<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/NCT04506944</url>
  </required_header>
  <id_info>
    <org_study_id>MRC typhus cohort 1</org_study_id>
    <nct_id>NCT04506944</nct_id>
  </id_info>
  <brief_title>The Epidemiology of Rickettsial Infections in South India: Cohort Study</brief_title>
  <official_title>The Epidemiology Of Scrub Typhus And Rickettsial Infections In A Highly Endemic Rural Setting In South India: Population-Based Cohort Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>London School of Hygiene and Tropical Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medical Research Council</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Christian Medical College, Vellore, India</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mahidol Oxford Tropical Medicine Research Unit</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Australian Rickettsial Reference Laboratory</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>London School of Hygiene and Tropical Medicine</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is enough evidence to suggest that scrub typhus and spotted fever group rickettsioses&#xD;
      are common causes of febrile illness in India. Serological evidence also exists for murine&#xD;
      typhus, but is rarely tested for. Incidence, risk factors, clinical features and molecular&#xD;
      epidemiology of these three infections are poorly understood. Delays in disease recognition&#xD;
      and treatment may cause thousands of preventable deaths across India.&#xD;
&#xD;
      The objectives of the research are to determine the incidence and risk factors of scrub&#xD;
      typhus, spotted fever and murine typhus by severity, to determine clinical features of these&#xD;
      neglected and often unrecognized infections. Further to study the effect of previous&#xD;
      infection on incidence and severity of subsequent infections. Finally to study the&#xD;
      association between vector parameters and scrub typhus risk.&#xD;
&#xD;
      Enrolled will be 30,000 individuals who will be followed up for the development of fever&#xD;
      using active and passive surveillance. Active surveillance will include household screening&#xD;
      every 3-6 weeks. Fever cases occuring in the past two months will be tested for Scrub typhus,&#xD;
      murine typhus and spotted fever IgG/IgM. 4000 individuals will be followed up by annual&#xD;
      serological testing to identify asymptomatic infections. Participants notifying the study&#xD;
      team with ongoing fever will undergo blood testing for acute diagnosis of rickettsial&#xD;
      infection (IgM, PCR). In addition, we will enroll fever cases at study clinics who are not&#xD;
      part of the main cohort. The research includes spatial and socio-economic risk factor&#xD;
      analysis. Rodents carrying mite larvae will be trapped to compare the intensity of mite&#xD;
      infestation between areas of high and low risk for human scrub typhus.&#xD;
&#xD;
      The data on incidence, burden of disease and environmental determinants of scrub typhus,&#xD;
      spotted fever and murine typhus will be used for health care planning and information&#xD;
      campaigns for the public and medical professionals.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The aim of the cohort study is to better understand the epidemiology, sero-epidemiology and&#xD;
      transmission of scrub typhus, murine typhus and tick-borne spotted fever. The overall focus&#xD;
      of the work will be on scrub typhus, being the most important of the three from the public&#xD;
      health perspective. We aim to determine the &quot;severity pyramid&quot; of serological, symptomatic&#xD;
      and severe infection. The results from this study will help clinicians to understand the&#xD;
      natural course of scrub typhus infection, health policy makers to estimate the global burden&#xD;
      and the scope for community-based interventions, and immunologists to better understand the&#xD;
      immunogenicity of single and repeat infections.&#xD;
&#xD;
      The specific objectives are to:&#xD;
&#xD;
        1. Estimate the incidence of symptomatic and severe scrub typhus infection in the&#xD;
           community.&#xD;
&#xD;
        2. Estimate the incidence of serological (asymptomatic) scrub typhus infection.&#xD;
&#xD;
        3. Estimate the effect of previous scrub typhus infection (sero-positive at baseline) on&#xD;
           the risk of subsequent infection and disease severity (subclinical vs clinically&#xD;
           apparent). This includes the effect of antibodies in mothers on the risk of severe&#xD;
           infection in young children via residual maternal antibodies.&#xD;
&#xD;
        4. Estimate the effect of potential risk factors such as age, gender, occupation,&#xD;
           water/sanitation access and comorbidity on the risk of scrub typhus infection.&#xD;
&#xD;
        5. Estimate the effect of spatial-temporal risk factors for scrub typhus by identifying&#xD;
           high risk areas, accounting for human population density and land use.&#xD;
&#xD;
        6. Compare the rate of rodent trappings and vector parameters of chiggers between high risk&#xD;
           and low risk areas identified under 5).&#xD;
&#xD;
        7. Estimate the disease burden associated with scrub typhus and the economic impact of&#xD;
           scrub typhus in terms of loss of earnings and health expenditure.&#xD;
&#xD;
        8. Estimate the incidence of asymptomatic and symptomatic murine typhus and spotted fever&#xD;
           infection and explore associated socio-demographic, spatial and vector-related risk&#xD;
           factors.&#xD;
&#xD;
      STUDY OVERVIEW&#xD;
&#xD;
      The study will be a population-based cohort study over two years (i.e. two scrub typhus&#xD;
      seasons) in about 30,000 people living in approximately 40 villages with a sero-prevalence of&#xD;
      at least 15% (see flow diagram above). These individuals will be followed-up through active&#xD;
      surveillance for recent febrile illnesses (clinical cohort). For passive surveillance,&#xD;
      participants will be encouraged to notify the study team in case of fever or come to one of 4&#xD;
      local study clinics. At study clinics we will also enrol fever cases who are not part of the&#xD;
      clinical cohort, i.e. have not been enrolled prior to their fever. The study will include a&#xD;
      smaller cohort (sero-cohort) for serological surveillance of 4000 people drawn from the&#xD;
      30,000 people of the clinical cohort. Longitudinal serological surveys linked to active&#xD;
      surveillance are essential to estimate true attack rates unbiased by disease severity. The&#xD;
      sero-cohort will consist of three annual blood testing in the same group of participants over&#xD;
      two scrub typhus seasons (baseline, inter-season, endline).&#xD;
&#xD;
      Target population- A pilot study showed that scrub typhus infection is highly focal This&#xD;
      makes it difficult to define a target population for the purpose of making inferences. We&#xD;
      will define the target population in terms of the village level sero-prevalence. The aim is&#xD;
      to correlate the incidence of scrub typhus with the sero-prevalence at village level. This&#xD;
      will allow using the results of the study to predict the expected incidence and burden of&#xD;
      scrub typhus in other settings with a known sero-prevalence, and eventually estimate the&#xD;
      global burden of scrub typhus (not part of the study but a potential extension of the work).&#xD;
      The target population for the study is therefore &quot;villages in which the IgG sero-prevalence&#xD;
      is at least 15%&quot;.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 15, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Actual">September 5, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of scrub typhus</measure>
    <time_frame>2 years</time_frame>
    <description>clinically apparent infection</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of spotted fever</measure>
    <time_frame>2 years</time_frame>
    <description>clinically apparent infection</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of murine typhus</measure>
    <time_frame>2 years</time_frame>
    <description>clinically apparent infection</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of serological infection (scrub typhus)</measure>
    <time_frame>2 years</time_frame>
    <description>measured using paired samples from sero-cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of serological infection (spotted fever)</measure>
    <time_frame>2 years</time_frame>
    <description>measured using paired samples from sero-cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of serological infection (murine typhus)</measure>
    <time_frame>2 years</time_frame>
    <description>measured using paired samples from sero-cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of complicated infection (scrub typhus)</measure>
    <time_frame>2 years</time_frame>
    <description>based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of complicated infection (spotted fever)</measure>
    <time_frame>2 years</time_frame>
    <description>based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of complicated infection (murine typhus)</measure>
    <time_frame>2 years</time_frame>
    <description>based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">32566</enrollment>
  <condition>Scrub Typhus</condition>
  <condition>Spotted Fever; India</condition>
  <condition>Murine Typhus</condition>
  <arm_group>
    <arm_group_label>General population</arm_group_label>
    <description>Whole population of scrub typhus endemic villages</description>
  </arm_group>
  <arm_group>
    <arm_group_label>hospital case population</arm_group_label>
    <description>cases recruited at study clinics who are not enrolled in general population cohort</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Serological cohort</arm_group_label>
    <description>random subset of 4000 participants above the age of 10 drawn from general population cohort</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>No intervention</intervention_name>
    <description>No specific exposure is explored.</description>
    <arm_group_label>General population</arm_group_label>
    <arm_group_label>Serological cohort</arm_group_label>
    <arm_group_label>hospital case population</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples from human participants: serum for serological testing, buffy coat for&#xD;
      rickettsia PCR Eschar and skin biopsies for rickettsia PCR&#xD;
&#xD;
      Arthropod vector samples: PCR for rickettsia Rodent tissue samples: PCR for rickettsia&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        General population cohort: all residents in scrub typhus endemic villages Serological&#xD;
        cohort: random sample of 4000 individuals older than 10 years present at the time of the&#xD;
        initial baseline survey visit&#xD;
&#xD;
        hospital case cohort: cases of all ages attending study clinics for undifferentiated fever&#xD;
        of at least 5 days duration&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  General population cohort: residing in study villages&#xD;
&#xD;
          -  serological cohort: aged 10 years or older&#xD;
&#xD;
          -  Hospital cohort: all ages&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Wolf-Peter Schmidt, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>LSHTM</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Daniel Chandramohan, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>LSHTM</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Christian Medical College</name>
      <address>
        <city>Vellore</city>
        <state>Tamil Nadu</state>
        <zip>632004</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>August 7, 2020</study_first_submitted>
  <study_first_submitted_qc>August 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2020</study_first_posted>
  <last_update_submitted>September 8, 2022</last_update_submitted>
  <last_update_submitted_qc>September 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Typhus, Epidemic Louse-Borne</mesh_term>
    <mesh_term>Scrub Typhus</mesh_term>
    <mesh_term>Spotted Fever Group Rickettsiosis</mesh_term>
    <mesh_term>Rickettsia Infections</mesh_term>
    <mesh_term>Typhus, Endemic Flea-Borne</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>de-identified case data will be made available at LSHTMs data repository</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>from 12/2022 indefinitely</ipd_time_frame>
    <ipd_access_criteria>on request</ipd_access_criteria>
    <ipd_url>https://datacompass.lshtm.ac.uk</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 12, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/44/NCT04506944/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 19, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/44/NCT04506944/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT04506944
org study id: MRC typhus cohort 1
nct id: NCT04506944
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
There is enough evidence to suggest that scrub typhus and spotted fever group rickettsioses
      are common causes of febrile illness in India. Serological evidence also exists for murine
      typhus, but is rarely tested for. Incidence, risk factors, clinical features and molecular
      epidemiology of these three infections are poorly understood. Delays in disease recognition
      and treatment may cause thousands of preventable deaths across India.

      The objectives of the research are to determine the incidence and risk factors of scrub
      typhus, spotted fever and murine typhus by severity, to determine clinical features of these
      neglected and often unrecognized infections. Further to study the effect of previous
      infection on incidence and severity of subsequent infections. Finally to study the
      association between vector parameters and scrub typhus risk.

      Enrolled will be 30,000 individuals who will be followed up for the development of fever
      using active and passive surveillance. Active surveillance will include household screening
      every 3-6 weeks. Fever cases occuring in the past two months will be tested for Scrub typhus,
      murine typhus and spotted fever IgG/IgM. 4000 individuals will be followed up by annual
      serological testing to identify asymptomatic infections. Participants notifying the study
      team with ongoing fever will undergo blood testing for acute diagnosis of rickettsial
      infection (IgM, PCR). In addition, we will enroll fever cases at study clinics who are not
      part of the main cohort. The research includes spatial and socio-economic risk factor
      analysis. Rodents carrying mite larvae will be trapped to compare the intensity of mite
      infestation between areas of high and low risk for human scrub typhus.

      The data on incidence, burden of disease and environmental determinants of scrub typhus,
      spotted fever and murine typhus will be used for health care planning and information
      campaigns for the public and medical professionals.
The aim of the cohort study is to better understand the epidemiology, sero-epidemiology and
      transmission of scrub typhus, murine typhus and tick-borne spotted fever. The overall focus
      of the work will be on scrub typhus, being the most important of the three from the public
      health perspective. We aim to determine the "severity pyramid" of serological, symptomatic
      and severe infection. The results from this study will help clinicians to understand the
      natural course of scrub typhus infection, health policy makers to estimate the global burden
      and the scope for community-based interventions, and immunologists to better understand the
      immunogenicity of single and repeat infections.

      The specific objectives are to:

        1. Estimate the incidence of symptomatic and severe scrub typhus infection in the
           community.

        2. Estimate the incidence of serological (asymptomatic) scrub typhus infection.

        3. Estimate the effect of previous scrub typhus infection (sero-positive at baseline) on
           the risk of subsequent infection and disease severity (subclinical vs clinically
           apparent). This includes the effect of antibodies in mothers on the risk of severe
           infection in young children via residual maternal antibodies.

        4. Estimate the effect of potential risk factors such as age, gender, occupation,
           water/sanitation access and comorbidity on the risk of scrub typhus infection.

        5. Estimate the effect of spatial-temporal risk factors for scrub typhus by identifying
           high risk areas, accounting for human population density and land use.

        6. Compare the rate of rodent trappings and vector parameters of chiggers between high risk
           and low risk areas identified under 5).

        7. Estimate the disease burden associated with scrub typhus and the economic impact of
           scrub typhus in terms of loss of earnings and health expenditure.

        8. Estimate the incidence of asymptomatic and symptomatic murine typhus and spotted fever
           infection and explore associated socio-demographic, spatial and vector-related risk
           factors.

      STUDY OVERVIEW

      The study will be a population-based cohort study over two years (i.e. two scrub typhus
      seasons) in about 30,000 people living in approximately 40 villages with a sero-prevalence of
      at least 15% (see flow diagram above). These individuals will be followed-up through active
      surveillance for recent febrile illnesses (clinical cohort). For passive surveillance,
      participants will be encouraged to notify the study team in case of fever or come to one of 4
      local study clinics. At study clinics we will also enrol fever cases who are not part of the
      clinical cohort, i.e. have not been enrolled prior to their fever. The study will include a
      smaller cohort (sero-cohort) for serological surveillance of 4000 people drawn from the
      30,000 people of the clinical cohort. Longitudinal serological surveys linked to active
      surveillance are essential to estimate true attack rates unbiased by disease severity. The
      sero-cohort will consist of three annual blood testing in the same group of participants over
      two scrub typhus seasons (baseline, inter-season, endline).

      Target population- A pilot study showed that scrub typhus infection is highly focal This
      makes it difficult to define a target population for the purpose of making inferences. We
      will define the target population in terms of the village level sero-prevalence. The aim is
      to correlate the incidence of scrub typhus with the sero-prevalence at village level. This
      will allow using the results of the study to predict the expected incidence and burden of
      scrub typhus in other settings with a known sero-prevalence, and eventually estimate the
      global burden of scrub typhus (not part of the study but a potential extension of the work).
      The target population for the study is therefore "villages in which the IgG sero-prevalence
      is at least 15%".
observational model: Cohort
time perspective: Prospective
measure: Incidence of scrub typhus
time frame: 2 years
description: clinically apparent infection
measure: Incidence of spotted fever
time frame: 2 years
description: clinically apparent infection
measure: Incidence of murine typhus
time frame: 2 years
description: clinically apparent infection
measure: Incidence of serological infection (scrub typhus)
time frame: 2 years
description: measured using paired samples from sero-cohort
measure: Incidence of serological infection (spotted fever)
time frame: 2 years
description: measured using paired samples from sero-cohort
measure: Incidence of serological infection (murine typhus)
time frame: 2 years
description: measured using paired samples from sero-cohort
measure: Incidence of complicated infection (scrub typhus)
time frame: 2 years
description: based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis
measure: Incidence of complicated infection (spotted fever)
time frame: 2 years
description: based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis
measure: Incidence of complicated infection (murine typhus)
time frame: 2 years
description: based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis
arm group label: General population
description: Whole population of scrub typhus endemic villages
arm group label: hospital case population
description: cases recruited at study clinics who are not enrolled in general population cohort
arm group label: Serological cohort
description: random subset of 4000 participants above the age of 10 drawn from general population cohort
intervention type: Other
intervention name: No intervention
description: No specific exposure is explored.
arm group label: General population
arm group label: Serological cohort
arm group label: hospital case population
Blood samples from human participants: serum for serological testing, buffy coat for
      rickettsia PCR Eschar and skin biopsies for rickettsia PCR

      Arthropod vector samples: PCR for rickettsia Rodent tissue samples: PCR for rickettsia
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Wolf-Peter Schmidt, PhD
role: Principal Investigator
affiliation: LSHTM
last name: Daniel Chandramohan, PhD
role: Study Chair
affiliation: LSHTM
facility: 
country: India
responsible party type: Sponsor
mesh term: Typhus, Epidemic Louse-Borne
mesh term: Scrub Typhus
mesh term: Spotted Fever Group Rickettsiosis
mesh term: Rickettsia Infections
mesh term: Typhus, Endemic Flea-Borne
sharing ipd: Yes
ipd description: de-identified case data will be made available at LSHTMs data repository
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd info type: Analytic Code
ipd time frame: from 12/2022 indefinitely
ipd access criteria: on request
ipd url: https://datacompass.lshtm.ac.uk
provided document: 
provided document: 