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: 1. To perform pharmacokinetic/pharmacodynamics (PK/PD) characterization of the therapeutic responses for doxycycline and azithromycin, incl. serial bacterial load measurements. 2. To define clinical, bacterial, pathophysiological and pharmacological factors associated with disease severity, fever-clearance times (FCT), treatment failures and relapse/re-infection. 3. To determine the minimum inhibitory concentrations (MIC) of clinical Orientia tsutsugamushi isolates to doxycycline, azithromycin and chloramphenicol, using in vitro growth-inhibition assays 4. To genotype all clinical isolates using whole genome sequencing for comparative genomics. 5. To dissect the natural immune response in scrub typhus, using antigen-specific cellular immune and antibody studies, and cytokine profiling
The funder is USAMRMC - MIDRP and Grant No. DHP-Award D6.7\_15\_C2\_I\_15\_J9\_1317
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
177
loading dose 200mg PO, then 100mg PO every 12 hours for 7 days
loading dose 200mg PO, then 100mg PO every 12 hours for 3 days
loading dose 1000mg PO on day 1, then 500mg PO every 24 hours on days 2 and 3
Shoklo-Malaria Research Unit (SMRU)
Mae Sot, Changwat Tak, Thailand
Chiangrai Prachanukroh Hospital
Chiang Rai, Thailand
Mae Chan District Hospital
Chiang Rai, Thailand
Mae Fah Luang District Hospital
Chiang Rai, Thailand
Mae Suai District Hospital
Chiang Rai, Thailand
Fever clearance time (FCT)
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.
Time frame: at least 24 hours
Resolution of bacteraemia in relation to Drug plasma level
Time frame: 8 Weeks
Occurrence of severe disease or treatment failure/relapse
Time frame: 8 Weeks
Presence of in vitro antimicrobial resistance
(Minimum inhibitory concentrations (MIC) over susceptibility cut off)
Time frame: 8 Weeks
Genotyping of clinical Orientia tsutsugamushi isolates (56kDa gene +/- whole genome sequencing)
Genotyping of clinical OT isolates will be performed on patient samples that are PCR positive (approximately 50-60%) and/or culture positive (approximately 30%). Extracted DNA will be sent for 56kDa gene sequencing +/- whole genome sequencing, revealing the clinically important strains and allowing for comparative analysis with disease severity and patient outcomes.
Time frame: 2 years
Antigen-specific positive cellular and humoral immune responses
Time frame: 8 Weeks
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