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

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.

Study Overview

• Status: Completed
• Conditions: Systemic Inflammation; Biomarker
• Intervention / Treatment: Other: Blood, urine, hair, synovial fluid and peri-prosthetic tissue collections; Other: Autopsy

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 Type: Interventional
• Enrollment (Actual): 159
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Hauts-des-Seine
    • Garches, Hauts-des-Seine, France, 92380
      • Service de Chirurgie orthopédique, Hôpital Raymond Poincaré

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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: 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
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: 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
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: 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
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: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunophenotyping of inflammatory cells activated in contact with trace element nanoparticles	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.	through study completion, an average of 2 years
Identification of specific circulating proteins (biomarkers) of inflammation related to trace element release	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	through study completion, an average of 2 years
Macroscopic characterization of tissue inflammation of autopsied patients	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	through study completion, an average of 2 years
Microscopic characterization of tissue inflammation of autopsied patients	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	through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trace elements dosing in liquids and tissues	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.	through study completion, an average of 2 years
Comparison of concentrations of 40 analyzed trace elements	Comparison of concentrations of 40 analyzed trace elements in different materials, depending on the groups.	through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: 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

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2019
• Primary Completion (Actual): March 19, 2021
• Study Completion (Actual): March 19, 2021

Study Registration Dates

• First Submitted: January 11, 2019
• First Submitted That Met QC Criteria: January 22, 2019
• First Posted (Actual): January 23, 2019

Study Record Updates

• Last Update Posted (Actual): April 21, 2022
• Last Update Submitted That Met QC Criteria: April 20, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Biomarker; Systemic inflammation; Implantable medical devices
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: APHP180539

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No