Scrub Typhus Antibiotic Resistance Trial (START)

• ClinicalTrials.gov Identifier: NCT03083197
• Recruitment Status: Recruiting
• First Posted: March 17, 2017
• Last Update Posted: March 23, 2022
• Sponsor: University of Oxford
• Collaborators: Shoklo Malaria Research Unit; Chiangrai Prachanukroh Hospital
• Information provided by (Responsible Party): University of Oxford

Tracking Information

• First Submitted Date: March 13, 2017
• First Posted Date: March 17, 2017
• Last Update Posted Date: March 23, 2022
• Actual Study Start Date: October 15, 2017
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 13, 2017)

Fever clearance time (FCT) [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 20, 2017)

• 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 [ Time Frame: 8 Weeks ]
  (Minimum inhibitory concentrations (MIC) over susceptibility cut off)
• Genotyping of clinical Orientia tsutsugamushi isolates (56kDa gene +/- whole genome sequencing) [ Time Frame: 2 years ]
  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.
• Antigen-specific positive cellular and humoral immune responses [ Time Frame: 8 Weeks ]

Original Secondary Outcome Measures (submitted: March 13, 2017)

• 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 [ Time Frame: 8 Weeks ]
  (Minimum inhibitory concentrations (MIC) over susceptibility cut off)
• Successful genotyping of causative strains [ Time Frame: 8 Weeks ]
• Antigen-specific positive cellular and humoral immune responses [ Time Frame: 8 Weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Scrub Typhus

Intervention

• Drug: Doxycycline 7 days
  loading dose 200mg PO, then 100mg PO every 12 hours for 7 days
• Drug: Doxycycline 3 days
  loading dose 200mg PO, then 100mg PO every 12 hours for 3 days
• Drug: Azithromycin 3 days
  loading dose 1000mg PO on day 1, then 500mg PO every 24 hours on days 2 and 3

Study Arms

• Active Comparator: Doxycycline 7 days
  loading dose 200mg PO, then 100mg PO every 12 hours for 7 days
  Intervention: Drug: Doxycycline 7 days
• Active Comparator: Doxycycline 3 days
  loading dose 200mg PO, then 100mg PO every 12 hours for 3 days
  Intervention: Drug: Doxycycline 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
  Intervention: Drug: Azithromycin 3 days

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 13, 2017): 177
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2024
• Estimated Primary Completion Date: October 2024 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Assoc. Prof. Daniel Paris; +6622036373; parigi@tropmedres.ac

Contact: Tri Wangrangsimakul; +6622036333; tri@tropmedres.ac

• Listed Location Countries: Thailand

Administrative Information

• NCT Number: NCT03083197
• Other Study ID Numbers: START
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: University of Oxford
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Oxford
• Original Study Sponsor: Same as current

Collaborators

• Shoklo Malaria Research Unit
• Chiangrai Prachanukroh Hospital

Investigators

• Principal Investigator: Assoc. Prof. Daniel Paris; Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand

• PRS Account: University of Oxford
• Verification Date: March 2022