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Study of Systemic Impact of Trace Elements Release by Implantable Medical Devices. Identification of Biomarkers of Systemic Inflammation (PROMETOX)

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ClinicalTrials.gov Identifier: NCT03812627
Recruitment Status : Active, not recruiting
First Posted : January 23, 2019
Last Update Posted : August 30, 2021
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Biomarker Systemic Inflammation Other: Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections Other: Autopsy Not Applicable

Detailed Description:

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 290 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Study of Systemic Impact of Trace Elements Release by Implantable Medical Devices. Identification of Biomarkers of Systemic Inflammation
Actual Study Start Date : June 24, 2019
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021
Arms and Interventions
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Arm Intervention/treatment
Experimental: Re-intervention of hip prosthesis made of ceramic or metal

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)

 Other: Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections

All inpatient subjects: following samples will be collected during hospitalization:

Twice blood and urine collections:

  1. at the beginning of hospitalization: 10 ml of blood + 5 ml of urine;
  2. 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
Experimental: Re-intervention of hip prosthesis of stainless steel ball

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.

 Other: Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections

All inpatient subjects: following samples will be collected during hospitalization:

Twice blood and urine collections:

  1. at the beginning of hospitalization: 10 ml of blood + 5 ml of urine;
  2. 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
Experimental: Re-intervention of knee prosthesis

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.

 Other: Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections

All inpatient subjects: following samples will be collected during hospitalization:

Twice blood and urine collections:

  1. at the beginning of hospitalization: 10 ml of blood + 5 ml of urine;
  2. 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
Experimental: Dead patients IMD holders autopsied
Autopsy: 80 dead patients IMD holders will be autopsied.
 Other: Autopsy
Dead patients will be autopsied: hair, urine, blood, peri-prosthetic tissue and viscera (liver, kidney, spleen, brain, heart, lung) sampling for each autopsy.
Active Comparator: Dead patients non-IMD holders autopsied
Autopsy: dead patients non-IMD holders autopsied, 30 subjects in this arm.
 Other: Autopsy
Dead patients will be autopsied: hair, urine, blood, peri-prosthetic tissue and viscera (liver, kidney, spleen, brain, heart, lung) sampling for each autopsy.
Active Comparator: patients before first prosthesis surgery
Before the initial prosthesis surgery: 30 patients Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections will be done
 Other: Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections

All inpatient subjects: following samples will be collected during hospitalization:

Twice blood and urine collections:

  1. at the beginning of hospitalization: 10 ml of blood + 5 ml of urine;
  2. 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


Outcome Measures
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Primary Outcome Measures :
  1. Immunophenotyping of inflammatory cells activated in contact with trace element nanoparticles [ Time Frame: through study completion, an average of 2 years ]

    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.


  2. Identification of specific circulating proteins (biomarkers) of inflammation related to trace element release [ Time Frame: through study completion, an average of 2 years ]

    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


  3. Macroscopic characterization of tissue inflammation of autopsied patients [ Time Frame: through study completion, an average of 2 years ]

    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


  4. Microscopic characterization of tissue inflammation of autopsied patients [ Time Frame: through study completion, an average of 2 years ]

    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



Secondary Outcome Measures :
  1. Trace elements dosing in liquids and tissues [ Time Frame: through study completion, an average of 2 years ]
    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.

  2. Comparison of concentrations of 40 analyzed trace elements [ Time Frame: through study completion, an average of 2 years ]
    Comparison of concentrations of 40 analyzed trace elements in different materials, depending on the groups.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Inpatient subjects for re-intervention of: hip prosthesis made by ceramic-on-ceramic or metal-on-metal, hip prosthesis made by stainless steel ball and knee prosthesis made by polyethylene-on-metal;
  • Autopsied patients with and without IMD;
  • Covered by a health insurance.

Exclusion Criteria:

  • Infection caused by prosthesis resumption;
  • Professional exposure to metals;
  • Patient under guardianship.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03812627


Locations
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France
Service de Chirurgie orthopédique, Hôpital Raymond Poincaré
Garches, Hauts-des-Seine, France, 92380
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Jean-Claude Alvarez, MD, PhD Laboratoire de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, Garches
Study Director: Thomas BAUER, MD, PhD Orthopédie et traumatologie, Hôpital Ambroise Paré, Boulogne-Billancourt
More Information
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03812627    
Other Study ID Numbers: APHP180539
First Posted: January 23, 2019    Key Record Dates
Last Update Posted: August 30, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Implantable medical devices
Biomarker
Systemic inflammation
Additional relevant MeSH terms:
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Inflammation
Pathologic Processes