Alternative Antibiotics for Syphilis

Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Status and phase: Enrolling; Phase 3

Conditions: Primary Syphilis; Early Latent Syphilis; Secondary Syphilis

Treatments: Drug: Linezolid 600 mg; Drug: Benzathine Penicilllin G

Study type: Interventional

Funder types: Other

Identifiers

NCT05069974

2020-005604-19 (EudraCT Number)

Trep-AB

Details and patient eligibility

About

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.

Full description

The syphilis epidemic is rampant around the world, and therapeutic options are restricted to an antibiotic, intramuscular (IM) 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 efficacy 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.

Enrollment: 224 estimated patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

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 positive test using darkfield examination (DFE) or Polymerase chain reaction (PCR) detection of T.p. with/without positive serological test for syphilis.
   2. Secondary syphilis is defined based on typical clinical symptoms with positive treponemal and non-treponemal tests.
   3. Early latent syphilis is defined as positive serological treponemal and non-treponemal tests 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 benecessary.

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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224 participants in 3 patient groups

Linezolid (LZD) 1200

Experimental group

Description:

Patients will take film coated tables of LZD 600 mg every 12 hours during 10 days

Treatment:

Drug: Linezolid 600 mg

Benzathine Penicillin G (BPG)

Active Comparator group

Description:

Administration of intramuscular BPG 2.4 MIU single dose during day 1

Treatment:

Drug: Benzathine Penicilllin G

Linezolid (LZD) 600

Experimental group

Description:

Patients will take film coated tables of LZD 600 mg every 24 hours during 5 days

Treatment:

Drug: Linezolid 600 mg