Early Latent Syphilis, Primary Syphilis, Secondary Syphilis
Conditions
Keywords
Syphilis, Benzathine penicillin G, RPR, Treponema pallidum, Linezolid
Brief summary
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
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.
Interventions
DRUGLinezolid 600 mg (post-interim)
Linezolid 600mg every 12hours during 10 days
DRUGBenzathine Penicilllin G (post-interim)
Single dose of intramuscular BPG 2.4 MUI
Sponsors
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The statistical analysis will be blinded.
Intervention model description
Open-label, non inferiority, randomized clinical trial. Eligible patients will be randomized to recieve Linezolid (experimental arm) or BPG (control arm).
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants achieving overall treatment success | at week 48 | Overall treatment success was defined as achievement of all outcome components applicable to the participant: clinical cure, serological cure, and absence of molecularly confirmed relapse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with clinical resolution of primary syphilis lesions (clinical cure, primary). | at week 2 | Assesment of clinical resolution defined as the complete healing of primary syphilis lesions within 2 weeks from treatment start. |
| Proportion of patients with clinical resolution of secondary syphilis lesions (clinical cure, secondary). | at week 6 | Assesment of clinical resolution defined as the complete healing of secondary syphilis lesions within 6 weeks from treatment start. |
| Proportion of patients with adequate serological response (serological cure, week 48). | at week 48 | Assessment of adequate serological response defined as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion to negative. |
| Proportion of patients with allelic variation in T. pallidum strain(s) DNA in recurrent syphilis or suspected treatment failure (absence of relapse). | From date of randomization until date of first documented recurrence or treatment failure, assesed up to 48 weeks | 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) in ulcer or mucosa lesions swabs, plasma, or oral swabs. |
| Proportion of patients with adequate serological response (serological cure, week 12). | at week 12 | Assessment of adequate serological response defined as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion to negative. |
| Proportion of patients with adequate serological response (serological cure, week 24). | at week 24 | Assessment of adequatesserological response defined as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion to negative. |
| Proportion of patients with antibiotic resistance genotype. | From date of randomization until date of first documented recurrence, assesed up to 48 weeks | 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. |
| Proportion of participants experiencing adverse events. | up to 12 weeks | Assesment of adverse events related to LZD treatment compared with adverse events related to standard BPG treatment in participants with early syphilis. |
| Proportion of patients who have a change in the RPR titer within 2 weeks after treatment start of primary syphilis. | at 2 weeks | Assessment of RPR titer variation at week 2 from treatment start of patients with primary syphilis. |
Countries
Spain, United Kingdom
Contacts
PRINCIPAL_INVESTIGATOROriol Mitjà Villar, PhD
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Outcome results
None listed