Rickettsia Clearance Study

NCT ID: NCT05972772

Last Updated: 2024-12-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2/PHASE3

Total Enrollment

72 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-11-01

Study Completion Date

2026-08-31

Brief Summary

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Murine typhus is a disease caused by Rickettisa typhi, an obligate intracellular bacterium transmitted by rodent fleas. The disease has a worldwide distribution; however the true burden is unknown, related to its non-specific presentation and lack of access to diagnosis in many regions. A systematic review of untreated murine typhus based on observational studies of a total of 239 patients has estimated the mortality associated with the disease at between 0.4% and 3.6%.

Scrub typhus is caused by Orientia tsutsugamushi and transmitted by the larval stage of chigger mites (Trombiculidae family). It has been estimated to affect at least one million people each year. A systematic review found varying reports of the mortality associated with untreated scrub typhus ranging from 0-70% (median 6%).

Polymerase chain reaction (PCR) based diagnosis of rickettsial infections is only available in one centre (Mahosot Hospital) in Vientiane. A number of hospitals use a variety of point-of-care antibody tests to diagnose rickettsial infections however many of these have not been validated and they are of uncertain sensitivity and specificity. In 2006 results of a two year prospective study of 427 patients presenting to Mahosot Hospital with a febrile illness and negative blood cultures showed that 115 (27%) patients had an acute rickettsial infection, confirmed by serological testing. Among these patients, 41 were diagnosed with murine typhus and 63 with scrub typhus. Antibacterial agents with activity against rickettsial pathogens include doxycycline, azithromycin, chloramphenicol and rifampicin. Azithromycin is often reserved for pregnant women or children below the age of 8 years due to lasting concerns after the tetracycline-associated staining of growing bones and teeth in the past. Evidence is accumulating that doxycycline is superior to azithromycin for the treatment of rickettsial disease. Clinical treatment failures have occurred following azithromycin treatment of murine typhus. The relationship between rickettsial bacteria load and both disease severity and response to treatment has not been characterised. Rickettsial concentrations in blood are generally low, of the order of 210 DNA copies/mL blood for R. typhi and 284 DNA copies/mL blood for O. tsutsugamushi. At present, there is no standard antibiotic susceptibility testing (AST) method for R. typhi and O. tsutsugamushi. The gold standard method for AST for Rickettsia pathogens is the plaque assay which determines minimal inhibitory concentration (MICs) from the smallest antimicrobial concentration inhibiting rickettsial plaque forming unit formation. This method is laborious and time consuming, taking approximately 14-16 days based on species to yield a result. Molecular detection methods are useful for diagnosing patients infected with rickettsial pathogens and has been applied for antibiotic susceptibility testing. Antibiotic susceptibility testing based on DNA synthesis inhibition detecting by quantitative PCR (qPCR) for O. tsutsugamushi clinical isolates has been reported. However, the relationship between antibiotic susceptibility profiles and treatment response has not been studied. There is a need to develop a reliable ex vivo method to characterize the treatment response and compare susceptibility of R. typhi and O. tsutsugamushi to different agents.

Detailed Description

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Conditions

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Infectious Disease Therapeutics

Keywords

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Scrub Typhus Typhus, Endemic Flea-Borne

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Doxycycline

Doxycycline (Vibramycin, 100-mg film-coated tablets; Pfizer)) 200-mg loading dose, followed by 100 mg every 12 hours for 3 days.

Group Type ACTIVE_COMPARATOR

Doxycyclin

Intervention Type DRUG

100-mg film-coated tablets; Pfizer

Azithromycin

Azithromycin (Zithromax, 250-mg capsules; Pfizer) with a 500-mg loading dose, followed by 250 mg every 24 hours for 2 days. This will be followed by three days of doxycycline at the dose in A.

Group Type ACTIVE_COMPARATOR

Azithromycin

Intervention Type DRUG

250-mg capsules; Pfizer

Interventions

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Doxycyclin

100-mg film-coated tablets; Pfizer

Intervention Type DRUG

Azithromycin

250-mg capsules; Pfizer

Intervention Type DRUG

Other Intervention Names

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vibramycin Zithromax

Eligibility Criteria

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Inclusion Criteria

* Age above or equal 18 years
* Able to take oral medication
* Rapid test positive for murine typhus or scrub typhus
* Agrees to stay in hospital for at least 36 hours and to attend for scheduled follow up visits
* Written informed consent to participate in the study
* A negative urinary pregnancy test for all women of child-bearing age

Exclusion Criteria

* Pregnancy or breast feeding
* Previous allergic reaction to doxycycline or azithromycin
* Received more than one dose of chloramphenicol, doxycycline, tetracycline, fluoroquinolones, rifampicin or azithromycin during this hospital admission or more than one dose of any of these drugs in the week before admission
* Contraindication to doxycycline: severe hepatic impairment, known SLE
* Contraindication to azithromycin: sever hepatic impairment
* Severe typhus defined as the presence of one or more of the following:

1. Reduced level of consciousness
2. Clinical jaundice
3. Shock (BP systolic \<80 mmHg)
4. Unable to take oral medication
5. Radiological evidence of pneumonia
6. Clinical evidence for meningitis/encephalitis or the need of LP
7. Alternative diagnosis confirmed that explains the presenting symptoms
8. Any other syndrome which in the opinion of the admitting doctor constitutes severe typhus (reason must be stated)
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Mahidol Oxford Tropical Medicine Research Unit

OTHER

Sponsor Role collaborator

Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Weerawat Phuklia, PhD

Role: PRINCIPAL_INVESTIGATOR

Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit

Locations

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Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)

Vientiane, Vientaine, Laos

Site Status RECRUITING

Vientiane Provincial Hospital

Vientiane Province, Vientiane Province, Laos

Site Status RECRUITING

Countries

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Laos

Central Contacts

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Weerawat Phuklia, PhD

Role: CONTACT

Phone: +8562056581365

Email: [email protected]

Elizabeth Ashley

Role: CONTACT

Phone: +8562052457028

Email: [email protected]

Facility Contacts

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Professor Elizabeth Ashley

Role: primary

Elizabeth Ashley

Role: primary

Other Identifiers

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26-23

Identifier Type: -

Identifier Source: org_study_id