Rickettsia Clearance Study (RiCS)

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: Recruiting
• Conditions: Infectious Disease; Therapeutics
• Intervention / Treatment: Drug: Doxycyclin; Drug: Azithromycin

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Weerawat Phuklia, PhD; Phone Number: +8562056581365; Email: weerawat@tropmedres.ac
• Study Contact Backup: Name: Elizabeth Ashley; Phone Number: +8562052457028; Email: elizabeth.ashley@tropmedres.ac

Study Locations

• Lao People's Democratic Republic
  • Vientiane Province, Lao People's Democratic Republic
    • Recruiting
    • Vientiane Provincial Hospital
    • Contact: Elizabeth Ashley; Phone Number: +85621250752; Email: elizabeth.ashley@tropmedres.ac
  • Vientaine
    • Vientiane, Vientaine, Lao People's Democratic Republic, 0103
      • Recruiting
      • Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)
      • Contact: Professor Elizabeth Ashley; Phone Number: +85621250752; Email: elizabeth.ashley@tropmedes.ac

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
Rate of clearance of R. typhi or O. tsutsugamushi from peripheral blood of patients using serial qPCR measurement	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

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	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	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	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	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	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	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	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	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	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)	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	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)	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

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)	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

• Sponsor: Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit
• Collaborators: Mahidol Oxford Tropical Medicine Research Unit
• Investigators: Principal Investigator: Weerawat Phuklia, PhD, Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: June 7, 2023
• First Submitted That Met QC Criteria: July 31, 2023
• First Posted (Actual): August 2, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 23, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Scrub Typhus; Typhus, Endemic Flea-Borne
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Doxycycline; Azithromycin
• Other Study ID 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