Scrub Typhus Antibiotic Resistance Trial (START)

The Scrub Typhus Antibiotic Resistance Trial (START) Comparing Doxycycline and Azithromycin Treatment Modalities in Areas of Reported Antimicrobial Resistance for Scrub Typhus

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

Study Overview

• Status: Recruiting
• Conditions: Scrub Typhus
• Intervention / Treatment: Drug: Doxycycline 7 days; Drug: Doxycycline 3 days; Drug: Azithromycin 3 days

Detailed Description

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

• Study Type: Interventional
• Enrollment (Anticipated): 177
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Assoc. Prof. Daniel Paris; Phone Number: +6622036373; Email: parigi@tropmedres.ac
• Study Contact Backup: Name: Tri Wangrangsimakul; Phone Number: +6622036333; Email: tri@tropmedres.ac

Study Locations

• Thailand
  • Chiang Rai, Thailand
    • Recruiting
    • Chiangrai Prachanukroh Hospital
    • Contact: Tri Wangrangsimakul, MD; Email: Tri@tropmedres.ac
  • Tak
    • Mae Sot, Tak, Thailand
      • Not yet recruiting
      • Shoklo-Malaria Research Unit (SMRU)
      • Contact: Rose McGready, Prof; Email: rose@shoklo-unit.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Doxycycline 7 days; loading dose 200mg PO, then 100mg PO every 12 hours for 7 days	Drug: Doxycycline 7 days; loading dose 200mg PO, then 100mg PO every 12 hours for 7 days
Active Comparator: Doxycycline 3 days; loading dose 200mg PO, then 100mg PO every 12 hours for 3 days	Drug: Doxycycline 3 days; loading dose 200mg PO, then 100mg PO every 12 hours for 3 days
Active Comparator: Azithromycin 3 days; loading dose 1000mg PO on day 1, then 500mg PO every 24 hours on days 2 and 3	Drug: Azithromycin 3 days; loading dose 1000mg PO on day 1, then 500mg PO every 24 hours on days 2 and 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	(Minimum inhibitory concentrations (MIC) over susceptibility cut off)	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.	2 years
Antigen-specific positive cellular and humoral immune responses		8 Weeks

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Shoklo Malaria Research Unit; Chiangrai Prachanukroh Hospital
• Investigators: Principal Investigator: Assoc. Prof. Daniel Paris, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2017
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): October 1, 2024

Study Registration Dates

• First Submitted: March 13, 2017
• First Submitted That Met QC Criteria: March 13, 2017
• First Posted (Actual): March 17, 2017

Study Record Updates

• Last Update Posted (Actual): March 23, 2022
• Last Update Submitted That Met QC Criteria: March 22, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Antibiotic Resistance; Scrub Typhus
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Rickettsia Infections; Rickettsiaceae Infections; Typhus, Epidemic Louse-Borne; Scrub Typhus; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline; Azithromycin
• Other Study ID Numbers: START

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No