Clinical trial NCT03083197: Scrub Typhus Antibiotic Resistance Trial
Official title: The Scrub Typhus Antibiotic Resistance Trial (START) Comparing Doxycycline and Azithromycin Treatment Modalities in Areas of Reported Antimicrobial Resistance for Scrub Typhus
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Scrub Typhus
Keywords: Scrub Typhus
Antibiotic Resistance
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Shoklo Malaria Research Unit
name: Chiangrai Prachanukroh Hospital
First posted: 2017-03-17
Enrollment: 177
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: The funder is USAMRMC - MIDRP and Grant No. DHP-Award D6.7_15_C2_I_15_J9_1317

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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)

Primary outcomes:
measure: Fever clearance time (FCT)
timeFrame: at least 24 hours
Secondary outcomes:
measure: Resolution of bacteraemia in relation to Drug plasma level
timeFrame: 8 Weeks
measure: Occurrence of severe disease or treatment failure/relapse
timeFrame: 8 Weeks
measure: Presence of in vitro antimicrobial resistance
timeFrame: 8 Weeks
measure: Genotyping of clinical Orientia tsutsugamushi isolates (56kDa gene +/- whole genome sequencing)
timeFrame: 2 years
measure: Antigen-specific positive cellular and humoral immune responses
timeFrame: 8 Weeks
Other outcomes:
Locations:
city: Mae Sot
country: Thailand
facility: Shoklo-Malaria Research Unit (SMRU)
state: Tak
city: Chiang Rai
country: Thailand
facility: Chiangrai Prachanukroh Hospital
Study officials:
affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand
name: Assoc. Prof. Daniel Paris
role: PRINCIPAL_INVESTIGATOR
References: