Rickettsia Clearance Study (RiCS)

December 23, 2024 updated by: Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit

A Pharmacokinetic-pharmacodynamic Study of Early Rickettsia Clearance in Murine Typhus or Scrub Typhus Patients Treated with Doxycycline or Azithromycin

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
72

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Lao People's Democratic Republic
      • Vientiane Province, Lao People's Democratic Republic
    • Vientaine
      • Vientiane, Vientaine, Lao People's Democratic Republic, 0103
        • Recruiting
        • Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Doxycycline
Doxycycline (Vibramycin, 100-mg film-coated tablets; Pfizer)) 200-mg loading dose, followed by 100 mg every 12 hours for 3 days.
Drug: Doxycyclin
100-mg film-coated tablets; Pfizer
Other Names:
  • vibramycin
Active Comparator: 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.
Drug: Azithromycin
250-mg capsules; Pfizer
Other Names:
  • Zithromax

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Rate of clearance of R. typhi or O. tsutsugamushi from peripheral blood of patients using serial qPCR measurement
Time Frame: Within 72 hours after treatment
Measure of clearance or R. typhi or O. tsutsugamushi DNA assessed by serial qPCR measurements on the blood from murine typhus patients treated with either doxycycline or azithromycin. Rickettsia clearance rate will be estimated from serial qPCR measurement in each patient. The clearance rate is the slope of the initial log linear decline in qPCR estimated bacteria densities
Within 72 hours after treatment

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Area under the plasma concentration versus time curve (AUC) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
AUC of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
Peak plasma concentration (Cmax) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
Cmax of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
Time to peak plasma concentration (Tmax) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
Tmax of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
Time at doxycycline or azithromycin has lost half its maximum concentration (T1/2) for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
T1/2 of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on plasma concentrations measure up to 96 hours after the last dose. Azithromycin: Based on plasma concentrations measure up to 2 weeks after the first dose.
Fever clearance time in patients with scrub typhus or murine typhus treated with doxycycline or azithromycin
Time Frame: First 7 days after treatment
Fever clearance time is defined as the time in hours from onset of antibiotic treatment, to the first Axillary temperature recording less than or equal 37.5°C, which then remains less than or equal 37.5°C for 24 hours
First 7 days after treatment
Area under the intracellular concentration in the buffy coat versus time curve (AUC) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in Buffy coat measure up to 2 weeks after the first dose.
AUC of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in Buffy coat measure up to 2 weeks after the first dose.
Peak of the intracellular concentration (Cmax) in the buffy coat of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in the buffy coat measure up to 2 weeks after the first dose.
Cmax of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in the buffy coat measure up to 2 weeks after the first dose.
Time to peak of the intracellular concentration (Tmax) in the buffy coat of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in the buffy coat measure up to 2 weeks after the first dose.
Tmax of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in the buffy coat measure up to 2 weeks after the first dose.
Time at doxycycline or azithromycin has lost half its maximum intracellular concentration (T1/2) for the treatment of murine typhus or scrub typhus
Time Frame: Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in the buffy coat measure up to 2 weeks after the first dose.
T1/2 of doxycycline or azithromycin versus time from zero to infinity in the treatment of murine typhus and scrub typhus will be estimated using a modelling approach
Doxycycline: Based on intracellular concentrations in the buffy coat measure up to 96 hours after the last dose. Azithromycin: Based on intracellular concentrations in the buffy coat measure up to 2 weeks after the first dose.
Evaluation the accuracy of the new brand RDT, Rickettsia IgG/IgM Combo (Lumiquick) compared to Scrub typhus Detect IgM Rapid System (Dipstick) (InBios)
Time Frame: Day 0
Sensitivity and specificity of Rickettsia IgG/IgM Combo (Lumiquick) compared to Scrub typhus Detect IgM Rapid System (Dipstick) (InBios) will be compared
Day 0
Frequency of serious adverse events (SAEs) after treatment
Time Frame: Day 0 to day 28
SAEs will be defined using the Common Toxicity Criteria (v5.0) of the US National Cancer Institute
Day 0 to day 28
Evaluation the accuracy of Rickettsia IgG/IgM Combo (Lumiquick) compared to a combined gold standard of PCR assays and serology (paired samples)
Time Frame: Day 0 and Day 28
Sensitivity and specificity of RDT (Lumiquick) result will be compared to a combined gold standard of PCR assays and serology (paired serum)
Day 0 and Day 28

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Evaluation the accuracy of the new brand RDT, Rickettsia IgG/IgM Combo (Lumiquick) compared to Scrub typhus Detect IgM Rapid System (Dipstick) (InBios)
Time Frame: Day 0
Sensitivity and specificity of Rickettsia IgG/IgM Combo (Lumiquick) compared to Scrub typhus Detect IgM Rapid System (Dipstick) (InBios) will be compared
Day 0

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Mahidol Oxford Tropical Medicine Research Unit

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Weerawat Phuklia, PhD, Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 31, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 31, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 7, 2023

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 31, 2023

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 2, 2023

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 23, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 26-23

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

With participant's consent, participant's data and results from blood analyses stored in the database may be shared according to the terms defined in the MORU data sharing policy with data repositories or other researchers to use in the future.

IPD Sharing Time Frame

approximately 2 years after the end of the study

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • CSR

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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