<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/NCT03769337</url>
  </required_header>
  <id_info>
    <org_study_id>Perimarkers</org_study_id>
    <nct_id>NCT03769337</nct_id>
  </id_info>
  <brief_title>New Markers for Diagnosis of Prosthetic Infections</brief_title>
  <acronym>Perimarkers</acronym>
  <official_title>Identification of New Biological Marker for Diagnosis of Periprosthetic 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>Yes</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>
      Implant infections are among the most dramatic complications in orthopaedic surgery with&#xD;
      heavy impact on life quality and health system. Their diagnosis is still challenging since,&#xD;
      till now, none othe proposed markers has shown a sensitivity and a specificity of100%.&#xD;
      Therefore, efforts in identification of new markers of infections are required. This study&#xD;
      aims to evaluate the applicability of Interleukin (IL)-6, Triggering receptor expressed on&#xD;
      myeloid cells (TREM-1), CC chemokine ligand 2 (CCL2), matrix metalloproteinases (MMP-9),&#xD;
      osteopontin (OPN), IL-1 receptor antagonist (IL1-RA), IL-6 receptor beta (GP130), C5a,&#xD;
      receptor for advanced glycation end products (sRAGE), urokinases and presepsin as serum&#xD;
      markers of prosthetic joint infection.&#xD;
&#xD;
      At this purpose, serum from 65 patients with infected implant and from 65 with aseptic&#xD;
      failure of their prosthesis will be collected before surgery and after 2 and 7 days from&#xD;
      revision.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Management of prosthetic joint infections involves long antibiotic therapy and, in most&#xD;
      cases, additional revision surgery with worsening of life quality for patients and high costs&#xD;
      for health system. Prosthetic joint infections occur at a rate of 1-2% but their incidence&#xD;
      grows up to 15-20% after the first revision surgery. Gram positive cocci, particularly&#xD;
      staphylococci, are the main pathogens responsible for these infections. Diagnostic workflow&#xD;
      is rather complicated, since a gold standard assay characterized by high sensitivity and&#xD;
      specificity has not been recognized. Consequently, the diagnosis is based on fulfillment of a&#xD;
      series of major and minor criteria derived from biochemical, hematological, microbiological,&#xD;
      histological analyses combined with clinical and radiological observations. Therefore, it is&#xD;
      evident that there is an urgent need to find early markers of infection, characterized by&#xD;
      high sensitivity and specificity able to differentiate between aseptic failure and prosthetic&#xD;
      joint infections caused by both high and low virulent microorganisms.&#xD;
&#xD;
      In the recent years, presepsin has been described as a marker for sepsis also able to&#xD;
      discriminate sepsis severity. Presepsin is a fragment of soluble receptor CD14 which is&#xD;
      released from monocyte surface during inflammation. The new inflammatory marker TREM-1 links&#xD;
      the activity of presepsin to other actors of inflammation process like Toll Like Receptors,&#xD;
      monocytes, inflammatory cytokines like IL-1 and IL-6, the chemokine CCL2. Presepsin activity&#xD;
      is also related to suPAR an inflammatory marker, we have recently shown to be associated with&#xD;
      prosthetic joint infections. Another potential marker of infection is osteopontin (OPN), a&#xD;
      multifunctional protein with pro-inflammatory properties, which correlates with mortality and&#xD;
      is associated to suPAR in inflammatory response. Similarly, receptor CD163, highly expressed&#xD;
      by macrophages during inflammation has been proposed as a promising serum marker of&#xD;
      inflammation. Equally important in inflammatory process is the role played by neutrophils,&#xD;
      which represent the first line of defense against infection, being able to kill bacteria by&#xD;
      producing oxygen reactive species (ROS). Recently ROS have been correlated with serum&#xD;
      Advanced Glycation End Products(AGEs) that are increased by oxidative stress. AGEs are able&#xD;
      to interact with their receptor RAGE, which exists in its soluble forms in plasma. For this&#xD;
      reason, RAGE might be used as serum biomarker to diagnose infection and related oxidative&#xD;
      stress. Despite the amount of scientific papers on the role of the above mentioned molecules,&#xD;
      a panel combining them for diagnosis of prosthetic joint infections is not yet available.&#xD;
&#xD;
      Aim of the study will be to evaluate new biological markers of prosthetic joint infection in&#xD;
      order to improve diagnostic workflow to support and integrate data from microbiological,&#xD;
      hematological and clinical examination.&#xD;
&#xD;
      At this purpose, differences in serum concentrations of IL-6, TREM-1, CCL2, MMP-9, OPN,&#xD;
      IL-1RA, GP-130, C5a, sRAGE, urokinases and presepsin between infected and not infected&#xD;
      patients will be evaluated by measuring sensitivity, specificity, positive and negative&#xD;
      predictive values, likelihood ratio for each parameter. Moreover, concentration of each&#xD;
      biomarker will be correlated with markers routinely used for diagnosis of these infections.&#xD;
&#xD;
      A total of 130 patients will be enrolled in the study: 65 patients with diagnosis of aseptic&#xD;
      failure, and 65 diagnosed with infection of prosthetic implant.&#xD;
&#xD;
      All of them will sign an informed consent before enrollment. An aliquot of serum sent to the&#xD;
      Laboratory for pre- and post-operative (2 and 7 days after surgery) routine analyses will be&#xD;
      stored at -20°C.&#xD;
&#xD;
      Serum concentrations of IL-6, TREM-1, CCL2, MMP-9, OPN, IL-1RA, GP-130, C5a, sRAGE, urokinase&#xD;
      and presepsin will be determined by means of commercially available ELISA assays.&#xD;
&#xD;
      Data regarding preoperative Erythrocyte Sedimentation Rate (ESR) and C-reactive protein&#xD;
      (CRP), Synovial fluid analysis (if available, both pre and intra operative), and&#xD;
      microbiological culture (implant and periprosthetic tissues) will be also collected.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 1, 2018</start_date>
  <completion_date type="Anticipated">September 30, 2020</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of IL-6 between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of IL-6 will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of TREM-1 between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of TREM-1 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of CCL-2 between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of CCL2 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of MMP-9 between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of MMP-9 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of OPN between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of OPN in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of IL-1RA, between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of IL-1RA in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of GP-130 between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of GP-130 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of C5a between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of C5a in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of sRAGE between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of sRAGE in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of urokinase between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of urokinase in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Statistically significant differences in serum concentrations of presepsin between infected and not-infected patients</measure>
    <time_frame>within 1 year after collection of all samples</time_frame>
    <description>Serum concentrations of presepsin in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">130</enrollment>
  <condition>Prosthetic Joint Infections</condition>
  <arm_group>
    <arm_group_label>Infected</arm_group_label>
    <description>Serum biomarkers in patients with diagnosis of prosthetic joint infection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Not Infected</arm_group_label>
    <description>Serum biomarkers in patients with implant failure not caused by infection</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>serum biomarkers</intervention_name>
    <description>Measurement of Serum concentrations of IL-6, TREM-1, CCL2, MMP-9, OPN, IL-1RA, GP-130, C5a, sRAGE, urokinase and presepsin before revision surgery and after 2 and 7 days after surgery</description>
    <arm_group_label>Infected</arm_group_label>
    <arm_group_label>Not Infected</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with failure of prosthetic implant&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with diagnosis of septic or aseptic failure of prosthetic implant&#xD;
&#xD;
          -  Informed consent signed&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients undergoing revision surgery for failure not due to the above mentioned causes&#xD;
&#xD;
          -  Known auto immune diseases or other conditions which might alter inflammatory response&#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>
  <location>
    <facility>
      <name>IRCCS Istituto Ortopedico Galeazzi</name>
      <address>
        <city>Milan</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>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>December 6, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 7, 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>serum markers of infections</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>De-identified participants data for all primary outcome measures 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 be made available within 1 year after completion of the study</ipd_time_frame>
    <ipd_access_criteria>Data access request will be sent to the facility</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/NCT03769337
org study id: Perimarkers
nct id: NCT03769337
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Implant infections are among the most dramatic complications in orthopaedic surgery with
      heavy impact on life quality and health system. Their diagnosis is still challenging since,
      till now, none othe proposed markers has shown a sensitivity and a specificity of100%.
      Therefore, efforts in identification of new markers of infections are required. This study
      aims to evaluate the applicability of Interleukin (IL)-6, Triggering receptor expressed on
      myeloid cells (TREM-1), CC chemokine ligand 2 (CCL2), matrix metalloproteinases (MMP-9),
      osteopontin (OPN), IL-1 receptor antagonist (IL1-RA), IL-6 receptor beta (GP130), C5a,
      receptor for advanced glycation end products (sRAGE), urokinases and presepsin as serum
      markers of prosthetic joint infection.

      At this purpose, serum from 65 patients with infected implant and from 65 with aseptic
      failure of their prosthesis will be collected before surgery and after 2 and 7 days from
      revision.
Management of prosthetic joint infections involves long antibiotic therapy and, in most
      cases, additional revision surgery with worsening of life quality for patients and high costs
      for health system. Prosthetic joint infections occur at a rate of 1-2% but their incidence
      grows up to 15-20% after the first revision surgery. Gram positive cocci, particularly
      staphylococci, are the main pathogens responsible for these infections. Diagnostic workflow
      is rather complicated, since a gold standard assay characterized by high sensitivity and
      specificity has not been recognized. Consequently, the diagnosis is based on fulfillment of a
      series of major and minor criteria derived from biochemical, hematological, microbiological,
      histological analyses combined with clinical and radiological observations. Therefore, it is
      evident that there is an urgent need to find early markers of infection, characterized by
      high sensitivity and specificity able to differentiate between aseptic failure and prosthetic
      joint infections caused by both high and low virulent microorganisms.

      In the recent years, presepsin has been described as a marker for sepsis also able to
      discriminate sepsis severity. Presepsin is a fragment of soluble receptor CD14 which is
      released from monocyte surface during inflammation. The new inflammatory marker TREM-1 links
      the activity of presepsin to other actors of inflammation process like Toll Like Receptors,
      monocytes, inflammatory cytokines like IL-1 and IL-6, the chemokine CCL2. Presepsin activity
      is also related to suPAR an inflammatory marker, we have recently shown to be associated with
      prosthetic joint infections. Another potential marker of infection is osteopontin (OPN), a
      multifunctional protein with pro-inflammatory properties, which correlates with mortality and
      is associated to suPAR in inflammatory response. Similarly, receptor CD163, highly expressed
      by macrophages during inflammation has been proposed as a promising serum marker of
      inflammation. Equally important in inflammatory process is the role played by neutrophils,
      which represent the first line of defense against infection, being able to kill bacteria by
      producing oxygen reactive species (ROS). Recently ROS have been correlated with serum
      Advanced Glycation End Products(AGEs) that are increased by oxidative stress. AGEs are able
      to interact with their receptor RAGE, which exists in its soluble forms in plasma. For this
      reason, RAGE might be used as serum biomarker to diagnose infection and related oxidative
      stress. Despite the amount of scientific papers on the role of the above mentioned molecules,
      a panel combining them for diagnosis of prosthetic joint infections is not yet available.

      Aim of the study will be to evaluate new biological markers of prosthetic joint infection in
      order to improve diagnostic workflow to support and integrate data from microbiological,
      hematological and clinical examination.

      At this purpose, differences in serum concentrations of IL-6, TREM-1, CCL2, MMP-9, OPN,
      IL-1RA, GP-130, C5a, sRAGE, urokinases and presepsin between infected and not infected
      patients will be evaluated by measuring sensitivity, specificity, positive and negative
      predictive values, likelihood ratio for each parameter. Moreover, concentration of each
      biomarker will be correlated with markers routinely used for diagnosis of these infections.

      A total of 130 patients will be enrolled in the study: 65 patients with diagnosis of aseptic
      failure, and 65 diagnosed with infection of prosthetic implant.

      All of them will sign an informed consent before enrollment. An aliquot of serum sent to the
      Laboratory for pre- and post-operative (2 and 7 days after surgery) routine analyses will be
      stored at -20°C.

      Serum concentrations of IL-6, TREM-1, CCL2, MMP-9, OPN, IL-1RA, GP-130, C5a, sRAGE, urokinase
      and presepsin will be determined by means of commercially available ELISA assays.

      Data regarding preoperative Erythrocyte Sedimentation Rate (ESR) and C-reactive protein
      (CRP), Synovial fluid analysis (if available, both pre and intra operative), and
      microbiological culture (implant and periprosthetic tissues) will be also collected.
observational model: Other
time perspective: Prospective
measure: Statistically significant differences in serum concentrations of IL-6 between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of IL-6 will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of TREM-1 between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of TREM-1 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of CCL-2 between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of CCL2 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of MMP-9 between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of MMP-9 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of OPN between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of OPN in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of IL-1RA, between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of IL-1RA in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of GP-130 between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of GP-130 in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of C5a between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of C5a in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of sRAGE between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of sRAGE in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of urokinase between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of urokinase in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
measure: Statistically significant differences in serum concentrations of presepsin between infected and not-infected patients
time frame: within 1 year after collection of all samples
description: Serum concentrations of presepsin in infected and not-infected patients will be compared before surgery and at 2 and 7 days after implant revision.
arm group label: Infected
description: Serum biomarkers in patients with diagnosis of prosthetic joint infection
arm group label: Not Infected
description: Serum biomarkers in patients with implant failure not caused by infection
intervention type: Diagnostic Test
intervention name: serum biomarkers
description: Measurement of Serum concentrations of IL-6, TREM-1, CCL2, MMP-9, OPN, IL-1RA, GP-130, C5a, sRAGE, urokinase and presepsin before revision surgery and after 2 and 7 days after surgery
arm group label: Infected
arm group label: Not Infected
Serum
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
facility: 
status: Recruiting
contact: 
country: Italy
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
sharing ipd: Yes
ipd description: De-identified participants data for all primary outcome measures will be made available
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Data will be made available within 1 year after completion of the study
ipd access criteria: Data access request will be sent to the facility