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Prevention of Posttraumatic Osteoarthritis After Acute Intraarticular Fractures

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ClinicalTrials.gov Identifier: NCT03769909
Recruitment Status : Active, not recruiting
First Posted : December 10, 2018
Last Update Posted : December 10, 2018
Sponsor:
Collaborators:
University of Freiburg
Odense University Hospital
The Danish Rheumatism Association
Hartmanns Fond
AP Møller Fond
Information provided by (Responsible Party):
University of Southern Denmark

Tracking Information
First Submitted Date November 9, 2018
First Posted Date December 10, 2018
Last Update Posted Date December 10, 2018
Actual Study Start Date October 31, 2017
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: December 5, 2018)
  • Concentration of cytokines in fracture ankle versus non-fracture ankle [ Time Frame: During surgery ]
    Multiplex ELISA kits will be use to identify cytokines in both ankles. Cytokines with significant difference will be identified.
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (AOFAS) [ Time Frame: 12 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of functional foot score (AOFAS), The American Orthopedic Foot and Ankle Score, includes pain, function, alignment, for AOFAS calculation the subscores are added, ranges between 0 (worst) and 100 (best) points
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: December 5, 2018)
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (FFI.DK) [ Time Frame: 12 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of FFI.DK, a functional foot score
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (EQ5D-5L) [ Time Frame: 12 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of EQ5D-5L
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (VAS-score) [ Time Frame: 12 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to VAS-score, a Visual Analog Scale.VAS 0 (best) - 10 (worst)
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (Swelling) [ Time Frame: 12 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to swelling, difference in fracture and non-fracture ankle, measured in millimeters
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (FFI.DK) [ Time Frame: 3 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of FFI.DK, a functional foot score
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (EQ5D-5L) [ Time Frame: 3 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of EQ5D-5L
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (VAS-score) [ Time Frame: 3 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of VAS-score, a Visual Analog Scale.VAS 0 (best) - 10 (worst)
  • Cytokines (identified in primary outcome 1) correlation with clinical outcomes (Swelling) [ Time Frame: 3 months after surgery ]
    The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to swelling, difference in fracture and non-fracture ankle, measured in millimeters
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 5, 2018)
  • Correlation between fracture classification and clinical outcomes (AOFAS) [ Time Frame: 12 months after surgery ]
    Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to the scores of functional foot score (AOFAS), The American Orthopedic Foot and Ankle Score, includes pain, function, alignment, for AOFAS calculation the subscores are added, ranges between 0 (worst) and 100 (best) points
  • Correlation between fracture classification and clinical outcomes (FFI.DK) [ Time Frame: 12 months after surgery ]
    Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to the scores of functional foot score (FFI.DK)
  • Correlation between fracture classification and clinical outcomes (EQ5D-5L) [ Time Frame: 12 months after surgery ]
    Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to the scores of EQ5D-5L
  • Correlation between fracture classification and clinical outcomes (VAS-score) [ Time Frame: 12 months after surgery ]
    Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to the scores of VAS-score, a Visual Analog Scale.VAS 0 (best) - 10 (worst)
  • Correlation between fracture classification and clinical outcomes (Swelling) [ Time Frame: 12 months after surgery ]
    Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to swelling, difference in fracture and non-fracture ankle, measured in millimeters
  • Correlation between fracture classification and clinical outcomes (activity) [ Time Frame: 12 months after surgery ]
    Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to activity, meassured with an activity tracker, recording number of active minutes per day
  • Correlation between fracture reduction and clinical outcomes (AOFAS) [ Time Frame: 12 months after surgery ]
    Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off>2 mm, tibiotalartilt >2° and deviation of rotation > 6°) will be correlated to the scores of functional foot score (AOFAS), The American Orthopedic Foot and Ankle Score, includes pain, function, alignment, for AOFAS calculation the subscores are added, ranges between 0 (worst) and 100 (best) points
  • Correlation between fracture reduction and clinical outcomes (FFI.DK) [ Time Frame: 12 months after surgery ]
    Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off>2 mm, tibiotalartilt >2° and deviation of rotation > 6°) will be correlated to the scores of functional foot score (FFI.DK)
  • Correlation between fracture reduction and clinical outcomes (EQ5D-5L) [ Time Frame: 12 months after surgery ]
    Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off>2 mm, tibiotalartilt >2° and deviation of rotation > 6°) will be correlated to the scores of EQ5D-5L
  • Correlation between fracture reduction and clinical outcomes (VAS-score) [ Time Frame: 12 months after surgery ]
    Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off>2 mm, tibiotalartilt >2° and deviation of rotation > 6°) will be correlated to the scores of VAS-score, a Visual Analog Scale.VAS 0 (best) - 10 (worst)
  • Correlation between fracture reduction and clinical outcomes (Swelling) [ Time Frame: 12 months after surgery ]
    Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off>2 mm, tibiotalartilt >2° and deviation of rotation > 6°) will be correlated to swelling, difference in fracture and non-fracture ankle, measured in millimeters
  • Correlation between fracture reduction and clinical outcomes (activity) [ Time Frame: 12 months after surgery ]
    Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off>2 mm, tibiotalartilt >2° and deviation of rotation > 6°) will be correlated to activity, meassured with an activity tracker, recording number of active minutes per day
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title Prevention of Posttraumatic Osteoarthritis After Acute Intraarticular Fractures
Official Title Inhibition of Inflammation for Prevention of Posttraumatic Osteoarthritis After Acute Intraarticular Fractures
Brief Summary

Intra-articular fracture is a very common fracture. The only method to treat these fractures is surgery with plate and screws followed by rehabilitation. Even though the surgeons do their best to restore the anatomy, up to 40 percent of the patients develop osteoarthritis after 10 years. Previous research has shown that immediately after fracture in the joint, the body starts an inflammatory response and activates a series of biomarkers inside the joint space. Some of these biomarkers are believed to break down the cartilage resulting in development of osteoarthritis, despite surgical treatment. Currently it is still unknown, which biomarkers are activated in the joint space, and how we can stop their deleterious action in order to prevent cartilage degradation.

The purpose of this project is to identify the biomarkers in the joint space after an intra-articular ankle fracture and to evaluate how these biomarkers affect the short- and mid-terms clinical outcomes. As secondary outcomes we evaluate how fracture classification and fracture reduction affect clinical outcomes and physical activity after surgery.

Detailed Description

Osteoarthritis (OA) affecting one in eight individuals and is the main reason for chronic pain and disability worldwide. The main cause for OA development is joint-affecting trauma and risk factors have primarily been associated to previous biomechanical treatment. Therefore, the principle of current fracture treatment is anatomical reconstruction of the joint surface combined with functional and adequate aftercare. However, despite correct restoration of anatomy and application of sufficient physiotherapy, the risk of posttraumatic OA remains as high as 40%.

Joint trauma initiates an inflammatory cascade leading to synovial catabolism and cartilage degradation, a fact, which to date has been ignored in standard therapy. Unfortunately, due to the lack of blood supply, cartilage regenerates much less efficient compared to bone. Previous studies suggest that the synovial biochemical milieu may be of decisive importance for chondrocyte and cartilage survival or degeneration. The investigators therefore hypothesize, that protecting cartilage and chondrocyte by inhibiting the post-injury inflammatory cascade, might contribute to durable successful results in fracture therapy. The purpose of this project is to identify the biomarkers in the joint space after an intra-articular ankle fracture and to evaluate how these biomarkers affect the short- and mid-terms clinical outcomes. As secondary outcomes we evaluate how fracture classification and reduction affect clinical outcomes and physical activity after surgery. In specific, we intend to answer the following research questions:

Study 1: Are there differentially regulated biomarkers in joint space in patients with and without an intra-articular ankle fracture?

Study 2: Do the identified biomarkers found in intra-articular ankle fracture correlate with short- and middle term clinical symptoms after surgery?

Study 3: Does fracture classification and fracture reduction effect clinical outcomes and physical activity?

Method

This study is approved by The National Committee on Health Research Ethics (S-20170139) and The Danish Data Protection Agency (17/28505). Patient recruitment is carried out in the Department of Orthopedic Surgery at Odense University Hospital, Svendborg, while biomarker analyses mainly take places in Department of Neurobiology Research.

All patients diagnosed with intra-articular ankle fracture hospitalized in Odense University Hospital, Svendborg will be recruited to this study.

Prior to surgery synovial fluids are collected from the fracture ankle and contralateral ankle of the same patient. The patient is lying in supine position and the disinfection of both ankles will follow our department's guidelines. A 1.5 x 50 mm needle is inserted in the joint line using the anteromedial or anterolateral approach. Once the needle is in the joint space, a volume of 5.0 ml isotonic saline will be injected in the joint place and mixed before retraction. All patients will have antibiotic coverage prior to surgery to minimize the risk of infection. This procedure is mainly performed by two surgeons (TP and HS), who have great experience in this procedure. In case other surgeons collect the sample, X-ray may be used for assistance. Synovial fluid will be collected, transferred in a 10 ml glass, and within 2 hours transported to the Department of Clinical Biochemistry and Pharmacology for centrifugation and storage at minus 80 degrees celsius. At the end of each month all samples will be transferred in dry ice to the Department of Molecular Endocrinology to be stored in liquid nitrogen. Blood samples will also be collected in Ethylenediaminetetraacetic acid (EDTA) glasses for comparison.

For the discrimination between the fracture and the anterolateral healthy joint, a proteomics analysis is used to identify the classical pro-inflammatory cytokines and the cytokines involving in the extracellular breakdown and cartilage degeneration. For that purpose, a custom multi-ELISA Plex including (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF-α), IL-1α, TNF-β, basic fibroblast growth factor (bFGF), IL-1RA), Human matrix metalloproteinase (MMP) 3-Plex Ultra-Sensitive Kit, U-PLEX TGF-β Combo, Aggrecan and CTX-2, will be performed.

The following epidemiological parameters will be recorded: age, sex, body mass index, classification of injury according to Arbeitsgemeinschaft für Osteosynthesefragen (AO) standards, allowed weight bearing, aftercare follows the Odense guidelines with a static walker. All patients will be evaluated at 3 and 12 months post injury according to the following clinical parameters:

Pain (visual analog scale), return to work (days), swelling (measurement of circumference at malleoli (cm)), ankle X-ray, 3D-rotational tomography, 7 days activity tracking and validated scores (the American Orthopedic Foot and Ankle Score (AOFAS), the Foot Function Index - DK (FFI.DK), the Euroqol 5D questionnaire (EQ5D).To reach a power of 80 %, we include 62 patients in our study. Because no previous studies have compared level of pro-inflammatory cytokines with clinical scores, the power estimation is based on a very high standard deviation, loss of follow-up and clinical importance. The investigators plan to perform an interim analysis, when a number of 40 patients is reached.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Whole blood (5.0-20.0 ml) Synovial Fluids (1.0-10.0 ml) from both ankle joints
Sampling Method Non-Probability Sample
Study Population All patients hospitalize in Odense University, Svendborg (31th. Oct. 2017-Jan. 2019) will be screened for eligibility.
Condition
  • Ankle Fractures
  • Intra-Articular Fractures
  • Osteoarthritis
Intervention Not Provided
Study Groups/Cohorts Not Provided
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 Active, not recruiting
Estimated Enrollment
 (submitted: December 5, 2018)
62
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 31, 2022
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Age between 18 and 65 years
  • Existence of an acute fracture involving the ankle (location AO43,AO44) requiring open or closed reduction and internal or external fixation within 14 days
  • Being able to read and understand Danish
  • Informed consent

Exclusion Criteria:

  • Open fractures
  • Associated arterial and nerve injuries
  • Multiple injured patients with an Injury Severity Score >16
  • Primary or secondary infections
  • Injuries associated to a Charcot foot
  • Signs of existing OA on X-ray

    • Others
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Denmark
Removed Location Countries  
 
Administrative Information
NCT Number NCT03769909
Other Study ID Numbers S-20170139
Has Data Monitoring Committee Yes
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: Undecided
Responsible Party University of Southern Denmark
Study Sponsor University of Southern Denmark
Collaborators
  • University of Freiburg
  • Odense University Hospital
  • The Danish Rheumatism Association
  • Hartmanns Fond
  • AP Møller Fond
Investigators
Principal Investigator: Søren Overgaard, Professor The Orthopaedic Research Unit
PRS Account University of Southern Denmark
Verification Date December 2018