The Scrub Typhus Antibiotic Resistance Trial (START) Comparing Doxycycline and Azithromycin Treatment Modalities in Areas of Reported Antimicrobial Resistance for Scrub Typhus
试验速览
- 阶段
- 4 期
- 状态
- 进行中（未招募）
- 入组人数
- 177
- 试验地点
- 7
- 主要终点
- Fever clearance time (FCT)
研究概览
简要总结
Study type: Randomized Control Treatment Trial
Study population: Male and female patients with ≥15 years of age and acute scrub typhus
Duration: 2 years
Study Design: Prospective, open-label, randomized-controlled treatment trial in patients ≥15 years old admitted to hospital with acute scrub typhus. Randomization into 3 oral treatment arms (each n=59 patients, total n=177): i) 7 days of doxycycline, ii) 3 days of doxycycline, and iii) 3 days of azithromycin
Primary Objective: To evaluate the clinical and microbiological responses in scrub typhus patients to three oral treatment regimens: 7 days of doxycycline, 3 days of doxycycline, and 3 days of azithromycin
Secondary Objectives:
- To perform pharmacokinetic/pharmacodynamics (PK/PD) characterization of the therapeutic responses for doxycycline and azithromycin, incl. serial bacterial load measurements.
- To define clinical, bacterial, pathophysiological and pharmacological factors associated with disease severity, fever-clearance times (FCT), treatment failures and relapse/re-infection.
- To determine the minimum inhibitory concentrations (MIC) of clinical Orientia tsutsugamushi isolates to doxycycline, azithromycin and chloramphenicol, using in vitro growth-inhibition assays
- To genotype all clinical isolates using whole genome sequencing for comparative genomics.
- To dissect the natural immune response in scrub typhus, using antigen-specific cellular immune and antibody studies, and cytokine profiling
详细描述
The funder is USAMRMC - MIDRP and Grant No. DHP-Award D6.7_15_C2_I_15_J9_1317
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
- None
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 15 years old
- •Hospitalization with acute undifferentiated fever (temperature > 37.5°C, tympanic) ≤14 days or patients admitted to hospital with a history of fever ≤ 14 days who subsequently develop fever within 24 hours of admission
- •Clinically suspected scrub typhus: defined as acute undifferentiated fever with no clear focus of infection and negative malaria blood smear and/or negative malaria RDT. Patients may have one, none, or a combination of other clinical findings such as eschar, rash, lymphadenopathy, headache, myalgia, cough, nausea and abdominal discomfort.
- •A positive scrub typhus RDT (Scrub Typhus IgM RDT, InBios International, Seattle, WA, USA) and/or positive PCR-based detection of O. tsutsugamushi DNA from the admission blood sample
- •Written informed consent and/or, written informed assent as required
- •Able to take oral medication
排除标准
- •Known hypersensitivity to tetracycline, doxycycline or azithromycin
- •Administration of doxycycline, azithromycin, chloramphenicol, rifampicin, or tetracycline during the preceding 7 days
- •Pregnancy or breast-feeding
- •Patients with myasthenia gravis or systemic lupus erythematosus
- •Patients with an established infection (diagnostic test required) e.g. acute malaria, dengue, leptospirosis, typhoid, Japanese encephalitis etc.
- •Current TB or TB treatment in ≤ 6 months (contain active antibiotics against Orientia spp.)
- •Current HAART use for HIV, long term use of immunosuppressants (e.g. steroids, chemotherapy, TNF-inhibitors and related agents)
- •Patients with severe disease whom the clinical team feel their condition necessitates the need for additional scrub typhus treatment beyond the allocated antibiotic treatment assigned at randomization (e.g. IV chloramphenicol and/or PO/NG rifampicin)
研究组 & 干预措施
Doxycycline 7 days
loading dose 200mg PO, then 100mg PO every 12 hours for 7 days
干预措施: Doxycycline 7 days (Drug)
Doxycycline 3 days
loading dose 200mg PO, then 100mg PO every 12 hours for 3 days
干预措施: Doxycycline 3 days (Drug)
Azithromycin 3 days
loading dose 1000mg PO on day 1, then 500mg PO every 24 hours on days 2 and 3
干预措施: Azithromycin 3 days (Drug)
结局指标
主要结局
Fever clearance time (FCT)
时间窗: at least 24 hours
Based on the time from first dose of antibiotic treatment to when the tympanic temperature first falls ≤37.5°C and remains ≤37.5°C for at least 24 hours, outside of the influence of paracetamol.
次要结局
- Resolution of bacteraemia in relation to Drug plasma level(8 Weeks)
- Genotyping of clinical Orientia tsutsugamushi isolates (56kDa gene +/- whole genome sequencing)(2 years)
- Antigen-specific positive cellular and humoral immune responses(8 Weeks)
- Presence of in vitro antimicrobial resistance(8 Weeks)
- Occurrence of severe disease or treatment failure/relapse(8 Weeks)