<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/NCT03765528</url>
  </required_header>
  <id_info>
    <org_study_id>PILGRIM</org_study_id>
    <nct_id>NCT03765528</nct_id>
  </id_info>
  <brief_title>Impact of Prescription Quality, Infection Control and Antimicrobial Stewardship on Gut Microbiota Domination by Healthcare-Associated Pathogens</brief_title>
  <acronym>PILGRIM</acronym>
  <official_title>Impact of Prescription Quality, Infection Control and Antimicrobial Stewardship on Gut Microbiota Domination by Healthcare-Associated Pathogens</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital of Cologne</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital of North Norway</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Rabin Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Latvia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>McGill University Health Centre/Research Institute of the McGill University Health Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Haukeland University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Akershus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Helse Stavanger HF</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Goethe University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital of Cologne</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Extended-spectrum beta-lactamase producing Enterobacteriaceae (EPE), vancomycin-resistant&#xD;
      enterococci (VRE) and Clostridium difficile have become a major threat to hospitalised&#xD;
      patients worldwide. We hypothesize that receiving inappropriate antibacterial treatment&#xD;
      places patients at high risk of intestinal domination and subsequent infection by these&#xD;
      bacteria. Further analyses will address cost-effectiveness of specific interventions,&#xD;
      behavioural analyses of the decision process leading to inappropriate antibacterial&#xD;
      treatment, and the rate of undetected colonization with EPE/VRE/C. difficile on admission.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The prevalence of antimicrobial resistant pathogens has dramatically increased among&#xD;
      hospitalised patients worldwide. While various management strategies have effectively reduced&#xD;
      the burden caused by methicillin-resistant Staphylococcus aureus, resistant pathogens with a&#xD;
      preference towards intestinal colonization are currently on the rise. E.g.,&#xD;
      vancomycin-resistant enterococci (VRE) and extended-spectrum beta-lactamase producing&#xD;
      Enterobacteriaceae (EPE) now constitute a significant threat to hospitalised patients&#xD;
      worldwide, as infections due to these organisms require prolonged treatments and result in&#xD;
      inferior outcomes. Similarly, the burden of disease caused by Clostridium difficile infection&#xD;
      (CDI), the main cause of healthcare-associated infectious diarrhoea, has increased driven by&#xD;
      the emergence of hypervirulent strains such as ribotypes 027 and 078. Molecular studies have&#xD;
      demonstrated that increased population-wide exposure to broad-spectrum antibacterials is a&#xD;
      crucial step in the initiation of outbreaks by selection and expansion of resistant C.&#xD;
      difficile.&#xD;
&#xD;
      This is a comprehensive, multinational, multi-centre clinical study aiming to assess the&#xD;
      impact of inappropriate antibacterial prescription on intestinal domination by EPE or VRE or&#xD;
      infection with C. difficile. To achieve this goal, the study will closely follow the&#xD;
      progression from first acquisition of drug-resistant organisms to infection with these&#xD;
      bacteria at an individual patient level.&#xD;
&#xD;
      In this study, we will establish the sequence and factors involved in acquisition,&#xD;
      colonization, selective pressure, bacterial overgrowth/domination/ and infection for EPE, VRE&#xD;
      and C. difficile. We hypothesize that IC (Infection Control; prevention of pathogen&#xD;
      acquisition) and AMS (Antimicrobial Stewardship; prevention of clonal expansion) measures&#xD;
      leading to a higher share of appropriate anti-infective use are effective strategies to&#xD;
      prevent this development. The study programme will allow an accurate estimation of the&#xD;
      preventable share of healthcare-acquired colonization and infection by VRE, EPE, and C.&#xD;
      difficile.&#xD;
&#xD;
      No direct interventions will be performed with study patients. Instead, study centres will&#xD;
      assess quality indicators for implementation of IC and AMS measures by active observation and&#xD;
      aggregation of data. Patients fulfilling all inclusion- and no exclusion criteria will be&#xD;
      asked for their consent to be recruited prospectively into a cohort study. During the&#xD;
      observational phase, participants will be monitored for receipt of antibacterial treatment&#xD;
      and regular stool samples will be obtained and stored. An interdisciplinary, international&#xD;
      AMS Board will comprehensively assess antibiotic treatment via review by a panel of experts.&#xD;
      After the observation is completed, stool samples will be batch-tested for intestinal&#xD;
      domination by the target pathogens of this study. Statistical analyses will be performed to&#xD;
      investigate an association between inappropriate antibiotic use as opposed to appropriate or&#xD;
      no antibiotic use and intestinal domination. If domination is detected, further analyses for&#xD;
      phenotype, quantity, resistance, and molecular biology will be performed. Finally, the&#xD;
      baseline sample will be tested for presence of the dominant species to understand the source&#xD;
      of the pathogen, i.e. nosocomial versus outpatient acquisition.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 1, 2019</start_date>
  <completion_date type="Anticipated">July 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2021</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>Impact of inappropriate antibacterial prescription on intestinal microbiota domination by healthcare associated pathogens</measure>
    <time_frame>up to 6 - 36 weeks</time_frame>
    <description>The differential impact of inappropriate antibacterial prescription compared to adequate or no antibacterial prescription on intestinal microbiota domination by EPE or VRE or infection with C. difficile measured by analysing stool samples.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time-point of Intestinal Colonization</measure>
    <time_frame>Baseline and up to 6 - 36 weeks</time_frame>
    <description>Determination of the rate of in-hospital vs. pre-admission intestinal colonization with EPE, VRE, and/or C. difficile measured by analysing stool samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time-point of Intestinal Domination</measure>
    <time_frame>Baseline and up to 6 - 36 weeks</time_frame>
    <description>Determination of the rate of in-hospital vs. pre-admission intestinal domination with EPE, VRE, and/or C. difficile measured by analysing stool samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inter-rater reliability of AMS specialists</measure>
    <time_frame>After complete documentation of each patient case (follow-up for 6-36 weeks) followed by completed ratings of AMS specialists</time_frame>
    <description>Determination of the inter-rater reliability of interdisciplinary AMS specialists rating antibacterial prescription appropriateness.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rationale for antibacterial prescription habits assessed by performing qualitative interviews with prescribing physicians</measure>
    <time_frame>After complete documentation of patient case (follow-up for 6-36 weeks) through study completion</time_frame>
    <description>Identification of behavioral determinants and knowledge gaps leading to inappropriate antibacterial prescriptions by interviewing approximately 50 prescribing physicians.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of prescription and AMS implementation</measure>
    <time_frame>Baseline, 12 months, 24 months</time_frame>
    <description>Assessment of the correlation of appropriate antibacterial prescription with quality indicators of AMS implementation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identification of risk factors responsible for disrupting the intestinal microbiota</measure>
    <time_frame>Baseline and weekly up to 6 - 36 weeks of follow-up</time_frame>
    <description>Identification of risk factors for colonization, intestinal domination, and infection by EPE, VRE and C. difficile, including comorbidities and drugs known to disrupt the intestinal microbiota, and high-risk bacterial clones prone to dominate the microbiota due to high fitness. Assessment by analysing stool samples and documented data.</description>
  </secondary_outcome>
  <enrollment type="Anticipated">1500</enrollment>
  <condition>Patients at High Risk of Antibacterial Treatment Upon Admission</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Stool samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Hospitalized patients at high risk of receiving antibiotic treatment during their hospital&#xD;
        stay will be screened for study eligibility.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years&#xD;
&#xD;
          2. Planned treatment or high likelihood of any systemic antibacterial treatment except&#xD;
             trimethoprim/sulfamethoxazole within the next 10 days for a duration of ≥ 5 days&#xD;
&#xD;
          3. Patients able to provide a stool sample before or within 4 hours of receiving first&#xD;
             antibiotic dosage&#xD;
&#xD;
          4. Written informed consent provided prior to inclusion&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients who have received courses of systemic antibacterials for 7 days or more&#xD;
             within the past two months&#xD;
&#xD;
          2. Patients having received any antibacterial compound other than&#xD;
             trimethoprim/sulfamethoxazole within 14 days prior to study enrolment except first&#xD;
             antibiotic dosage within 4 hours prior enrolment&#xD;
&#xD;
          3. Patients with diarrhea at enrolment (≥3 unformed bowel movements within 24h)&#xD;
&#xD;
          4. Patients with a stoma (jejunostomy, ileostomy, or colostomy) at time of inclusion&#xD;
&#xD;
          5. Patients on enteral (tube fed or PEG) or parenteral nutrition&#xD;
&#xD;
          6. Patient with any social or logistical condition which in the opinion of the&#xD;
             investigator may interfere with the conduct of the study, such as incapacity to well&#xD;
             understand, not willing to collaborate, or cannot easily be contacted after discharge&#xD;
&#xD;
          7. Patients exclusively treated as outpatients without prior hospital admission&#xD;
&#xD;
          8. Previous participation in this study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jörg Janne Vehreschild, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital Cologne</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jörg Janne Vehreschild, MD</last_name>
    <phone>+49227478</phone>
    <phone_ext>88794</phone_ext>
    <email>joerg.vehreschild@uk-koeln.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Annika Löhnert, MD</last_name>
    <email>annika.loehnert@uk-koeln.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Hospital of Cologne</name>
      <address>
        <city>Cologne</city>
        <state>NRW</state>
        <zip>50931</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jörg Janne Vehreschild, MD</last_name>
      <email>joerg.vehreschild@uk-koeln.de</email>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>November 16, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 5, 2018</study_first_posted>
  <last_update_submitted>July 30, 2020</last_update_submitted>
  <last_update_submitted_qc>July 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital of Cologne</investigator_affiliation>
    <investigator_full_name>Dr. med. Jörg Janne Vehreschild</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Clostridium difficile</keyword>
  <keyword>Extended-Spectrum β-Lactamase producing Enterobacteriaceae</keyword>
  <keyword>Vancomycin-resistant enterococci</keyword>
  <keyword>Antimicrobial resistance</keyword>
  <keyword>Microbiome</keyword>
  <keyword>Nosocomial infection</keyword>
  <keyword>Antimicrobial Stewardship</keyword>
  <keyword>Infection Control</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03765528
org study id: PILGRIM
nct id: NCT03765528
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Extended-spectrum beta-lactamase producing Enterobacteriaceae (EPE), vancomycin-resistant
      enterococci (VRE) and Clostridium difficile have become a major threat to hospitalised
      patients worldwide. We hypothesize that receiving inappropriate antibacterial treatment
      places patients at high risk of intestinal domination and subsequent infection by these
      bacteria. Further analyses will address cost-effectiveness of specific interventions,
      behavioural analyses of the decision process leading to inappropriate antibacterial
      treatment, and the rate of undetected colonization with EPE/VRE/C. difficile on admission.
The prevalence of antimicrobial resistant pathogens has dramatically increased among
      hospitalised patients worldwide. While various management strategies have effectively reduced
      the burden caused by methicillin-resistant Staphylococcus aureus, resistant pathogens with a
      preference towards intestinal colonization are currently on the rise. E.g.,
      vancomycin-resistant enterococci (VRE) and extended-spectrum beta-lactamase producing
      Enterobacteriaceae (EPE) now constitute a significant threat to hospitalised patients
      worldwide, as infections due to these organisms require prolonged treatments and result in
      inferior outcomes. Similarly, the burden of disease caused by Clostridium difficile infection
      (CDI), the main cause of healthcare-associated infectious diarrhoea, has increased driven by
      the emergence of hypervirulent strains such as ribotypes 027 and 078. Molecular studies have
      demonstrated that increased population-wide exposure to broad-spectrum antibacterials is a
      crucial step in the initiation of outbreaks by selection and expansion of resistant C.
      difficile.

      This is a comprehensive, multinational, multi-centre clinical study aiming to assess the
      impact of inappropriate antibacterial prescription on intestinal domination by EPE or VRE or
      infection with C. difficile. To achieve this goal, the study will closely follow the
      progression from first acquisition of drug-resistant organisms to infection with these
      bacteria at an individual patient level.

      In this study, we will establish the sequence and factors involved in acquisition,
      colonization, selective pressure, bacterial overgrowth/domination/ and infection for EPE, VRE
      and C. difficile. We hypothesize that IC (Infection Control; prevention of pathogen
      acquisition) and AMS (Antimicrobial Stewardship; prevention of clonal expansion) measures
      leading to a higher share of appropriate anti-infective use are effective strategies to
      prevent this development. The study programme will allow an accurate estimation of the
      preventable share of healthcare-acquired colonization and infection by VRE, EPE, and C.
      difficile.

      No direct interventions will be performed with study patients. Instead, study centres will
      assess quality indicators for implementation of IC and AMS measures by active observation and
      aggregation of data. Patients fulfilling all inclusion- and no exclusion criteria will be
      asked for their consent to be recruited prospectively into a cohort study. During the
      observational phase, participants will be monitored for receipt of antibacterial treatment
      and regular stool samples will be obtained and stored. An interdisciplinary, international
      AMS Board will comprehensively assess antibiotic treatment via review by a panel of experts.
      After the observation is completed, stool samples will be batch-tested for intestinal
      domination by the target pathogens of this study. Statistical analyses will be performed to
      investigate an association between inappropriate antibiotic use as opposed to appropriate or
      no antibiotic use and intestinal domination. If domination is detected, further analyses for
      phenotype, quantity, resistance, and molecular biology will be performed. Finally, the
      baseline sample will be tested for presence of the dominant species to understand the source
      of the pathogen, i.e. nosocomial versus outpatient acquisition.
observational model: Cohort
time perspective: Prospective
measure: Impact of inappropriate antibacterial prescription on intestinal microbiota domination by healthcare associated pathogens
time frame: up to 6 - 36 weeks
description: The differential impact of inappropriate antibacterial prescription compared to adequate or no antibacterial prescription on intestinal microbiota domination by EPE or VRE or infection with C. difficile measured by analysing stool samples.
measure: Time-point of Intestinal Colonization
time frame: Baseline and up to 6 - 36 weeks
description: Determination of the rate of in-hospital vs. pre-admission intestinal colonization with EPE, VRE, and/or C. difficile measured by analysing stool samples.
measure: Time-point of Intestinal Domination
time frame: Baseline and up to 6 - 36 weeks
description: Determination of the rate of in-hospital vs. pre-admission intestinal domination with EPE, VRE, and/or C. difficile measured by analysing stool samples.
measure: Inter-rater reliability of AMS specialists
time frame: After complete documentation of each patient case (follow-up for 6-36 weeks) followed by completed ratings of AMS specialists
description: Determination of the inter-rater reliability of interdisciplinary AMS specialists rating antibacterial prescription appropriateness.
measure: Rationale for antibacterial prescription habits assessed by performing qualitative interviews with prescribing physicians
time frame: After complete documentation of patient case (follow-up for 6-36 weeks) through study completion
description: Identification of behavioral determinants and knowledge gaps leading to inappropriate antibacterial prescriptions by interviewing approximately 50 prescribing physicians.
measure: Correlation of prescription and AMS implementation
time frame: Baseline, 12 months, 24 months
description: Assessment of the correlation of appropriate antibacterial prescription with quality indicators of AMS implementation
measure: Identification of risk factors responsible for disrupting the intestinal microbiota
time frame: Baseline and weekly up to 6 - 36 weeks of follow-up
description: Identification of risk factors for colonization, intestinal domination, and infection by EPE, VRE and C. difficile, including comorbidities and drugs known to disrupt the intestinal microbiota, and high-risk bacterial clones prone to dominate the microbiota due to high fitness. Assessment by analysing stool samples and documented data.
Stool samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jörg Janne Vehreschild, MD
role: Principal Investigator
affiliation: University Hospital Cologne
last name: Jörg Janne Vehreschild, MD
phone: +49227478
phone ext: 88794
email: joerg.vehreschild@uk-koeln.de
last name: Annika Löhnert, MD
email: annika.loehnert@uk-koeln.de
facility: 
status: Recruiting
contact: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: University Hospital of Cologne
investigator full name: Dr. med. Jörg Janne Vehreschild
investigator title: Professor
mesh term: Infections
sharing ipd: No