Oral and Neuro-Penetrative Alternative Antibiotics for Patients With Syphilis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 165
- 试验地点
- 14
- 主要终点
- Proportion of patients with adequate serological response (serological cure, week 48).
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
The statistical analysis will be blinded.
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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)
结局指标
主要结局
Proportion of patients with adequate serological response (serological cure, week 48).
时间窗: 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 clinical resolution of primary syphilis lesions (clinical cure, primary).
时间窗: 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).
时间窗: 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 24).
时间窗: 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 adequate serological response (serological cure, week 12).
时间窗: 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 allelic variation in T. pallidum strain(s) DNA in recurrent syphilis or suspected treatment failure (molecular cure).
时间窗: 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).
Proportion of participants achieving overall treatment success
时间窗: 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.
次要结局
- Proportion of patients with suspicion of neurosyphilis that have allelic variation in Treponema pallidum (T.p) isolates DNA in CSF (re-infection).(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 ulcer or mucosa lesions swabs (re-infection).(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).(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).(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).(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).(From date of randomization until date of first documented recurrence, assesed up to 48 weeks)
- Proportion of patients with antibiotic resistance genotype.(From date of randomization until date of first documented recurrence, assesed up to 48 weeks)
- Proportion of participants experiencing adverse events.(up to 12 weeks)
- Proportion of patients who have a change in the RPR titer within 2 weeks after treatment start of primary syphilis.(at 2 weeks)
- Proportion of patients with clinical resolution of primary syphilis lesions (clinical cure, primary).(at week 2)
- Proportion of patients with clinical resolution of secondary syphilis lesions (clinical cure, secondary).(at week 6)
- Proportion of patients with adequate serological response (serological cure, week 48).(at week 48)
- 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)
- Proportion of patients with adequate serological response (serological cure, week 12).(at week 12)
- Proportion of patients with adequate serological response (serological cure, week 24).(at week 24)
研究者
Oriol Mitja
Principal Investigator
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia