Rickettsia Clearance Study

NCT05972772 | Recruiting Phase 2

• 1 other identifier: 26-23
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Infectious Disease; Therapeutics

Keywords

Scrub Typhus; Typhus, Endemic Flea-Borne

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• Area under the plasma concentration versus time curve (AUC) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus

  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.

• 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

  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 plasma concentration (Cmax) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus

  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 of the intracellular concentration (Cmax) in the buffy coat of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus

  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 plasma concentration (Tmax) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus

  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.

Study Arms (2)

Doxycycline

ACTIVE COMPARATOR

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

Drug: Doxycyclin

Azithromycin

ACTIVE COMPARATOR

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

Interventions

Doxycyclin DRUG

100-mg film-coated tablets; Pfizer

Also known as: vibramycin

Doxycycline

Azithromycin DRUG

250-mg capsules; Pfizer

Also known as: Zithromax

Azithromycin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• Reduced level of consciousness
• Clinical jaundice
• Shock (BP systolic \<80 mmHg)
• Unable to take oral medication
• Radiological evidence of pneumonia
• Clinical evidence for meningitis/encephalitis or the need of LP
• Alternative diagnosis confirmed that explains the presenting symptoms
• Any other syndrome which in the opinion of the admitting doctor constitutes severe typhus (reason must be stated)

Sponsors & Collaborators

• Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit: lead
• Mahidol Oxford Tropical Medicine Research Unit: collaborator

Study Sites (2)

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

Vientiane, Vientaine, 0103, Laos

RECRUITING

Vientiane Provincial Hospital

Vientiane Province, Vientiane Province, Laos

RECRUITING

MeSH Terms

Conditions

Communicable Diseases; Scrub Typhus; Typhus, Endemic Flea-Borne

Interventions

Doxycycline; Azithromycin

Condition Hierarchy (Ancestors)

Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Rickettsiaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Vector Borne Diseases; Rickettsia Infections

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Erythromycin; Macrolides; Polyketides; Lactones

Study Officials

• Weerawat Phuklia, PhD

  Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weerawat Phuklia, PhD

CONTACT

+8562056581365; weerawat@tropmedres.ac

Elizabeth Ashley

CONTACT

+8562052457028; elizabeth.ashley@tropmedres.ac

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2023
• First Posted: August 2, 2023
• Study Start: November 1, 2024
• Primary Completion: August 31, 2025
• Study Completion (Estimated): August 31, 2026
• Last Updated: December 27, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: approximately 2 years after the end of the study

Locations

LA (2)