xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05972772</url>
    </required_header>
    <id_info>
      <org_study_id>26-23</org_study_id>
      <nct_id>NCT05972772</nct_id>
    </id_info>
    <brief_title>A Pharmacokinetic-pharmacodynamic Study of Early Rickettsia Clearance in Murine Typhus or Scrub Typhus Patients Treated With Doxycycline or Azithromycin</brief_title>
    <acronym>PHARC</acronym>
    <official_title>A Pharmacokinetic-pharmacodynamic Study of Early Rickettsia Clearance in Murine Typhus or Scrub Typhus Patients Treated With Doxycycline or Azithromycin</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Mahidol Oxford Tropical Medicine Research Unit</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        Murine typhus is a disease caused by Rickettisa typhi, an obligate intracellular bacterium&#xD;
        transmitted by rodent fleas. The disease has a worldwide distribution; however the true&#xD;
        burden is unknown, related to its non-specific presentation and lack of access to diagnosis&#xD;
        in many regions. A systematic review of untreated murine typhus based on observational&#xD;
        studies of a total of 239 patients has estimated the mortality associated with the disease at&#xD;
        between 0.4% and 3.6%.&#xD;
  &#xD;
        Scrub typhus is caused by Orientia tsutsugamushi and transmitted by the larval stage of&#xD;
        chigger mites (Trombiculidae family). It has been estimated to affect at least one million&#xD;
        people each year. A systematic review found varying reports of the mortality associated with&#xD;
        untreated scrub typhus ranging from 0-70% (median 6%).&#xD;
  &#xD;
        Polymerase chain reaction (PCR) based diagnosis of rickettsial infections is only available&#xD;
        in one centre (Mahosot Hospital) in Vientiane. A number of hospitals use a variety of&#xD;
        point-of-care antibody tests to diagnose rickettsial infections however many of these have&#xD;
        not been validated and they are of uncertain sensitivity and specificity. In 2006 results of&#xD;
        a two year prospective study of 427 patients presenting to Mahosot Hospital with a febrile&#xD;
        illness and negative blood cultures showed that 115 (27%) patients had an acute rickettsial&#xD;
        infection, confirmed by serological testing. Among these patients, 41 were diagnosed with&#xD;
        murine typhus and 63 with scrub typhus. Antibacterial agents with activity against&#xD;
        rickettsial pathogens include doxycycline, azithromycin, chloramphenicol and rifampicin.&#xD;
        Azithromycin is often reserved for pregnant women or children below the age of 8 years due to&#xD;
        lasting concerns after the tetracycline-associated staining of growing bones and teeth in the&#xD;
        past. Evidence is accumulating that doxycycline is superior to azithromycin for the treatment&#xD;
        of rickettsial disease. Clinical treatment failures have occurred following azithromycin&#xD;
        treatment of murine typhus. The relationship between rickettsial bacteria load and both&#xD;
        disease severity and response to treatment has not been characterised. Rickettsial&#xD;
        concentrations in blood are generally low, of the order of 210 DNA copies/mL blood for R.&#xD;
        typhi and 284 DNA copies/mL blood for O. tsutsugamushi. At present, there is no standard&#xD;
        antibiotic susceptibility testing (AST) method for R. typhi and O. tsutsugamushi. The gold&#xD;
        standard method for AST for Rickettsia pathogens is the plaque assay which determines minimal&#xD;
        inhibitory concentration (MICs) from the smallest antimicrobial concentration inhibiting&#xD;
        rickettsial plaque forming unit formation. This method is laborious and time consuming,&#xD;
        taking approximately 14-16 days based on species to yield a result. Molecular detection&#xD;
        methods are useful for diagnosing patients infected with rickettsial pathogens and has been&#xD;
        applied for antibiotic susceptibility testing. Antibiotic susceptibility testing based on DNA&#xD;
        synthesis inhibition detecting by quantitative PCR (qPCR) for O. tsutsugamushi clinical&#xD;
        isolates has been reported. However, the relationship between antibiotic susceptibility&#xD;
        profiles and treatment response has not been studied. There is a need to develop a reliable&#xD;
        ex vivo method to characterize the treatment response and compare susceptibility of R. typhi&#xD;
        and O. tsutsugamushi to different agents.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">August 31, 2026</completion_date>
    <primary_completion_date type="Anticipated">August 31, 2025</primary_completion_date>
    <phase>Phase 2/Phase 3</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Rate of clearance of R. typhi or O. tsutsugamushi from peripheral blood of patients using serial qPCR measurement</measure>
      <time_frame>Within 72 hours after treatment</time_frame>
      <description>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</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Area under the plasma concentration versus time curve (AUC) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus</measure>
      <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.</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Peak plasma concentration (Cmax) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus</measure>
      <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.</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to peak plasma concentration (Tmax) of doxycycline or azithromycin for the treatment of murine typhus or scrub typhus</measure>
      <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.</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time at doxycycline or azithromycin has lost half its maximum concentration (T1/2) for the treatment of murine typhus or scrub typhus</measure>
      <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.</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Fever clearance time in patients with scrub typhus or murine typhus treated with doxycycline or azithromycin</measure>
      <time_frame>First 7 days after treatment</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Frequency of adverse events (AEs) after treatment</measure>
      <time_frame>Day 0 to day 28</time_frame>
      <description>AEs will be defined using the Common Toxicity Criteria (v5.0) of the US National Cancer Institute</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">72</enrollment>
    <condition>Infectious Disease</condition>
    <condition>Therapeutics</condition>
    <arm_group>
      <arm_group_label>Doxycycline</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Doxycycline (Vibramycin, 100-mg film-coated tablets; Pfizer)) 200-mg loading dose, followed by 100 mg every 12 hours for 3 days.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Azithromycin</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>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.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Doxycyclin</intervention_name>
      <description>100-mg film-coated tablets; Pfizer</description>
      <arm_group_label>Doxycycline</arm_group_label>
      <other_name>vibramycin</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Azithromycin</intervention_name>
      <description>250-mg capsules; Pfizer</description>
      <arm_group_label>Azithromycin</arm_group_label>
      <other_name>Zithromax</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age above or equal 15 years&#xD;
  &#xD;
            -  Able to take oral medication&#xD;
  &#xD;
            -  Agrees to stay in hospital for at least 72 hours and to attend for scheduled follow up&#xD;
               visits&#xD;
  &#xD;
            -  Written informed consent to participate in the study&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Pregnancy (urine pregnancy test to be performed on women of childbearing age)&#xD;
  &#xD;
            -  Previous allergic reaction to doxycycline or azithromycin&#xD;
  &#xD;
            -  Received more than one dose of chloramphenicol, doxycycline, tetracycline,&#xD;
               fluoroquinolones, rifampicin or azithromycin during the preceding week&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Weerawat Phuklia, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Weerawat Phuklia, PhD</last_name>
      <phone>+8562056581365</phone>
      <email>weerawat@tropmedres.ac</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Elizabeth Ashley</last_name>
      <phone>+8562052457028</phone>
      <email>elizabeth.ashley@tropmedres.ac</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)</name>
        <address>
          <city>Vientiane</city>
          <state>Vientaine</state>
          <zip>0103</zip>
          <country>Lao People's Democratic Republic</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Lao People's Democratic Republic</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 7, 2023</study_first_submitted>
    <study_first_submitted_qc>July 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 2, 2023</study_first_posted>
    <last_update_submitted>July 31, 2023</last_update_submitted>
    <last_update_submitted_qc>July 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 2, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Scrub Typhus</keyword>
    <keyword>Typhus, Endemic Flea-Borne</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Communicable Diseases</mesh_term>
      <mesh_term>Infections</mesh_term>
      <mesh_term>Typhus, Epidemic Louse-Borne</mesh_term>
      <mesh_term>Scrub Typhus</mesh_term>
      <mesh_term>Typhus, Endemic Flea-Borne</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Azithromycin</mesh_term>
      <mesh_term>Doxycycline</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_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_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_time_frame>approximately 2 years after the end of the study</ipd_time_frame>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05972772
  org study id: 26-23
  nct id: NCT05972772
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  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.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: 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
  description: 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
  measure: 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.
  description: 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
  measure: 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.
  description: 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
  measure: 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.
  description: 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
  measure: 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.
  description: 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
  measure: Fever clearance time in patients with scrub typhus or murine typhus treated with doxycycline or azithromycin
  time frame: First 7 days after treatment
  description: 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
  measure: Frequency of adverse events (AEs) after treatment
  time frame: Day 0 to day 28
  description: AEs will be defined using the Common Toxicity Criteria (v5.0) of the US National Cancer Institute
  arm group label: Doxycycline
  arm group type: Active Comparator
  description: Doxycycline (Vibramycin, 100-mg film-coated tablets; Pfizer)) 200-mg loading dose, followed by 100 mg every 12 hours for 3 days.
  arm group label: Azithromycin
  arm group type: Active Comparator
  description: 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.
  intervention type: Drug
  intervention name: Doxycyclin
  description: 100-mg film-coated tablets; Pfizer
  arm group label: Doxycycline
  other name: vibramycin
  intervention type: Drug
  intervention name: Azithromycin
  description: 250-mg capsules; Pfizer
  arm group label: Azithromycin
  other name: Zithromax
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: Accepts Healthy Volunteers
  last name: Weerawat Phuklia, PhD
  role: Principal Investigator
  affiliation: Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit
  last name: Weerawat Phuklia, PhD
  phone: +8562056581365
  email: weerawat@tropmedres.ac
  last name: Elizabeth Ashley
  phone: +8562052457028
  email: elizabeth.ashley@tropmedres.ac
  facility: 
  country: Lao People's Democratic Republic
  responsible party type: Sponsor
  mesh term: Communicable Diseases
  mesh term: Infections
  mesh term: Typhus, Epidemic Louse-Borne
  mesh term: Scrub Typhus
  mesh term: Typhus, Endemic Flea-Borne
  mesh term: Azithromycin
  mesh term: Doxycycline
  sharing ipd: Yes
  ipd 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 info type: Study Protocol
  ipd info type: Informed Consent Form (ICF)
  ipd info type: Clinical Study Report (CSR)
  ipd time frame: approximately 2 years after the end of the study