Scrub Typhus Antibiotic Resistance Trial

NCT03083197 | Active Not Recruiting Phase 4

• 1 other identifier: START
• Study Type: interventional
• Target: 177
• Locations: 1 country
• Sites: 5

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. 1.To perform pharmacokinetic/pharmacodynamics (PK/PD) characterization of the therapeutic responses for doxycycline and azithromycin, incl. serial bacterial load measurements.
2. 2.To define clinical, bacterial, pathophysiological and pharmacological factors associated with disease severity, fever-clearance times (FCT), treatment failures and relapse/re-infection.
3. 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. 4.To genotype all clinical isolates using whole genome sequencing for comparative genomics.
5. 5.To dissect the natural immune response in scrub typhus, using antigen-specific cellular immune and antibody studies, and cytokine profiling

Conditions

Scrub Typhus

Keywords

Scrub Typhus; Antibiotic Resistance

Outcome Measures

Primary Outcomes (1)

• 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.

  at least 24 hours

Secondary Outcomes (5)

• Resolution of bacteraemia in relation to Drug plasma level

  8 Weeks

• Occurrence of severe disease or treatment failure/relapse

  8 Weeks

• Presence of in vitro antimicrobial resistance

  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

Study Arms (3)

Doxycycline 7 days

ACTIVE COMPARATOR

loading dose 200mg PO, then 100mg PO every 12 hours for 7 days

Drug: Doxycycline 7 days

Doxycycline 3 days

ACTIVE COMPARATOR

loading dose 200mg PO, then 100mg PO every 12 hours for 3 days

Drug: Doxycycline 3 days

Azithromycin 3 days

ACTIVE COMPARATOR

loading dose 1000mg PO on day 1, then 500mg PO every 24 hours on days 2 and 3

Drug: Azithromycin 3 days

Interventions

Doxycycline 7 days DRUG

loading dose 200mg PO, then 100mg PO every 12 hours for 7 days

Doxycycline 7 days

Doxycycline 3 days DRUG

loading dose 200mg PO, then 100mg PO every 12 hours for 3 days

Doxycycline 3 days

Azithromycin 3 days DRUG

loading dose 1000mg PO on day 1, then 500mg PO every 24 hours on days 2 and 3

Azithromycin 3 days

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Mae Suai District Hospital: collaborator
• Mae Chan District Hospital: collaborator
• Mae Fa Luang District Hospital: collaborator
• University of Oxford: lead
• Shoklo Malaria Research Unit: collaborator
• Chiangrai Prachanukroh Hospital: collaborator

Study Sites (5)

Shoklo-Malaria Research Unit (SMRU)

Mae Sot, Changwat Tak, Thailand

Location

Chiangrai Prachanukroh Hospital

Chiang Rai, Thailand

Location

Mae Chan District Hospital

Chiang Rai, Thailand

Location

Mae Fah Luang District Hospital

Chiang Rai, Thailand

Location

Mae Suai District Hospital

Chiang Rai, Thailand

Location

MeSH Terms

Conditions

Scrub Typhus

Interventions

Doxycycline; Azithromycin

Condition Hierarchy (Ancestors)

Rickettsiaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Erythromycin; Macrolides; Polyketides; Lactones

Study Officials

• Assoc. Prof. Daniel Paris

  Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 13, 2017
• First Posted: March 17, 2017
• Study Start: October 15, 2017
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 1, 2028
• Last Updated: April 28, 2026

Record last verified: 2026-04

Locations

TH (5)