<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/NCT03812627</url>
  </required_header>
  <id_info>
    <org_study_id>APHP180539</org_study_id>
    <nct_id>NCT03812627</nct_id>
  </id_info>
  <brief_title>Study of Systemic Impact of Trace Elements Release by Implantable Medical Devices. Identification of Biomarkers of Systemic Inflammation</brief_title>
  <acronym>PROMETOX</acronym>
  <official_title>Study of Systemic Impact of Trace Elements Release by Implantable Medical Devices. Identification of Biomarkers of Systemic Inflammation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</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>
      The main objective of this study is to evaluate the systemic impact of salting out of trace&#xD;
      elements (TE) by metallic and nonmetallic implantable medical devices (IMD) and in particular&#xD;
      the immune response of the organism to these trace elements and of their target organs, and&#xD;
      to identify circulating protein biomarkers which might indicate an evolution of inflammation&#xD;
      caused by an IMD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      As secondary objectives, the study aims:&#xD;
&#xD;
        -  to establish the norms of concentrations of free TE and nanoparticles for some forty of&#xD;
           elements (in particular Chrome, Cobalt, Nickel, Titanium, Tantalum, Zirconium, Tungsten,&#xD;
           Gold, Silver, Mercury, Molybdenum, Strontium ...) in different materials (blood, urine,&#xD;
           hair and the viscera), with non-IMD holder subjects, before and after mineralization of&#xD;
           these materials (dead patients and autopsied non-IMD holder subjects and subjects before&#xD;
           placement of IMD.&#xD;
&#xD;
        -  to evaluate the distribution of concentrations of metals in the same materials and in&#xD;
           peri-prothetic environment with IMD holder subjects (dead autopsied patients), more&#xD;
           often with no inflammatory sign, with possibility of some probably inflammatory IMD.&#xD;
&#xD;
        -  to evaluate the parameters of distributions of concentrations of metals in same&#xD;
           materials (with the exception of the viscera) with living IMD holder patients, with&#xD;
           inflammatory reaction (during revision surgery).&#xD;
&#xD;
        -  to define the most suitable material (accessibility, concentrations, absence of&#xD;
           contamination) for follow-up and evolution of inflammation in order to determinate norms&#xD;
           of studied metals concentration.&#xD;
&#xD;
        -  to determinate proportion between different forms of circulation: particulate form&#xD;
           (analysis after full mineralization) or free form (analysis without mineralization,&#xD;
           permitting measurement of free forms), trace elements in organism.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 24, 2019</start_date>
  <completion_date type="Actual">March 19, 2021</completion_date>
  <primary_completion_date type="Actual">March 19, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Immunophenotyping of inflammatory cells activated in contact with trace element nanoparticles</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:&#xD;
1/ A measure by flow cytometry to identify hyperactivated circulating mononuclear cells (macrophages, dendritic cells, T and B lymphocytes), in contact with trace element nanoparticles and thus, to highlight an immunophenotype of this inflammation.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Identification of specific circulating proteins (biomarkers) of inflammation related to trace element release</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:&#xD;
2/ A measure by multiplex LuminexTM (Bio-plex ProTM human inflammation panel, Bio-rad) to identify specific circulating proteins such as TNF, IFN, cytokines, chemokines, metalloproteins, related to activation of the cells of inflammation throughout release of particles and salting out of trace elements by IMD</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Macroscopic characterization of tissue inflammation of autopsied patients</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:&#xD;
- 3/ A macroscopic study of organs to determine the possible presence of tumor foci</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Microscopic characterization of tissue inflammation of autopsied patients</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:&#xD;
- 4/ Cytopathological analysis on slides, after sampling, fixation, inclusion and staining with hematoxylin-eosin-saffron to evaluate semi-quantitatively the type of inflammation (chronic if mononuclear cells or acute if neutrophils) and degree according to the number of inflammatory cells</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Trace elements dosing in liquids and tissues</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Trace elements dosing in liquids and tissue by high resolution ICP mass spectrometry in studied sub-population (autopsied IMD holder and non-holder dead subjects, IMD holder living patients with inflammatory reaction and will undergo re-intervention) and in each analyzed material in non-mineralized form, in order to determinate concentrations of free trace elements and after full mineralization to determinate the concentrations of trace elements in nanoparticle form.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of concentrations of 40 analyzed trace elements</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Comparison of concentrations of 40 analyzed trace elements in different materials, depending on the groups.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">159</enrollment>
  <condition>Biomarker</condition>
  <condition>Systemic Inflammation</condition>
  <arm_group>
    <arm_group_label>Re-intervention of hip prosthesis made of ceramic or metal</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Re-intervention surgery: blood, urine, hair, synovial fluid and peri-prosthetic tissue collections.&#xD;
50 patients for re-intervention of hip prosthesis with friction couples of: ceramic-on-ceramic or metal-on-metal&#xD;
(25 patients by group)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Re-intervention of hip prosthesis of stainless steel ball</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Re-intervention surgery: blood, urine, hair, synovial fluid and peri-prosthetic tissue collections.&#xD;
50 patients for re-intervention of hip prosthesis of stainless steel ball.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Re-intervention of knee prosthesis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Re-intervention surgery: blood, urine, hair, synovial fluid and peri-prosthetic tissue collections.&#xD;
50 inpatient subjects for re-intervention of knee prosthesis polyethylene-on-metal.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dead patients IMD holders autopsied</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Autopsy: 80 dead patients IMD holders will be autopsied.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dead patients non-IMD holders autopsied</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Autopsy: dead patients non-IMD holders autopsied, 30 subjects in this arm.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>patients before first prosthesis surgery</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Before the initial prosthesis surgery: 30 patients Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections will be done</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections</intervention_name>
    <description>All inpatient subjects: following samples will be collected during hospitalization:&#xD;
Twice blood and urine collections:&#xD;
at the beginning of hospitalization: 10 ml of blood + 5 ml of urine;&#xD;
at the end of hospitalization: 5 ml of blood + 5 ml of urine. Synovial fluid collection: 1 ml Peri-prosthetic tissue collection: about 1 cm3 Hair collection: a single hair of 0.5 cm diameter</description>
    <arm_group_label>Re-intervention of hip prosthesis made of ceramic or metal</arm_group_label>
    <arm_group_label>Re-intervention of hip prosthesis of stainless steel ball</arm_group_label>
    <arm_group_label>Re-intervention of knee prosthesis</arm_group_label>
    <arm_group_label>patients before first prosthesis surgery</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Autopsy</intervention_name>
    <description>Dead patients will be autopsied: hair, urine, blood, peri-prosthetic tissue and viscera (liver, kidney, spleen, brain, heart, lung) sampling for each autopsy.</description>
    <arm_group_label>Dead patients IMD holders autopsied</arm_group_label>
    <arm_group_label>Dead patients non-IMD holders autopsied</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Inpatient subjects for re-intervention of: hip prosthesis made by ceramic-on-ceramic&#xD;
             or metal-on-metal, hip prosthesis made by stainless steel ball and knee prosthesis&#xD;
             made by polyethylene-on-metal;&#xD;
&#xD;
          -  Autopsied patients with and without IMD;&#xD;
&#xD;
          -  Covered by a health insurance.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Infection caused by prosthesis resumption;&#xD;
&#xD;
          -  Professional exposure to metals;&#xD;
&#xD;
          -  Patient under guardianship.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jean-Claude Alvarez, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Laboratoire de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, Garches</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Thomas BAUER, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Orthopédie et traumatologie, Hôpital Ambroise Paré, Boulogne-Billancourt</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Service de Chirurgie orthopédique, Hôpital Raymond Poincaré</name>
      <address>
        <city>Garches</city>
        <state>Hauts-des-Seine</state>
        <zip>92380</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>January 11, 2019</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <last_update_submitted>April 20, 2022</last_update_submitted>
  <last_update_submitted_qc>April 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Implantable medical devices</keyword>
  <keyword>Biomarker</keyword>
  <keyword>Systemic inflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</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/NCT03812627
org study id: APHP180539
nct id: NCT03812627
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The main objective of this study is to evaluate the systemic impact of salting out of trace
      elements (TE) by metallic and nonmetallic implantable medical devices (IMD) and in particular
      the immune response of the organism to these trace elements and of their target organs, and
      to identify circulating protein biomarkers which might indicate an evolution of inflammation
      caused by an IMD.
As secondary objectives, the study aims:

        -  to establish the norms of concentrations of free TE and nanoparticles for some forty of
           elements (in particular Chrome, Cobalt, Nickel, Titanium, Tantalum, Zirconium, Tungsten,
           Gold, Silver, Mercury, Molybdenum, Strontium ...) in different materials (blood, urine,
           hair and the viscera), with non-IMD holder subjects, before and after mineralization of
           these materials (dead patients and autopsied non-IMD holder subjects and subjects before
           placement of IMD.

        -  to evaluate the distribution of concentrations of metals in the same materials and in
           peri-prothetic environment with IMD holder subjects (dead autopsied patients), more
           often with no inflammatory sign, with possibility of some probably inflammatory IMD.

        -  to evaluate the parameters of distributions of concentrations of metals in same
           materials (with the exception of the viscera) with living IMD holder patients, with
           inflammatory reaction (during revision surgery).

        -  to define the most suitable material (accessibility, concentrations, absence of
           contamination) for follow-up and evolution of inflammation in order to determinate norms
           of studied metals concentration.

        -  to determinate proportion between different forms of circulation: particulate form
           (analysis after full mineralization) or free form (analysis without mineralization,
           permitting measurement of free forms), trace elements in organism.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: Immunophenotyping of inflammatory cells activated in contact with trace element nanoparticles
time frame: through study completion, an average of 2 years
description: Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:
1/ A measure by flow cytometry to identify hyperactivated circulating mononuclear cells (macrophages, dendritic cells, T and B lymphocytes), in contact with trace element nanoparticles and thus, to highlight an immunophenotype of this inflammation.
measure: Identification of specific circulating proteins (biomarkers) of inflammation related to trace element release
time frame: through study completion, an average of 2 years
description: Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:
2/ A measure by multiplex LuminexTM (Bio-plex ProTM human inflammation panel, Bio-rad) to identify specific circulating proteins such as TNF, IFN, cytokines, chemokines, metalloproteins, related to activation of the cells of inflammation throughout release of particles and salting out of trace elements by IMD
measure: Macroscopic characterization of tissue inflammation of autopsied patients
time frame: through study completion, an average of 2 years
description: Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:
- 3/ A macroscopic study of organs to determine the possible presence of tumor foci
measure: Microscopic characterization of tissue inflammation of autopsied patients
time frame: through study completion, an average of 2 years
description: Demonstration of systemic inflammation induced by the trace elements existing in IMD with blood and tissue criteria:
- 4/ Cytopathological analysis on slides, after sampling, fixation, inclusion and staining with hematoxylin-eosin-saffron to evaluate semi-quantitatively the type of inflammation (chronic if mononuclear cells or acute if neutrophils) and degree according to the number of inflammatory cells
measure: Trace elements dosing in liquids and tissues
time frame: through study completion, an average of 2 years
description: Trace elements dosing in liquids and tissue by high resolution ICP mass spectrometry in studied sub-population (autopsied IMD holder and non-holder dead subjects, IMD holder living patients with inflammatory reaction and will undergo re-intervention) and in each analyzed material in non-mineralized form, in order to determinate concentrations of free trace elements and after full mineralization to determinate the concentrations of trace elements in nanoparticle form.
measure: Comparison of concentrations of 40 analyzed trace elements
time frame: through study completion, an average of 2 years
description: Comparison of concentrations of 40 analyzed trace elements in different materials, depending on the groups.
arm group label: Re-intervention of hip prosthesis made of ceramic or metal
arm group type: Experimental
description: Re-intervention surgery: blood, urine, hair, synovial fluid and peri-prosthetic tissue collections.
50 patients for re-intervention of hip prosthesis with friction couples of: ceramic-on-ceramic or metal-on-metal
(25 patients by group)
arm group label: Re-intervention of hip prosthesis of stainless steel ball
arm group type: Experimental
description: Re-intervention surgery: blood, urine, hair, synovial fluid and peri-prosthetic tissue collections.
50 patients for re-intervention of hip prosthesis of stainless steel ball.
arm group label: Re-intervention of knee prosthesis
arm group type: Experimental
description: Re-intervention surgery: blood, urine, hair, synovial fluid and peri-prosthetic tissue collections.
50 inpatient subjects for re-intervention of knee prosthesis polyethylene-on-metal.
arm group label: Dead patients IMD holders autopsied
arm group type: Experimental
description: Autopsy: 80 dead patients IMD holders will be autopsied.
arm group label: Dead patients non-IMD holders autopsied
arm group type: Active Comparator
description: Autopsy: dead patients non-IMD holders autopsied, 30 subjects in this arm.
arm group label: patients before first prosthesis surgery
arm group type: Active Comparator
description: Before the initial prosthesis surgery: 30 patients Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections will be done
intervention type: Other
intervention name: Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections
description: All inpatient subjects: following samples will be collected during hospitalization:
Twice blood and urine collections:
at the beginning of hospitalization: 10 ml of blood + 5 ml of urine;
at the end of hospitalization: 5 ml of blood + 5 ml of urine. Synovial fluid collection: 1 ml Peri-prosthetic tissue collection: about 1 cm3 Hair collection: a single hair of 0.5 cm diameter
arm group label: Re-intervention of hip prosthesis made of ceramic or metal
arm group label: Re-intervention of hip prosthesis of stainless steel ball
arm group label: Re-intervention of knee prosthesis
arm group label: patients before first prosthesis surgery
intervention type: Other
intervention name: Autopsy
description: Dead patients will be autopsied: hair, urine, blood, peri-prosthetic tissue and viscera (liver, kidney, spleen, brain, heart, lung) sampling for each autopsy.
arm group label: Dead patients IMD holders autopsied
arm group label: Dead patients non-IMD holders autopsied
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Jean-Claude Alvarez, MD, PhD
role: Principal Investigator
affiliation: Laboratoire de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, Garches
last name: Thomas BAUER, MD, PhD
role: Study Director
affiliation: Orthopédie et traumatologie, Hôpital Ambroise Paré, Boulogne-Billancourt
facility: 
country: France
responsible party type: Sponsor
mesh term: Inflammation
sharing ipd: No