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Scrub Typhus Antibiotic Resistance Trial (START)

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ClinicalTrials.gov Identifier: NCT03083197
Recruitment Status : Recruiting
First Posted : March 17, 2017
Last Update Posted : February 15, 2019
Sponsor:
Collaborators:
Shoklo Malaria Research Unit
Chiangrai Prachanukroh Hospital
Information provided by (Responsible Party):
University of Oxford

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

Condition or disease Intervention/treatment Phase
Scrub Typhus Drug: Doxycycline 7 days Drug: Doxycycline 3 days Drug: Azithromycin 3 days Phase 4

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 177 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Scrub Typhus Antibiotic Resistance Trial (START) Comparing Doxycycline and Azithromycin Treatment Modalities in Areas of Reported Antimicrobial Resistance for Scrub Typhus
Actual Study Start Date : October 15, 2017
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2019


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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Resolution of bacteraemia in relation to Drug plasma level [ Time Frame: 8 Weeks ]
  2. Occurrence of severe disease or treatment failure/relapse [ Time Frame: 8 Weeks ]
  3. Presence of in vitro antimicrobial resistance [ Time Frame: 8 Weeks ]
    (Minimum inhibitory concentrations (MIC) over susceptibility cut off)

  4. 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.

  5. Antigen-specific positive cellular and humoral immune responses [ Time Frame: 8 Weeks ]


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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03083197


Contacts
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Contact: Assoc. Prof. Daniel Paris +6622036373 parigi@tropmedres.ac
Contact: Tri Wangrangsimakul +6622036333 tri@tropmedres.ac

Locations
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Thailand
Shoklo-Malaria Research Unit (SMRU) Not yet recruiting
Mae Sot, Tak, Thailand
Contact: Rose McGready, Prof       rose@shoklo-unit.com   
Chiangrai Prachanukroh Hospital Recruiting
Chiang Rai, Thailand
Contact: Tri Wangrangsimakul, MD       Tri@tropmedres.ac   
Sponsors and Collaborators
University of Oxford
Shoklo Malaria Research Unit
Chiangrai Prachanukroh Hospital
Investigators
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Principal Investigator: Assoc. Prof. Daniel Paris Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand

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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03083197     History of Changes
Other Study ID Numbers: START
First Posted: March 17, 2017    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Keywords provided by University of Oxford:
Scrub Typhus
Antibiotic Resistance

Additional relevant MeSH terms:
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Typhus, Epidemic Louse-Borne
Scrub Typhus
Rickettsia Infections
Rickettsiaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Anti-Bacterial Agents
Doxycycline
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents