<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/NCT03784807</url>
  </required_header>
  <id_info>
    <org_study_id>Diafilm</org_study_id>
    <nct_id>NCT03784807</nct_id>
  </id_info>
  <brief_title>New Strategies for Biofilm Related Infections</brief_title>
  <acronym>Diafilm</acronym>
  <official_title>New Strategies for Diagnosis and Management of Biofilm Related Infections</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istituto Ortopedico Galeazzi</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Istituto Ortopedico Galeazzi</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>
      This study aims to develop new assays for synovial fluid analysis able to improve diagnosis&#xD;
      of prosthetic joint infections. In particular, use of synovial calprotectin as marker of&#xD;
      infection, confocal laser scanning microscopy (CLSM) analysis and methods to assess&#xD;
      antimicrobial susceptibility will be evaluated in synovial fluids collected from patients&#xD;
      with septic and aseptic failure of the prosthetic implant.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Infection of prosthetic joints is a common complication that may occur any time after&#xD;
      implantation. These infections require a prompt and accurate diagnosis to ensure an optimal&#xD;
      surgical and medical management of infected patient. Despite acute infections occurring in&#xD;
      the first weeks after surgery are easy to diagnose or when they are associated to bacteremia,&#xD;
      diagnosis becomes challenging when infection develops for several months before diagnosis or&#xD;
      it is caused by low virulent pathogens. Prosthetic joint infections and more widely&#xD;
      osteo-articular infections represent the classic biofilm related infections. Biofilm is&#xD;
      usually defined as a microbial community enveloped in a self-produced polymeric matrix.&#xD;
      Biofilm production allows bacteria to strictly adhere to inert and biotic substrates, evade&#xD;
      host defenses and resist to antibiotics by building a physical barrier to penetration of&#xD;
      antimicrobials and favoring dissemination of determinants of resistance. Microbiological&#xD;
      cultures contribute to diagnosis of infection, providing identification of the pathogen and,&#xD;
      most importantly, definition of antibiotic susceptibility. Nonetheless, in about 15-20% of&#xD;
      cases, culture fails to growth the pathogen. Diagnosis of prosthetic joint infection may&#xD;
      occur either pre- or intra-operatively. In both cases analysis of synovial fluid is crucial,&#xD;
      especially when performed before surgery when results from culture, leukocyte esterase, alpha&#xD;
      defensin test, leukocyte count and differential may lead to define the most accurate strategy&#xD;
      to approach patients with implant failure. However, culture of synovial fluid is&#xD;
      characterized by a limited sensitivity in respect, for instance to culture of periprosthetic&#xD;
      tissues or implant components. One of the causes of the lower sensitivity of synovial fluid&#xD;
      culture might be the presence of the so called &quot;biofilm like aggregates&quot;, agglomerates of&#xD;
      microorganisms embedded in a matrix which has been hypothesized to act as a protective&#xD;
      barrier. Leukocyte esterase test may give false positive results in samples strongly&#xD;
      contaminated by blood or with metal on metal reaction, while the high costs for alpha&#xD;
      defensin determination markedly limited its use. On the other hand, studies aiming to&#xD;
      evaluate other synovial markers of infections like calprotectin are insufficient to support&#xD;
      their use in routine diagnosis of prosthetic joint infection.&#xD;
&#xD;
      An alternative approach to diagnosis of these infections could be represented by use of&#xD;
      confocal laser scanning microscopy (CLSM) which allows to detect microorganisms in synovial&#xD;
      fluid and in tissues. This novel approach could also be used for a &quot;real time&quot; diagnosis&#xD;
      during surgery while waiting for culture results.&#xD;
&#xD;
      Another issue in diagnosis of prosthetic joint infections is related to assessment of&#xD;
      antimicrobial susceptibility. In fact, it is well known that biofilm embedded bacteria are&#xD;
      more resistant to antibiotics than their planktonic counterpart. Since available methods for&#xD;
      determination of antibiotic susceptibility are based on planktonic cells, it may be&#xD;
      hypothesized that they underestimate the real antimicrobial concentration able to inhibit&#xD;
      growth of bacteria embedded in a biofilm as occur during infection. Although several methods&#xD;
      have been proposed to evaluate antimicrobial susceptibility pattern of biofilm&#xD;
      microorganisms, none of them has been proposed for routinely use. However, in some cases when&#xD;
      therapy fails to eradicate infection, evaluation of antibiotic susceptibility of biofilm&#xD;
      embedded bacteria could provide important information to optimize antimicrobial therapy.&#xD;
&#xD;
      Therefore, diagnosis of biofilm related infections, particularly prosthetic ones is quite far&#xD;
      from being optimized. In this sense, development of a panel able to shorten turn around time&#xD;
      of microbiological analyses and to improve patient management could significantly ameliorate&#xD;
      approach to patients, limiting worsening in patient's quality of life and reducing costs for&#xD;
      health system.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 2, 2018</start_date>
  <completion_date type="Anticipated">November 30, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Assessment of analytical performance of calprotectin and CLSM for diagnosis of prosthetic joint infections</measure>
    <time_frame>preoperative visit or during surgery</time_frame>
    <description>Sensitivity, specificity, predictive values and diagnostic accuracy of calprotectin and CLSM will be calculated and compared to those of assays already used for diagnosis of prosthetic joint infections</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement in antibiotic therapy applying data obtained from antibiotic susceptibility testing on biofilm</measure>
    <time_frame>Afetr isolation of the pathogen, within 2 months</time_frame>
    <description>Antimicrobial profiles obtained on biofilm bacteria will be compared with those obtained with traditional methods on planktonic cells</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">99</enrollment>
  <condition>Prosthetic Joint Infection</condition>
  <arm_group>
    <arm_group_label>Infected</arm_group_label>
    <description>Patients with prosthetic joint or osteoarticular infection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Not infected</arm_group_label>
    <description>Patients with implant failure not due to infection</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>synovial calprotectin, confocal laser microscopy</intervention_name>
    <description>Calprotectin will be determined in synovial fluid of patients with septic and aseptic failure of their prosthesis. CLSM will be used to detect presence of microorganisms in synovial fluid. Susceptibility to antimicrobials of bacterial strains isolated from patients with prosthetic joint infections will be assessed using planktonic cells and biofilm associated bacteria</description>
    <arm_group_label>Infected</arm_group_label>
    <arm_group_label>Not infected</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Bacterial strains&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with osteoarticular or prosthetic joint infection&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of implant failure or osteoarticular infections&#xD;
&#xD;
          -  Collection of a sufficient amount of synovial fluid&#xD;
&#xD;
          -  Informed Consent signed&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients not fulfilling the inclusion criteria&#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>Elena De Vecchi, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Istituto Ortopedico Galeazzi</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Elena Cittera, MSc</last_name>
    <phone>00390266214057</phone>
    <email>elena.cittera@grupposandonato.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Elena De Vecchi, MSc</last_name>
    <phone>00390266214080</phone>
    <email>elena.devecchi@grupposandonato.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>IRCCS Istituto Ortopedico Galeazzi</name>
      <address>
        <city>Milano</city>
        <state>MI</state>
        <zip>20161</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elena Cittera, MSc</last_name>
      <phone>00390266214057</phone>
      <email>elena.cittera@grupposandonato.it</email>
    </contact>
    <investigator>
      <last_name>Elena De Vecchi, MSc</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>December 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 2018</study_first_posted>
  <last_update_submitted>December 20, 2018</last_update_submitted>
  <last_update_submitted_qc>December 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 24, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>synovial fluid analysis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Primary and secondary outcomes measures for all participants to the study will be made available</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>Data will become available within 1 year from study conclusion</ipd_time_frame>
    <ipd_access_criteria>Requests should be sent by e-mail to the Institution</ipd_access_criteria>
  </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/NCT03784807
org study id: Diafilm
nct id: NCT03784807
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study aims to develop new assays for synovial fluid analysis able to improve diagnosis
      of prosthetic joint infections. In particular, use of synovial calprotectin as marker of
      infection, confocal laser scanning microscopy (CLSM) analysis and methods to assess
      antimicrobial susceptibility will be evaluated in synovial fluids collected from patients
      with septic and aseptic failure of the prosthetic implant.
Infection of prosthetic joints is a common complication that may occur any time after
      implantation. These infections require a prompt and accurate diagnosis to ensure an optimal
      surgical and medical management of infected patient. Despite acute infections occurring in
      the first weeks after surgery are easy to diagnose or when they are associated to bacteremia,
      diagnosis becomes challenging when infection develops for several months before diagnosis or
      it is caused by low virulent pathogens. Prosthetic joint infections and more widely
      osteo-articular infections represent the classic biofilm related infections. Biofilm is
      usually defined as a microbial community enveloped in a self-produced polymeric matrix.
      Biofilm production allows bacteria to strictly adhere to inert and biotic substrates, evade
      host defenses and resist to antibiotics by building a physical barrier to penetration of
      antimicrobials and favoring dissemination of determinants of resistance. Microbiological
      cultures contribute to diagnosis of infection, providing identification of the pathogen and,
      most importantly, definition of antibiotic susceptibility. Nonetheless, in about 15-20% of
      cases, culture fails to growth the pathogen. Diagnosis of prosthetic joint infection may
      occur either pre- or intra-operatively. In both cases analysis of synovial fluid is crucial,
      especially when performed before surgery when results from culture, leukocyte esterase, alpha
      defensin test, leukocyte count and differential may lead to define the most accurate strategy
      to approach patients with implant failure. However, culture of synovial fluid is
      characterized by a limited sensitivity in respect, for instance to culture of periprosthetic
      tissues or implant components. One of the causes of the lower sensitivity of synovial fluid
      culture might be the presence of the so called "biofilm like aggregates", agglomerates of
      microorganisms embedded in a matrix which has been hypothesized to act as a protective
      barrier. Leukocyte esterase test may give false positive results in samples strongly
      contaminated by blood or with metal on metal reaction, while the high costs for alpha
      defensin determination markedly limited its use. On the other hand, studies aiming to
      evaluate other synovial markers of infections like calprotectin are insufficient to support
      their use in routine diagnosis of prosthetic joint infection.

      An alternative approach to diagnosis of these infections could be represented by use of
      confocal laser scanning microscopy (CLSM) which allows to detect microorganisms in synovial
      fluid and in tissues. This novel approach could also be used for a "real time" diagnosis
      during surgery while waiting for culture results.

      Another issue in diagnosis of prosthetic joint infections is related to assessment of
      antimicrobial susceptibility. In fact, it is well known that biofilm embedded bacteria are
      more resistant to antibiotics than their planktonic counterpart. Since available methods for
      determination of antibiotic susceptibility are based on planktonic cells, it may be
      hypothesized that they underestimate the real antimicrobial concentration able to inhibit
      growth of bacteria embedded in a biofilm as occur during infection. Although several methods
      have been proposed to evaluate antimicrobial susceptibility pattern of biofilm
      microorganisms, none of them has been proposed for routinely use. However, in some cases when
      therapy fails to eradicate infection, evaluation of antibiotic susceptibility of biofilm
      embedded bacteria could provide important information to optimize antimicrobial therapy.

      Therefore, diagnosis of biofilm related infections, particularly prosthetic ones is quite far
      from being optimized. In this sense, development of a panel able to shorten turn around time
      of microbiological analyses and to improve patient management could significantly ameliorate
      approach to patients, limiting worsening in patient's quality of life and reducing costs for
      health system.
observational model: Case-Control
time perspective: Prospective
measure: Assessment of analytical performance of calprotectin and CLSM for diagnosis of prosthetic joint infections
time frame: preoperative visit or during surgery
description: Sensitivity, specificity, predictive values and diagnostic accuracy of calprotectin and CLSM will be calculated and compared to those of assays already used for diagnosis of prosthetic joint infections
measure: Improvement in antibiotic therapy applying data obtained from antibiotic susceptibility testing on biofilm
time frame: Afetr isolation of the pathogen, within 2 months
description: Antimicrobial profiles obtained on biofilm bacteria will be compared with those obtained with traditional methods on planktonic cells
arm group label: Infected
description: Patients with prosthetic joint or osteoarticular infection
arm group label: Not infected
description: Patients with implant failure not due to infection
intervention type: Diagnostic Test
intervention name: synovial calprotectin, confocal laser microscopy
description: Calprotectin will be determined in synovial fluid of patients with septic and aseptic failure of their prosthesis. CLSM will be used to detect presence of microorganisms in synovial fluid. Susceptibility to antimicrobials of bacterial strains isolated from patients with prosthetic joint infections will be assessed using planktonic cells and biofilm associated bacteria
arm group label: Infected
arm group label: Not infected
Bacterial strains
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Elena De Vecchi, MSc
role: Principal Investigator
affiliation: IRCCS Istituto Ortopedico Galeazzi
last name: Elena Cittera, MSc
phone: 00390266214057
email: elena.cittera@grupposandonato.it
last name: Elena De Vecchi, MSc
phone: 00390266214080
email: elena.devecchi@grupposandonato.it
facility: 
status: Recruiting
contact: 
investigator: 
country: Italy
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
sharing ipd: Yes
ipd description: Primary and secondary outcomes measures for all participants to the study will be made available
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Data will become available within 1 year from study conclusion
ipd access criteria: Requests should be sent by e-mail to the Institution