Alternative Antibiotics for Syphilis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Oral and Neuro-Penetrative Alternative Antibiotics for Patients With Syphilis

Conditions
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Early Latent Syphilis, Primary Syphilis, Secondary Syphilis

Intervention / Treatment
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* Drug: Linezolid 600 mg
* Drug: Benzathine Penicilllin G


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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, non inferiority, two arms and randomized clinical trial. Eligible patients will be randomized (1:1) to recieve Linezolid (experimental arm) or BPG (control arm). Patients in Linezolid arm will receive one tablet (600 mg) every 12h for 10 days. Patients in BPG arm will receive an injection of 2.4 million units intramuscularly (IM).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linezolid (LZD) 1200<br>Patients will take film coated tables of LZD 600 mg every 12 hours during 10 days | Drug: Linezolid 600 mg<br>* After randomized to the experimental arm, the patient will take 1 tablet of Linezolid every 12hours during 10 days or 1 tablet of of Linezolid every 24hours during 5 days.<br>|
| Active Comparator: Benzathine Penicillin G (BPG)<br>Administration of intramuscular BPG 2.4 MIU single dose during day 1 | Drug: Benzathine Penicilllin G<br>* After randomized to the control arm, the patient will receive a single dose of intramuscular BPG.<br>|
| Experimental: Linezolid (LZD) 600<br>Patients will take film coated tables of LZD 600 mg every 24 hours during 5 days | Drug: Linezolid 600 mg<br>* After randomized to the experimental arm, the patient will take 1 tablet of Linezolid every 12hours during 10 days or 1 tablet of of Linezolid every 24hours during 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with clinical resolution of primary syphilis lesions (clinical cure, primary). | Assesment of clinical resolution defined as the complete healing of primary syphilis lesions within 2 weeks from treatment start. | at week 2 | 
| Proportion of patients with clinical resolution of secondary syphilis lesions (clinical cure, secondary). | Assesment of clinical resolution defined as the complete healing of secondary syphilis lesions within 6 weeks from treatment start. | at week 6 | 
| Proportion of patients with adequate serological response (serological cure, week 12). | Assessment of adequate serological response defined as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion to negative. | at week 12 | 
| Proportion of patients with adequate serological response (serological cure, week 24). | Assessment of adequatesserological response defined as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion to negative. | at week 24 | 
| Proportion of patients with adequate serological response (serological cure, week 48). | Assessment of adequate serological response defined as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion to negative. | at week 48 | 
| Proportion of patients with allelic variation in T. pallidum strain(s) DNA in recurrent syphilis or suspected treatment failure (molecular cure). | Assessment of re-infection in recurrent syphilis as defined by allelic variation in core genes of T. pallidum strain(s) compared to baseline using a molecular method (MLST-WGS). | From date of randomization until date of first documented recurrence or treatment failure, assesed up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with allelic variation in T. pallidum strain(s) DNA in ulcer or mucosa lesions swabs (re-infection). | Assessment of re-infection in recurrent syphilis lesions as defined by allelic variation in core genes of T. pallidum strain(s) compared to baseline using a molecular method (MLST-WGS). | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 
| Proportion of patients with allelic variation in T. pallidum strain(s) DNA in plasma (re-infection). | Assessment of re-infection in recurrent syphilis (secondary or early latent) as defined by allelic variation in core genes of T. pallidum strain(s) compared to baseline using a molecular method (MLST-WGS). | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 
| Proportion of patients with allelic variation in T. pallidum strain(s) DNA in oral swab/saliva (re-infection). | Assessment of re-infection in recurrent syphilis (secondary or early latent) as defined by allelic variation in core genes of T. pallidum strain(s) compared to baseline using a molecular method (MLST-WGS). | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 
| Proportion of patients with allelic variation in T. pallidum strain(s) DNA in skin punch biopsy (re-infection). | Assessment of re-infection in recurrent syphilis lesions as defined by allelic variation in core genes of T. pallidum strain(s) compared to baseline using a molecular method (MLST-WGS). | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 
| Proportion of patients with allelic variation in T. pallidum strain(s) DNA in ear lobe scraping (re-infection). | Assessment of re-infection in recurrent syphilis (secondary or early latent) as defined by allelic variation in core genes of T. pallidum strain(s) compared to baseline using a molecular method (MLST-WGS). (Optional,in a selected group of patients). | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 
| Proportion of patients with suspicion of neurosyphilis that have allelic variation in Treponema pallidum (T.p) isolates DNA in CSF (re-infection). | Assessment of re-infection in patients with suspicion of neurosyphilis as defined by allelic variation in core genes of T. pallidum strains compared to baseline using a molecular method (MLST-WGS). (in a selected group of patients with suspicion of neurosyphilis). | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 
| Proportion of patients with antibiotic resistance genotype. | Assesment of allelic variation in core genes conferring antimicrobial resistance in clinical specimens from patients who are considered to have treatment failure compared to patients with adequate clinical and serological response. | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 
| Proportion of participants experiencing adverse events. | Assesment of adverse events related to LZD treatment compared with adverse events related to standard BPG treatment in participants with early syphilis. | up to 12 weeks | 
| Proportion of patients who have a change in the RPR titer within 2 weeks after treatment start of primary syphilis. | Assessment of RPR titer variation at week 2 from treatment start of patients with primary syphilis. | at 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Syphilis, Benzathine penicillin G, RPR, Treponema pallidum, Linezolid