<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/NCT03769909</url>
  </required_header>
  <id_info>
    <org_study_id>S-20170139</org_study_id>
    <nct_id>NCT03769909</nct_id>
  </id_info>
  <brief_title>Prevention of Posttraumatic Osteoarthritis After Acute Intraarticular Fractures</brief_title>
  <official_title>Inhibition of Inflammation for Prevention of Posttraumatic Osteoarthritis After Acute Intraarticular Fractures</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southern Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Freiburg</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Odense University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Danish Rheumatism Association</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hartmann Fonden</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>AP Møller Fond</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Southern Denmark</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Intra-articular fracture is a very common fracture. The only method to treat these fractures&#xD;
      is surgery with plate and screws followed by rehabilitation. Even though the surgeons do&#xD;
      their best to restore the anatomy, up to 40 percent of the patients develop osteoarthritis&#xD;
      after 10 years. Previous research has shown that immediately after fracture in the joint, the&#xD;
      body starts an inflammatory response and activates a series of biomarkers inside the joint&#xD;
      space. Some of these biomarkers are believed to break down the cartilage resulting in&#xD;
      development of osteoarthritis, despite surgical treatment. Currently it is still unknown,&#xD;
      which biomarkers are activated in the joint space, and how we can stop their deleterious&#xD;
      action in order to prevent cartilage degradation.&#xD;
&#xD;
      The purpose of this project is to identify the biomarkers in the joint space after an&#xD;
      intra-articular ankle fracture and to evaluate how these biomarkers affect the short- and&#xD;
      mid-terms clinical outcomes. As secondary outcomes we evaluate how fracture classification&#xD;
      and fracture reduction affect clinical outcomes and physical activity after surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Osteoarthritis (OA) affecting one in eight individuals and is the main reason for chronic&#xD;
      pain and disability worldwide. The main cause for OA development is joint-affecting trauma&#xD;
      and risk factors have primarily been associated to previous biomechanical treatment.&#xD;
      Therefore, the principle of current fracture treatment is anatomical reconstruction of the&#xD;
      joint surface combined with functional and adequate aftercare. However, despite correct&#xD;
      restoration of anatomy and application of sufficient physiotherapy, the risk of posttraumatic&#xD;
      OA remains as high as 40%.&#xD;
&#xD;
      Joint trauma initiates an inflammatory cascade leading to synovial catabolism and cartilage&#xD;
      degradation, a fact, which to date has been ignored in standard therapy. Unfortunately, due&#xD;
      to the lack of blood supply, cartilage regenerates much less efficient compared to bone.&#xD;
      Previous studies suggest that the synovial biochemical milieu may be of decisive importance&#xD;
      for chondrocyte and cartilage survival or degeneration. The investigators therefore&#xD;
      hypothesize, that protecting cartilage and chondrocyte by inhibiting the post-injury&#xD;
      inflammatory cascade, might contribute to durable successful results in fracture therapy. The&#xD;
      purpose of this project is to identify the biomarkers in the joint space after an&#xD;
      intra-articular ankle fracture and to evaluate how these biomarkers affect the short- and&#xD;
      mid-terms clinical outcomes. As secondary outcomes we evaluate how fracture classification&#xD;
      and reduction affect clinical outcomes and physical activity after surgery. In specific, we&#xD;
      intend to answer the following research questions:&#xD;
&#xD;
      Study 1: Are there differentially regulated biomarkers in joint space in patients with and&#xD;
      without an intra-articular ankle fracture?&#xD;
&#xD;
      Study 2: Do the identified biomarkers found in intra-articular ankle fracture correlate with&#xD;
      short- and middle term clinical symptoms after surgery?&#xD;
&#xD;
      Study 3: Does fracture classification and fracture reduction effect clinical outcomes and&#xD;
      physical activity?&#xD;
&#xD;
      Method&#xD;
&#xD;
      This study is approved by The National Committee on Health Research Ethics (S-20170139) and&#xD;
      The Danish Data Protection Agency (17/28505). Patient recruitment is carried out in the&#xD;
      Department of Orthopedic Surgery at Odense University Hospital, Svendborg, while biomarker&#xD;
      analyses mainly take places in Department of Neurobiology Research.&#xD;
&#xD;
      All patients diagnosed with intra-articular ankle fracture hospitalized in Odense University&#xD;
      Hospital, Svendborg will be recruited to this study.&#xD;
&#xD;
      Prior to surgery synovial fluids are collected from the fracture ankle and contralateral&#xD;
      ankle of the same patient. The patient is lying in supine position and the disinfection of&#xD;
      both ankles will follow our department's guidelines. A 1.5 x 50 mm needle is inserted in the&#xD;
      joint line using the anteromedial or anterolateral approach. Once the needle is in the joint&#xD;
      space, a volume of 5.0 ml isotonic saline will be injected in the joint place and mixed&#xD;
      before retraction. All patients will have antibiotic coverage prior to surgery to minimize&#xD;
      the risk of infection. This procedure is mainly performed by two surgeons (TP and HS), who&#xD;
      have great experience in this procedure. In case other surgeons collect the sample, X-ray may&#xD;
      be used for assistance. Synovial fluid will be collected, transferred in a 10 ml glass, and&#xD;
      within 2 hours transported to the Department of Clinical Biochemistry and Pharmacology for&#xD;
      centrifugation and storage at minus 80 degrees celsius. At the end of each month all samples&#xD;
      will be transferred in dry ice to the Department of Molecular Endocrinology to be stored in&#xD;
      liquid nitrogen. Blood samples will also be collected in Ethylenediaminetetraacetic acid&#xD;
      (EDTA) glasses for comparison.&#xD;
&#xD;
      For the discrimination between the fracture and the anterolateral healthy joint, a proteomics&#xD;
      analysis is used to identify the classical pro-inflammatory cytokines and the cytokines&#xD;
      involving in the extracellular breakdown and cartilage degeneration. For that purpose, a&#xD;
      custom multi-ELISA Plex including (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70,&#xD;
      IL-13, tumor necrosis factor (TNF-α), IL-1α, TNF-β, basic fibroblast growth factor (bFGF),&#xD;
      IL-1RA), Human matrix metalloproteinase (MMP) 3-Plex Ultra-Sensitive Kit, U-PLEX TGF-β Combo,&#xD;
      Aggrecan and CTX-2, will be performed.&#xD;
&#xD;
      The following epidemiological parameters will be recorded: age, sex, body mass index,&#xD;
      classification of injury according to Arbeitsgemeinschaft für Osteosynthesefragen (AO)&#xD;
      standards, allowed weight bearing, aftercare follows the Odense guidelines with a static&#xD;
      walker. All patients will be evaluated at 3 and 12 months post injury according to the&#xD;
      following clinical parameters:&#xD;
&#xD;
      Pain (visual analog scale), return to work (days), swelling (measurement of circumference at&#xD;
      malleoli (cm)), ankle X-ray, 3D-rotational tomography, 7 days activity tracking and validated&#xD;
      scores (the American Orthopedic Foot and Ankle Score (AOFAS), the Foot Function Index - DK&#xD;
      (FFI.DK), the Euroqol 5D questionnaire (EQ5D).To reach a power of 80 %, we include 62&#xD;
      patients in our study. Because no previous studies have compared level of pro-inflammatory&#xD;
      cytokines with clinical scores, the power estimation is based on a very high standard&#xD;
      deviation, loss of follow-up and clinical importance. The investigators plan to perform an&#xD;
      interim analysis, when a number of 40 patients is reached.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">October 31, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Concentration of cytokines in fracture ankle versus non-fracture ankle</measure>
    <time_frame>During surgery</time_frame>
    <description>Multiplex ELISA kits will be use to identify cytokines in both ankles. Cytokines with significant difference will be identified.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (AOFAS)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (FFI.DK)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (EQ5D-5L)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of EQ5D-5L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (VAS-score)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (Swelling)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (FFI.DK)</measure>
    <time_frame>3 months after surgery</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (EQ5D-5L)</measure>
    <time_frame>3 months after surgery</time_frame>
    <description>The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of EQ5D-5L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (VAS-score)</measure>
    <time_frame>3 months after surgery</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines (identified in primary outcome 1) correlation with clinical outcomes (Swelling)</measure>
    <time_frame>3 months after surgery</time_frame>
    <description>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</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation between fracture classification and clinical outcomes (AOFAS)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture classification and clinical outcomes (FFI.DK)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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)</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture classification and clinical outcomes (EQ5D-5L)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to the scores of EQ5D-5L</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture classification and clinical outcomes (VAS-score)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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)</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture classification and clinical outcomes (Swelling)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture classification and clinical outcomes (activity)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture reduction and clinical outcomes (AOFAS)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off&gt;2 mm, tibiotalartilt &gt;2° and deviation of rotation &gt; 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</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture reduction and clinical outcomes (FFI.DK)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off&gt;2 mm, tibiotalartilt &gt;2° and deviation of rotation &gt; 6°) will be correlated to the scores of functional foot score (FFI.DK)</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture reduction and clinical outcomes (EQ5D-5L)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off&gt;2 mm, tibiotalartilt &gt;2° and deviation of rotation &gt; 6°) will be correlated to the scores of EQ5D-5L</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture reduction and clinical outcomes (VAS-score)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off&gt;2 mm, tibiotalartilt &gt;2° and deviation of rotation &gt; 6°) will be correlated to the scores of VAS-score, a Visual Analog Scale.VAS 0 (best) - 10 (worst)</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture reduction and clinical outcomes (Swelling)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off&gt;2 mm, tibiotalartilt &gt;2° and deviation of rotation &gt; 6°) will be correlated to swelling, difference in fracture and non-fracture ankle, measured in millimeters</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between fracture reduction and clinical outcomes (activity)</measure>
    <time_frame>12 months after surgery</time_frame>
    <description>Fracture reduction with conventional X-ray and 3D-rotation CT (e.g. step-off&gt;2 mm, tibiotalartilt &gt;2° and deviation of rotation &gt; 6°) will be correlated to activity, meassured with an activity tracker, recording number of active minutes per day</description>
  </other_outcome>
  <enrollment type="Anticipated">62</enrollment>
  <condition>Ankle Fractures</condition>
  <condition>Intra-Articular Fractures</condition>
  <condition>Osteoarthritis</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood (5.0-20.0 ml) Synovial Fluids (1.0-10.0 ml) from both ankle joints&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        All patients hospitalize in Odense University, Svendborg (31th. Oct. 2017-Jan. 2019) will&#xD;
        be screened for eligibility.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 18 and 65 years&#xD;
&#xD;
          -  Existence of an acute fracture involving the ankle (location AO43,AO44) requiring open&#xD;
             or closed reduction and internal or external fixation within 14 days&#xD;
&#xD;
          -  Being able to read and understand Danish&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Open fractures&#xD;
&#xD;
          -  Associated arterial and nerve injuries&#xD;
&#xD;
          -  Multiple injured patients with an Injury Severity Score &gt;16&#xD;
&#xD;
          -  Primary or secondary infections&#xD;
&#xD;
          -  Injuries associated to a Charcot foot&#xD;
&#xD;
          -  Signs of existing OA on X-ray&#xD;
&#xD;
               -  Others&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Søren Overgaard, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Orthopaedic Research Unit</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Orthopaedic Research Unit</name>
      <address>
        <city>Odense</city>
        <zip>5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>November 9, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>December 5, 2018</last_update_submitted>
  <last_update_submitted_qc>December 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 10, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>PTOA</keyword>
  <keyword>Osteoarthritis</keyword>
  <keyword>Intra-Articular Fractures</keyword>
  <keyword>Ankle Fractures</keyword>
  <keyword>Cytokines</keyword>
  <keyword>Biomarkers</keyword>
  <keyword>Inflammation</keyword>
  <keyword>Pro-inflammatory</keyword>
  <keyword>Cartilage</keyword>
  <keyword>Fracture</keyword>
  <keyword>Joint Injury</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Fractures, Bone</mesh_term>
    <mesh_term>Ankle Fractures</mesh_term>
    <mesh_term>Intra-Articular Fractures</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03769909
org study id: S-20170139
nct id: NCT03769909
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
observational model: Cohort
time perspective: Prospective
measure: Concentration of cytokines in fracture ankle versus non-fracture ankle
time frame: During surgery
description: Multiplex ELISA kits will be use to identify cytokines in both ankles. Cytokines with significant difference will be identified.
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (AOFAS)
time frame: 12 months after surgery
description: 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
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (FFI.DK)
time frame: 12 months after surgery
description: 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
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (EQ5D-5L)
time frame: 12 months after surgery
description: The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of EQ5D-5L
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (VAS-score)
time frame: 12 months after surgery
description: 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)
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (Swelling)
time frame: 12 months after surgery
description: 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
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (FFI.DK)
time frame: 3 months after surgery
description: 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
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (EQ5D-5L)
time frame: 3 months after surgery
description: The identified cytokines in the fracture ankle (fracture non fracture ratio above 2.0) will be coupled to the scores of EQ5D-5L
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (VAS-score)
time frame: 3 months after surgery
description: 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)
measure: Cytokines (identified in primary outcome 1) correlation with clinical outcomes (Swelling)
time frame: 3 months after surgery
description: 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
measure: Correlation between fracture classification and clinical outcomes (AOFAS)
time frame: 12 months after surgery
description: 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
measure: Correlation between fracture classification and clinical outcomes (FFI.DK)
time frame: 12 months after surgery
description: 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)
measure: Correlation between fracture classification and clinical outcomes (EQ5D-5L)
time frame: 12 months after surgery
description: Fracture classification on pre-operative X-ray (AO classification, 43A, 43B, 43C, 44A, 44B,44C), will be correlated to the scores of EQ5D-5L
measure: Correlation between fracture classification and clinical outcomes (VAS-score)
time frame: 12 months after surgery
description: 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)
measure: Correlation between fracture classification and clinical outcomes (Swelling)
time frame: 12 months after surgery
description: 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
measure: Correlation between fracture classification and clinical outcomes (activity)
time frame: 12 months after surgery
description: 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
measure: Correlation between fracture reduction and clinical outcomes (AOFAS)
time frame: 12 months after surgery
description: 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
measure: Correlation between fracture reduction and clinical outcomes (FFI.DK)
time frame: 12 months after surgery
description: 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)
measure: Correlation between fracture reduction and clinical outcomes (EQ5D-5L)
time frame: 12 months after surgery
description: 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
measure: Correlation between fracture reduction and clinical outcomes (VAS-score)
time frame: 12 months after surgery
description: 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)
measure: Correlation between fracture reduction and clinical outcomes (Swelling)
time frame: 12 months after surgery
description: 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
measure: Correlation between fracture reduction and clinical outcomes (activity)
time frame: 12 months after surgery
description: 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
Whole blood (5.0-20.0 ml) Synovial Fluids (1.0-10.0 ml) from both ankle joints
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Søren Overgaard, Professor
role: Principal Investigator
affiliation: The Orthopaedic Research Unit
facility: 
country: Denmark
responsible party type: Sponsor
mesh term: Osteoarthritis
mesh term: Fractures, Bone
mesh term: Ankle Fractures
mesh term: Intra-Articular Fractures
sharing ipd: Undecided