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出境医 / 临床实验 / Diagnostic Utility of a Novel Point-of-Care Test of Calprotectin for Revision Total Knee Arthroplasty

Diagnostic Utility of a Novel Point-of-Care Test of Calprotectin for Revision Total Knee Arthroplasty

Study Description
Brief Summary:
The purpose of this study is to investigate whether there are quantifiable differences in the level of calprotectin in the synovial fluid that allow separation of different modes of joint implant failure (e.g. infected, aseptic loosening). A subset of primary TKA patients (with history of OA) will be included as a baseline.

Condition or disease Intervention/treatment
Prosthetic Joint Infection Diagnostic Test: Calprotectin test

Detailed Description:

Calprotectin is a biomarker closely associated with leucocytes in general, and is present in high volumes in neutrophil cells. Calprotectin is also produced by infiltrating monocytes and macrophages, where calprotectin is released upon phagocytosis. In neutrophils, calprotectin is stored intracellularly and are released upon activation of the cell. The determination of number of neutrophils and proportion of neutrophils out of total number of inflammatory cells is a diagnostic strategy commonly used in diagnosis of infection. Upon encounter with a pathogen, neutrophils have several strategies to fight infections , and produce high-levels of calprotectin. Activation of neutrophils, and release of calprotectin, can be for any reason causing activation of the complement system and aseptic Inflammatory responses. Moreover, Calprotectin is a danger associated molecular patterns (DAMP) signal influencing the inflammatory responses. The level of activated neutrophils in PJI provide basis of the presence of calprotectin in the synovial fluid of PJI patients, and thus, for calprotectin as a potential biomarker for PJI. Calprotectin-levels in the synovial fluid do not merely reflect the level of leucocytes and neutrophils present in the synovial fluid, but levels are correlated to the WBC content. Calprotectin is likely to reflect the number of activated cells and surpass the diagnostic accuracy of total WBC counts and neutrophil percentage for PJI diagnosis.

A level of calprotectin of 50 mg/L in the synovial fluid has very good diagnostic accuracy for PJI, supported by area under the curve values of more than 0.9. In a subgroup analysis for patients with chronic PJI, a NPV of 97% was observed. The excellent NPV may assist in the orthopaedic clinic to rule out the presence of infection and consider diagnostic alternatives for aseptic loosening and pain revision of the joint patient. A rapid and accurate distinction between these two causes is important as PJI and aseptic loosening are managed differently with regards to surgical Intervention and followup.

Point of Care Test diagnostics by lateral flow devices provides reliable test results within minutes of sample collection. Currently, Calprotectin can be detected by such lateral flow devices (developed by Orthogenics, Tromsø, Norway). The speed and ease of use of this test allows for diagnosis at patient's bed side. These tests can be applied in the physician's office, operating room, an ambulance, the home, the field, or in the hospital. As the results are timely they allow rapid diagnostic and identifies treatment alternatives for the patient. This technology empowers clinicians to make decisions at the "point-of-care" and can have significant impact on health care delivery and ability to address challenges of health disparities. However, it is important to validate the diagnostic utility of calprotectin POC in a diverse set of patients undergoing revision arthroplasty.

Study Design
Layout table for study information
Study Type : Observational
Actual Enrollment : 156 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Diagnostic Utility of a Novel Point-of-Care Test of Calprotectin for Revision Total
Actual Study Start Date : October 29, 2018
Actual Primary Completion Date : January 7, 2020
Actual Study Completion Date : March 4, 2020
Arms and Interventions
Group/Cohort Intervention/treatment
Primary total knee arthroplasty
Primary TKA patients included in the study, to provide a baseline level for calprotectin.
 Diagnostic Test: Calprotectin test
Calprotectin will be measured both by ELISA and point of care test.
Aseptic revision total knee arthroplasty
Aseptic revision TKA patients included in the study. These are patients who are not considered infected according to Musculoskeletal Infection Society criteria for infection.
 Diagnostic Test: Calprotectin test
Calprotectin will be measured both by ELISA and point of care test.
Revision septic total knee arthroplasty
Septic revision TKA patients included in the study. These are patients who are considered infected according to Musculoskeletal Infection Society criteria for infection.
 Diagnostic Test: Calprotectin test
Calprotectin will be measured both by ELISA and point of care test.
Outcome Measures
Primary Outcome Measures :
  1. Calprotectin POC [ Time Frame: Day of surgery ]
    lateral flow point of care test


Secondary Outcome Measures :
  1. Calprotectin ELISA [ Time Frame: Day of surgery ]
    ELISA analysis


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Three groups:

Primary total knee arthroplasty Aseptic revision total knee arthroplasty Septic revision total knee arthroplasty

Criteria

Inclusion Criteria:

  • Subject is ≥18 years of age
  • Patient with a diagnosis of OA (for primary TKA only)
  • Subject has had no recent injections or surgeries of the joint (within past 6 weeks)
  • Subject has or will have all of the medical tests required to allow MSIS classification
  • Subject signs informed consent form

Exclusion Criteria:

  • Subjects with a diagnostic synovial fluid specimen collection within the past 7 days
  • Results are not available for medical tests required to perform MSIS classification
  • Sample was obtained via lavage
  • Quantity not sufficient (at least 1 ml required)
Contacts and Locations

Locations
Layout table for location information
United States, Florida
Cleveland Clinic Florida
Weston, Florida, United States, 33331
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
Sponsors and Collaborators
The Cleveland Clinic
Investigators
Layout table for investigator information
Principal Investigator: Carlos Higuera, MD The Cleveland Clinic
Tracking Information
First Submitted Date October 2, 2018
First Posted Date October 3, 2018
Results First Submitted Date June 8, 2020
Results First Posted Date December 17, 2020
Last Update Posted Date December 17, 2020
Actual Study Start Date October 29, 2018
Actual Primary Completion Date January 7, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: November 23, 2020) 		Calprotectin POC [ Time Frame: Day of surgery ]
lateral flow point of care test
Original Primary Outcome Measures
 (submitted: October 2, 2018) 		Calprotectin POC [ Time Frame: Day of surgery ]
Point of care test
Change History
Current Secondary Outcome Measures
 (submitted: October 2, 2018) 		Calprotectin ELISA [ Time Frame: Day of surgery ]
ELISA analysis
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Diagnostic Utility of a Novel Point-of-Care Test of Calprotectin for Revision Total Knee Arthroplasty
Official Title Diagnostic Utility of a Novel Point-of-Care Test of Calprotectin for Revision Total
Brief Summary The purpose of this study is to investigate whether there are quantifiable differences in the level of calprotectin in the synovial fluid that allow separation of different modes of joint implant failure (e.g. infected, aseptic loosening). A subset of primary TKA patients (with history of OA) will be included as a baseline.
Detailed Description

Calprotectin is a biomarker closely associated with leucocytes in general, and is present in high volumes in neutrophil cells. Calprotectin is also produced by infiltrating monocytes and macrophages, where calprotectin is released upon phagocytosis. In neutrophils, calprotectin is stored intracellularly and are released upon activation of the cell. The determination of number of neutrophils and proportion of neutrophils out of total number of inflammatory cells is a diagnostic strategy commonly used in diagnosis of infection. Upon encounter with a pathogen, neutrophils have several strategies to fight infections , and produce high-levels of calprotectin. Activation of neutrophils, and release of calprotectin, can be for any reason causing activation of the complement system and aseptic Inflammatory responses. Moreover, Calprotectin is a danger associated molecular patterns (DAMP) signal influencing the inflammatory responses. The level of activated neutrophils in PJI provide basis of the presence of calprotectin in the synovial fluid of PJI patients, and thus, for calprotectin as a potential biomarker for PJI. Calprotectin-levels in the synovial fluid do not merely reflect the level of leucocytes and neutrophils present in the synovial fluid, but levels are correlated to the WBC content. Calprotectin is likely to reflect the number of activated cells and surpass the diagnostic accuracy of total WBC counts and neutrophil percentage for PJI diagnosis.

A level of calprotectin of 50 mg/L in the synovial fluid has very good diagnostic accuracy for PJI, supported by area under the curve values of more than 0.9. In a subgroup analysis for patients with chronic PJI, a NPV of 97% was observed. The excellent NPV may assist in the orthopaedic clinic to rule out the presence of infection and consider diagnostic alternatives for aseptic loosening and pain revision of the joint patient. A rapid and accurate distinction between these two causes is important as PJI and aseptic loosening are managed differently with regards to surgical Intervention and followup.

Point of Care Test diagnostics by lateral flow devices provides reliable test results within minutes of sample collection. Currently, Calprotectin can be detected by such lateral flow devices (developed by Orthogenics, Tromsø, Norway). The speed and ease of use of this test allows for diagnosis at patient's bed side. These tests can be applied in the physician's office, operating room, an ambulance, the home, the field, or in the hospital. As the results are timely they allow rapid diagnostic and identifies treatment alternatives for the patient. This technology empowers clinicians to make decisions at the "point-of-care" and can have significant impact on health care delivery and ability to address challenges of health disparities. However, it is important to validate the diagnostic utility of calprotectin POC in a diverse set of patients undergoing revision arthroplasty.
Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population

Three groups:

Primary total knee arthroplasty Aseptic revision total knee arthroplasty Septic revision total knee arthroplasty
Condition Prosthetic Joint Infection
Intervention Diagnostic Test: Calprotectin test
Calprotectin will be measured both by ELISA and point of care test.
Study Groups/Cohorts
  • Primary total knee arthroplasty
    Primary TKA patients included in the study, to provide a baseline level for calprotectin.
    Intervention: Diagnostic Test: Calprotectin test
  • Aseptic revision total knee arthroplasty
    Aseptic revision TKA patients included in the study. These are patients who are not considered infected according to Musculoskeletal Infection Society criteria for infection.
    Intervention: Diagnostic Test: Calprotectin test
  • Revision septic total knee arthroplasty
    Septic revision TKA patients included in the study. These are patients who are considered infected according to Musculoskeletal Infection Society criteria for infection.
    Intervention: Diagnostic Test: Calprotectin test
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: November 23, 2020) 		156
Original Estimated Enrollment
 (submitted: October 2, 2018) 		150
Actual Study Completion Date March 4, 2020
Actual Primary Completion Date January 7, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Subject is ≥18 years of age
  • Patient with a diagnosis of OA (for primary TKA only)
  • Subject has had no recent injections or surgeries of the joint (within past 6 weeks)
  • Subject has or will have all of the medical tests required to allow MSIS classification
  • Subject signs informed consent form

Exclusion Criteria:

  • Subjects with a diagnostic synovial fluid specimen collection within the past 7 days
  • Results are not available for medical tests required to perform MSIS classification
  • Sample was obtained via lavage
  • Quantity not sufficient (at least 1 ml required)
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03694925
Other Study ID Numbers 18-882
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Plan Description: The only group we will be sharing data with is the company (Lyfstone) which is funding the research.
Responsible Party Carlos Higuera-Rueda, The Cleveland Clinic
Study Sponsor The Cleveland Clinic
Collaborators Not Provided
Investigators
Principal Investigator: Carlos Higuera, MD The Cleveland Clinic
PRS Account The Cleveland Clinic
Verification Date November 2020