis

Oral and Neuro-Penetrative Alternative Antibiotics for Patients With Syphilis

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.

Inclusion Criteria:

1. Age 18 years or older at baseline visit.

2. Primary, secondary or early latent syphilis diagnosis based on SEIMC/IUSTI Guidelines*

   1. 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.
   2. Secondary syphilis is defined based on typical clinical symptoms with positive treponemal and non-treponemal tests (RPR≥1:4).
   3. 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.

3. Signature of written informed consent.

4. Ability to comply with the requirements of the study protocol.

5. 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.

6. 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:

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