<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/NCT03774121</url>
  </required_header>
  <id_info>
    <org_study_id>CryoKnee01</org_study_id>
    <nct_id>NCT03774121</nct_id>
  </id_info>
  <brief_title>Cryoneurolysis for the Management of Chronic Pain in Patients With Knee Osteoarthritis</brief_title>
  <official_title>Cryoneurolysis for the Management of Chronic Pain in Patients With Knee Osteoarthritis; A Randomized Controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital of South West Jutland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Odense University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital of South West Jutland</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pain is the principal symptom in knee osteoarthritis (OA) and results in a considerable&#xD;
      amount of years lived with disability, emotional distress and has significant socioeconomic&#xD;
      consequences. Conservative treatment options, such as exercise, often fail to provide&#xD;
      long-term pain relief and alternatively patients may be subjected to total knee arthroplasty.&#xD;
      More than 20% of these patients experience persistent and unchanged pain post-surgery. Novel&#xD;
      advances in the field of cryoneurolysis applies low temperatures to disrupt nerve signaling&#xD;
      at the painful area and a recent study showed that it was possible to target the peripheral&#xD;
      nerves in the knee and provide significant pain relief in patients with knee OA. This could&#xD;
      potentially improve the efficacy of other therapies such as exercise, delaying or perhaps&#xD;
      avoiding surgical intervention and improving quality of life in OA patients considerably.&#xD;
      Further prospective randomized controlled studies are needed to confirm the effects of&#xD;
      cryoneurolysis treatment in patients with knee OA. The primary objective of the current&#xD;
      project is to determine the effectiveness of cryoneurolysis in its ability to decrease pain&#xD;
      in patients with knee OA. The secondary objective is to evaluate the safety and effectiveness&#xD;
      of cryoneurolysis in its ability to improve outcomes in the GLA:D program to potentially&#xD;
      delay or avoid surgical intervention. 90 individuals with knee OA in the knee will be&#xD;
      randomly allocated in either a cryoneurolysis intervention group or a sham group. Both groups&#xD;
      will be assessed at baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24&#xD;
      month follow-up. The patients, therapists and data-manager will be blinded to the allocation.&#xD;
      The primary outcome will be VAS knee pain intensity score, measured post cryoneurolysis&#xD;
      treatment. Secondary outcome measures include functional performance, PRO-data (KOOS, EQ5D),&#xD;
      analgesic use, a socio-economic evaluation and adverse effects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND Pain is the principal symptom in knee osteoarthritis (OA) and results in a&#xD;
      considerable amount of years lived with disability, emotional distress and has significant&#xD;
      socioeconomic consequences. Knee OA in particular, has a high prevalence rate compared to&#xD;
      other types of OA, and is also present in the younger working age population. The treatment&#xD;
      of knee OA typically focuses on pain relief, however the effects of current conservative&#xD;
      treatment options remain small to moderate and most are associated with side effects. In many&#xD;
      cases patients alternatively may be subjected to partial/total knee arthroplasty (TKA). TKA&#xD;
      is considered to be an effective treatment for end-stage knee osteoarthritis however more&#xD;
      than 20% of patients receiving TKA, experience persistent and unchanged pain post-surgery.&#xD;
      Reviewing these results, focus should be on low-risk, minimally invasive therapies. Novel&#xD;
      advances in the field of cryoneurolysis are in that respect promising. Cryoneurolysis has&#xD;
      made it possible to apply low temperatures to a target percutaneous peripheral nerve, causing&#xD;
      Wallerian degeneration. This has been shown to provide pain relief in a variety of chronic&#xD;
      pain conditions. Recently, Radnovich et al. (2017) targeted the genicular nerves to reduce&#xD;
      pain in patients with knee OA. The authors reported significant pain relief in patients with&#xD;
      knee OA for up to 150 days. The authors reported expected adverse effects, that were&#xD;
      transient, with mild severity, requiring no further intervention. These results might suggest&#xD;
      that cryoneurolysis treatment is a safe procedure, that may reduce both pain and symptoms in&#xD;
      patients with knee OA. Further prospective randomized controlled studies, with adequate power&#xD;
      are needed to confirm the efficacy and safety of cryoneurolysis treatment in patients with&#xD;
      knee OA.&#xD;
&#xD;
      In Denmark, a neuromuscular exercise program (GLA:D) has been implemented, for the treatment&#xD;
      of knee and hip OA in clinical practice. Recent studies show that exercise reduce pain and&#xD;
      improve function in people with knee or hip OA. Despite of these reports the beneficial&#xD;
      effects remains moderate with difficulties in maintaining these effects at long-term&#xD;
      follow-up and includes a significant discontinuation rate for patients reporting high pain&#xD;
      levels. In this line, pain and muscle weakness, among others, have been reported to be major&#xD;
      barriers for physical exercise. The application of cryoneurolysis treatment as an effective&#xD;
      pain reducing treatment prior to a standardized exercise program could perhaps provide&#xD;
      significant pain relief, resulting in improved adherence, exercise effectiveness and&#xD;
      long-term benefits of both therapies.&#xD;
&#xD;
      The primary objective of the current project is to determine the effectiveness of&#xD;
      cryoneurolysis in its proposed ability to decrease pain in patients with knee osteoarthritis.&#xD;
      The secondary objective is to evaluate the safety and effectiveness of cryoneurolysis in its&#xD;
      ability to improve outcomes in the GLA:D program to potentially delay or avoid surgical&#xD;
      intervention.&#xD;
&#xD;
      We hypothesize that cryoneurolysis in combination with GLA:D will be a safe and effective&#xD;
      therapeutic option with few side effects to reduce pain in patients with knee osteoarthritis&#xD;
      and may post pone surgical intervention.&#xD;
&#xD;
      TRIAL DESIGN This study is a randomized, controlled, trial (RCT) designed to test the&#xD;
      efficacy of cryoneurolysis treatment in patients with knee osteoarthritis followed by a&#xD;
      neuromuscular exercise program (GLA:D). The patients will be randomly allocated in either a&#xD;
      cryoneurolysis intervention group (CRYO) or a sham group (SHAM) and will be assessed at&#xD;
      baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up. The&#xD;
      tests will include both patient-reported outcomes (PRO) and objective functional&#xD;
      measurements.&#xD;
&#xD;
      RECRUITMENT AND SAMPLE SIZE Patients with pain and knee OA confirmed by radiography, are&#xD;
      referred to GLA:D by their general practitioner prior to assessment of surgery eligibility at&#xD;
      the hospital. The current project will recruit these patients in collaboration with selected&#xD;
      general practitioners in the Region of Southern Denmark. According the Region of Southern&#xD;
      Denmark, an average of 270 patients participate in the GLA:D program every year. Based on&#xD;
      this estimation and considering the eligibility criteria to participate in the current&#xD;
      project, recruitment will continue for up to 1 year.&#xD;
&#xD;
      The planned number of trial participants is based on the assumed superiority of the&#xD;
      cryoneurolysis treatment over control. Estimating the sample size for a two-sample means test&#xD;
      with a level of significance at 0.05, assuming a common standard deviation (SD) of 30 in VAS&#xD;
      pain intensity scores indicates that for the intention-to-treat (ITT) population, 74&#xD;
      individuals is required to obtain a power of at least 80% to establish a minimal clinically&#xD;
      significant difference (MCSD) of 20 in VAS pain scores. The MCSD and common standard&#xD;
      deviation is based on previous findings with a similar patient group and intervention. With&#xD;
      an expected drop-out rate of 20%, a total of 94 individuals will be included in the project,&#xD;
      47 in each group.&#xD;
&#xD;
      ALLOCATION AND BLINDING Randomization will be performed as computer-generated block&#xD;
      randomization with a 1:1 allocation ratio using random block sizes of 2, 4 and 6 in either&#xD;
      group CRYO or group SHAM. The randomization restrictions will not be disclosed to ensure&#xD;
      allocation concealment and the sequence will be performed by an external co-investigator.&#xD;
&#xD;
      To account for the placebo effect and reduce the risk of bias, the patients, therapists and&#xD;
      data-manager will be blinded to the allocation. Blinding will be assured using a sham trial&#xD;
      that includes the same procedures as cryoneurolysis treatment but without any freezing&#xD;
      temperatures. Thus, visible marks as a result of the procedures in both groups will be&#xD;
      similar.&#xD;
&#xD;
      INTERVENTIONS Diagnostic nerve block. All patients reporting a decrease of ≥ 50 % in VAS pain&#xD;
      scores at least 15 min after a diagnostic nerve block of the genicular nerves.&#xD;
&#xD;
      Cryoneurolysis. The current project involves the novel application and test of&#xD;
      cryoneurolysis, in the treatment of OA related pain. The rationale behind this method, is&#xD;
      based on previous reports showing that low temperature conditions can alter nerve function.&#xD;
      This technology allows for reversible destruction of nerves, also known as Wallerian&#xD;
      degeneration, that prevents nerve signaling and potentially alleviate pain and motor&#xD;
      dysfunction in a number of medical conditions. A probe will be inserted percutaneously at the&#xD;
      target anterior femoral cutaneous nerve and infrapatellar branch of the saphenous nerve&#xD;
      guided by ultrasound visualization to accurately determine the location of the nerve and to&#xD;
      account for adjacent neurovascular structures and variations in anatomical structures. The&#xD;
      target locations are drawn directly on the patients' skin prior to treatment along which a&#xD;
      dose of local anesthetic will be injected subcutaneously before treatment. Cryoneurolysis at&#xD;
      each target site requires 2-4 freeze cycles with a duration of 3 mins, and with thaw cycles&#xD;
      between 20-40 seconds. A temperature probe will be inserted adjacent to the target nerve and&#xD;
      cryoneurolysis-probe to ensure a controlled cooling effect and to control nerve damage. The&#xD;
      sham intervention includes a similar procedure but using a sham probe.&#xD;
&#xD;
      GLA:D. SHAM and CRYO will both participate in the GLA:D program, which is a standard&#xD;
      education and exercise program for patients with osteoarthritis in Denmark. The program is&#xD;
      performed in groups and with the supervision of an experienced physiotherapist specialized in&#xD;
      training of musculoskeletal disorders and has a duration of 8 weeks.&#xD;
&#xD;
      STATISTICAL METHODS The treatment groups will be examined for comparability based on baseline&#xD;
      demographic and prognostic measures. An Intention-To-Treat (ITT) analysis will be used for&#xD;
      all allocated patients and a mixed effects model will be used on the continuous outcome&#xD;
      measures to determine the effects of cryoneurolysis treatment from baseline to post treatment&#xD;
      and follow-ups [Between groups factor: CRYO vs SHAM, within groups factor: time]. The model&#xD;
      will use robust estimation methods to account for outliers. Finally, a multiple imputation&#xD;
      approach will be used in case of missing data. All P-values &lt; 0.05 will be considered&#xD;
      statistically significant.&#xD;
&#xD;
      ETHICS AND SIGNIFICANCE The project will be conducted according to the declaration of&#xD;
      Helsinki and will be registered in ClinicalTrials.gov. The Project has been approved by the&#xD;
      Regional Committee on Health Research Ethics for Southern Denmark (S-20180089).&#xD;
&#xD;
      Cryoneurolysis could potentially provide an effective, safe and minimally invasive option to&#xD;
      treat pain in OA patients. The potential benefits include increased functional capacity and&#xD;
      quality of life as a result of significant pain relief and improved benefits of physical&#xD;
      exercise, ultimately postponing or making surgical intervention unnecessary. Finally, an&#xD;
      important perspective, is the application of cryoneurolysis in other areas - such as managing&#xD;
      pain, related to surgery, to improve rehabilitation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 26, 2019</start_date>
  <completion_date type="Actual">March 1, 2023</completion_date>
  <primary_completion_date type="Actual">March 1, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in NRS knee pain intensity score</measure>
    <time_frame>Change in NRS pain score, between baseline and two weeks post surgery</time_frame>
    <description>NRS consists of a numerical, from 0 to 10, anchored by two verbal descriptors, &quot;no pain&quot; for the score of zero and &quot;worst pain imaginable&quot; for the score of 10. NRS is a self-reported tool where the respondent is asked their current pain intensity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Pain location</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>Pain location as drawn by the patient.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Functional Performance Evaluated by the 30 second chair-stand test.</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>The outcome is the total number of complete chair stands performed for the duration of the task (one chair stand represents a stand followed by a sit movement).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in use of Analgesics</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>Use of analgesics from medical records</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Adverse effects</measure>
    <time_frame>Reported adverse effects 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>Pre-defined and unexpected adverse effects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pain type</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>Change in pain type using prespecified pain definitions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Functional Performance Evaluated by the 40m fast-paced walk test.</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>The outcome is expressed as speed. i.e. walking distance (40m) divided by the time to perform the task (s).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Functional Performance Evaluated by the 9 step stair test.</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>The outcome is the total time to perform the task (s).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Functional Performance Evaluated by Maximum Voluntary Contraction</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>As measured in moment force of the knee extensors (Nm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Quality of Life using the Quality of Life questionnaire (EQ5D)</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>EQ5D consists of 5 subscales; Mobility, Self-care, Usual activities, Pain/Discomfort and Anxiety / depression. An health state score is obtained based on the responses from 1-5 in each subscale, from which a single index value is calculated representing patients' overall health state.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in self-rated health using the Quality of Life questionnaire (EQ5D)</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>EQ5D includes a so called EQ VAS score which is the patients' self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled &quot;the best health you can imagine&quot; and &quot;the worst health you can imagine&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the subscale &quot;Pain&quot; using the Knee injury and Osteoarthritis Score (KOOS score)</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the subscale &quot;other Symptoms&quot; using the Knee injury and Osteoarthritis Score (KOOS score)</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the subscale &quot;Function in daily living (ADL)&quot; using the Knee injury and Osteoarthritis Score (KOOS score)</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the subscale &quot;Function in sport and recreation (Sport/Rec)&quot; using the Knee injury and Osteoarthritis Score (KOOS score)</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the subscale &quot;Knee related Quality of Life (QoL)&quot; using the Knee injury and Osteoarthritis Score (KOOS score)</measure>
    <time_frame>Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.</time_frame>
    <description>KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">87</enrollment>
  <condition>Chronic Pain</condition>
  <condition>Osteoarthritis, Knee</condition>
  <arm_group>
    <arm_group_label>CRYO</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjected to Cryoneurolysis treatment and Neuromuscular training (GLA:D).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SHAM</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Subjected to similar procedures as CRYO, but without freezing temperatures. Subjected to Neuromuscular training (GLA:D).</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Cryoneurolysis</intervention_name>
    <description>A cryoprobe will be inserted percutaneously and freeze the target nerves (infrapatellar branch of the saphenous nerve &amp; anterior femoral cutaneous nerve) guided by ultrasound visualization.</description>
    <arm_group_label>CRYO</arm_group_label>
    <other_name>Cryoablation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Neuromuscular exercise (GLA:D)</intervention_name>
    <description>The GLA:D program, is a standard education and exercise program for patients with osteoarthritis in Denmark. The program is performed in groups and with the supervision of an experienced physiotherapist specialized in training of musculoskeletal disorders.</description>
    <arm_group_label>CRYO</arm_group_label>
    <arm_group_label>SHAM</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham</intervention_name>
    <description>The sham intervention includes a similar procedure but without freezing temperatures.</description>
    <arm_group_label>SHAM</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Referred to GLA:D by a physician.&#xD;
&#xD;
          -  Age ≥ 18y&#xD;
&#xD;
          -  Chronic knee pain for a minimum duration of 6 months.&#xD;
&#xD;
          -  Pain intensity ≥ 40mm on a 100mm visual analogue scale (VAS).&#xD;
&#xD;
          -  Radiographic confirmation of osteoarthritis; Grade 2-4 changes according to the&#xD;
             Kellgren Lawrence classification system&#xD;
&#xD;
          -  A decrease of ≥ 50 % in VAS scores with diagnostic genicular nerve block.&#xD;
&#xD;
          -  Written and oral understanding of Danish.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of systemic inflammatory conditions such as rheumatoid arthritis.&#xD;
&#xD;
          -  Previous recipient of cryoneurolysis for the knee.&#xD;
&#xD;
          -  Use of hyaluronic acid within the previous 30 days.&#xD;
&#xD;
          -  Injection of corticosteroid within the previous 3 months.&#xD;
&#xD;
          -  Clinical significant structural abnormities affecting locomotion and knee function&#xD;
             aside from osteoarthritis and which might cause chronic knee pain.&#xD;
&#xD;
          -  Body mass index ≥ 18 and ≤ 40 kg/m&#xD;
&#xD;
          -  In treatment for other pain conditions.&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Coagulopathy&#xD;
&#xD;
          -  Uncontrolled serious disease (cancer, diabetes, etc.)&#xD;
&#xD;
          -  Disease associated with reactions to cold, such as cryoglobulinemia, cold urticarial&#xD;
             and Renaud's syndrome.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bibi (Valgerdur) Gram, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Hospital of South West Jutland</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Carsten Kock-Jensen, MD</last_name>
    <role>Study Director</role>
    <affiliation>Hospital of South West Jutland</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Niels-Peter B Nielsen, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital of South West Jutland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital of Southwest Jutland</name>
      <address>
        <city>Esbjerg</city>
        <state>Region Of Southern Denmark</state>
        <zip>6700</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>SUNDERLAND S. A classification of peripheral nerve injuries producing loss of function. Brain. 1951 Dec;74(4):491-516. doi: 10.1093/brain/74.4.491. No abstract available.</citation>
    <PMID>14895767</PMID>
  </reference>
  <reference>
    <citation>Ilfeld BM, Preciado J, Trescot AM. Novel cryoneurolysis device for the treatment of sensory and motor peripheral nerves. Expert Rev Med Devices. 2016 Aug;13(8):713-25. doi: 10.1080/17434440.2016.1204229. Epub 2016 Jul 13.</citation>
    <PMID>27333989</PMID>
  </reference>
  <reference>
    <citation>Radnovich R, Scott D, Patel AT, Olson R, Dasa V, Segal N, Lane NE, Shrock K, Naranjo J, Darr K, Surowitz R, Choo J, Valadie A, Harrell R, Wei N, Metyas S. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. Osteoarthritis Cartilage. 2017 Aug;25(8):1247-1256. doi: 10.1016/j.joca.2017.03.006. Epub 2017 Mar 20.</citation>
    <PMID>28336454</PMID>
  </reference>
  <reference>
    <citation>Trescot AM. Cryoanalgesia in interventional pain management. Pain Physician. 2003 Jul;6(3):345-60.</citation>
    <PMID>16880882</PMID>
  </reference>
  <reference>
    <citation>Skou ST, Roos EM. Good Life with osteoArthritis in Denmark (GLA:D): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide. BMC Musculoskelet Disord. 2017 Feb 7;18(1):72. doi: 10.1186/s12891-017-1439-y.</citation>
    <PMID>28173795</PMID>
  </reference>
  <reference>
    <citation>Dasa V, Lensing G, Parsons M, Harris J, Volaufova J, Bliss R. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. Knee. 2016 Jun;23(3):523-8. doi: 10.1016/j.knee.2016.01.011. Epub 2016 Feb 10.</citation>
    <PMID>26875052</PMID>
  </reference>
  <reference>
    <citation>Lewis GN, Rice DA, McNair PJ, Kluger M. Predictors of persistent pain after total knee arthroplasty: a systematic review and meta-analysis. Br J Anaesth. 2015 Apr;114(4):551-61. doi: 10.1093/bja/aeu441. Epub 2014 Dec 26.</citation>
    <PMID>25542191</PMID>
  </reference>
  <reference>
    <citation>O'Brien T, Breivik H. The impact of chronic pain-European patients' perspective over 12 months. Scand J Pain. 2012 Jan 1;3(1):23-29. doi: 10.1016/j.sjpain.2011.11.004.</citation>
    <PMID>29913762</PMID>
  </reference>
  <reference>
    <citation>Ageberg E, Link A, Roos EM. Feasibility of neuromuscular training in patients with severe hip or knee OA: the individualized goal-based NEMEX-TJR training program. BMC Musculoskelet Disord. 2010 Jun 17;11:126. doi: 10.1186/1471-2474-11-126.</citation>
    <PMID>20565735</PMID>
  </reference>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 12, 2018</study_first_posted>
  <last_update_submitted>April 21, 2023</last_update_submitted>
  <last_update_submitted_qc>April 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 24, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital of South West Jutland</investigator_affiliation>
    <investigator_full_name>Niels-Peter Brøchner Nielsen, PhD</investigator_full_name>
    <investigator_title>Post doc, Research employee</investigator_title>
  </responsible_party>
  <keyword>Cryoneurolysis</keyword>
  <keyword>Exercise</keyword>
  <keyword>Pain</keyword>
  <keyword>Physical capacity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Osteoarthritis, Knee</mesh_term>
    <mesh_term>Chronic Pain</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/NCT03774121
org study id: CryoKnee01
nct id: NCT03774121
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
Pain is the principal symptom in knee osteoarthritis (OA) and results in a considerable
      amount of years lived with disability, emotional distress and has significant socioeconomic
      consequences. Conservative treatment options, such as exercise, often fail to provide
      long-term pain relief and alternatively patients may be subjected to total knee arthroplasty.
      More than 20% of these patients experience persistent and unchanged pain post-surgery. Novel
      advances in the field of cryoneurolysis applies low temperatures to disrupt nerve signaling
      at the painful area and a recent study showed that it was possible to target the peripheral
      nerves in the knee and provide significant pain relief in patients with knee OA. This could
      potentially improve the efficacy of other therapies such as exercise, delaying or perhaps
      avoiding surgical intervention and improving quality of life in OA patients considerably.
      Further prospective randomized controlled studies are needed to confirm the effects of
      cryoneurolysis treatment in patients with knee OA. The primary objective of the current
      project is to determine the effectiveness of cryoneurolysis in its ability to decrease pain
      in patients with knee OA. The secondary objective is to evaluate the safety and effectiveness
      of cryoneurolysis in its ability to improve outcomes in the GLA:D program to potentially
      delay or avoid surgical intervention. 90 individuals with knee OA in the knee will be
      randomly allocated in either a cryoneurolysis intervention group or a sham group. Both groups
      will be assessed at baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24
      month follow-up. The patients, therapists and data-manager will be blinded to the allocation.
      The primary outcome will be VAS knee pain intensity score, measured post cryoneurolysis
      treatment. Secondary outcome measures include functional performance, PRO-data (KOOS, EQ5D),
      analgesic use, a socio-economic evaluation and adverse effects.
BACKGROUND Pain is the principal symptom in knee osteoarthritis (OA) and results in a
      considerable amount of years lived with disability, emotional distress and has significant
      socioeconomic consequences. Knee OA in particular, has a high prevalence rate compared to
      other types of OA, and is also present in the younger working age population. The treatment
      of knee OA typically focuses on pain relief, however the effects of current conservative
      treatment options remain small to moderate and most are associated with side effects. In many
      cases patients alternatively may be subjected to partial/total knee arthroplasty (TKA). TKA
      is considered to be an effective treatment for end-stage knee osteoarthritis however more
      than 20% of patients receiving TKA, experience persistent and unchanged pain post-surgery.
      Reviewing these results, focus should be on low-risk, minimally invasive therapies. Novel
      advances in the field of cryoneurolysis are in that respect promising. Cryoneurolysis has
      made it possible to apply low temperatures to a target percutaneous peripheral nerve, causing
      Wallerian degeneration. This has been shown to provide pain relief in a variety of chronic
      pain conditions. Recently, Radnovich et al. (2017) targeted the genicular nerves to reduce
      pain in patients with knee OA. The authors reported significant pain relief in patients with
      knee OA for up to 150 days. The authors reported expected adverse effects, that were
      transient, with mild severity, requiring no further intervention. These results might suggest
      that cryoneurolysis treatment is a safe procedure, that may reduce both pain and symptoms in
      patients with knee OA. Further prospective randomized controlled studies, with adequate power
      are needed to confirm the efficacy and safety of cryoneurolysis treatment in patients with
      knee OA.

      In Denmark, a neuromuscular exercise program (GLA:D) has been implemented, for the treatment
      of knee and hip OA in clinical practice. Recent studies show that exercise reduce pain and
      improve function in people with knee or hip OA. Despite of these reports the beneficial
      effects remains moderate with difficulties in maintaining these effects at long-term
      follow-up and includes a significant discontinuation rate for patients reporting high pain
      levels. In this line, pain and muscle weakness, among others, have been reported to be major
      barriers for physical exercise. The application of cryoneurolysis treatment as an effective
      pain reducing treatment prior to a standardized exercise program could perhaps provide
      significant pain relief, resulting in improved adherence, exercise effectiveness and
      long-term benefits of both therapies.

      The primary objective of the current project is to determine the effectiveness of
      cryoneurolysis in its proposed ability to decrease pain in patients with knee osteoarthritis.
      The secondary objective is to evaluate the safety and effectiveness of cryoneurolysis in its
      ability to improve outcomes in the GLA:D program to potentially delay or avoid surgical
      intervention.

      We hypothesize that cryoneurolysis in combination with GLA:D will be a safe and effective
      therapeutic option with few side effects to reduce pain in patients with knee osteoarthritis
      and may post pone surgical intervention.

      TRIAL DESIGN This study is a randomized, controlled, trial (RCT) designed to test the
      efficacy of cryoneurolysis treatment in patients with knee osteoarthritis followed by a
      neuromuscular exercise program (GLA:D). The patients will be randomly allocated in either a
      cryoneurolysis intervention group (CRYO) or a sham group (SHAM) and will be assessed at
      baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up. The
      tests will include both patient-reported outcomes (PRO) and objective functional
      measurements.

      RECRUITMENT AND SAMPLE SIZE Patients with pain and knee OA confirmed by radiography, are
      referred to GLA:D by their general practitioner prior to assessment of surgery eligibility at
      the hospital. The current project will recruit these patients in collaboration with selected
      general practitioners in the Region of Southern Denmark. According the Region of Southern
      Denmark, an average of 270 patients participate in the GLA:D program every year. Based on
      this estimation and considering the eligibility criteria to participate in the current
      project, recruitment will continue for up to 1 year.

      The planned number of trial participants is based on the assumed superiority of the
      cryoneurolysis treatment over control. Estimating the sample size for a two-sample means test
      with a level of significance at 0.05, assuming a common standard deviation (SD) of 30 in VAS
      pain intensity scores indicates that for the intention-to-treat (ITT) population, 74
      individuals is required to obtain a power of at least 80% to establish a minimal clinically
      significant difference (MCSD) of 20 in VAS pain scores. The MCSD and common standard
      deviation is based on previous findings with a similar patient group and intervention. With
      an expected drop-out rate of 20%, a total of 94 individuals will be included in the project,
      47 in each group.

      ALLOCATION AND BLINDING Randomization will be performed as computer-generated block
      randomization with a 1:1 allocation ratio using random block sizes of 2, 4 and 6 in either
      group CRYO or group SHAM. The randomization restrictions will not be disclosed to ensure
      allocation concealment and the sequence will be performed by an external co-investigator.

      To account for the placebo effect and reduce the risk of bias, the patients, therapists and
      data-manager will be blinded to the allocation. Blinding will be assured using a sham trial
      that includes the same procedures as cryoneurolysis treatment but without any freezing
      temperatures. Thus, visible marks as a result of the procedures in both groups will be
      similar.

      INTERVENTIONS Diagnostic nerve block. All patients reporting a decrease of ≥ 50 % in VAS pain
      scores at least 15 min after a diagnostic nerve block of the genicular nerves.

      Cryoneurolysis. The current project involves the novel application and test of
      cryoneurolysis, in the treatment of OA related pain. The rationale behind this method, is
      based on previous reports showing that low temperature conditions can alter nerve function.
      This technology allows for reversible destruction of nerves, also known as Wallerian
      degeneration, that prevents nerve signaling and potentially alleviate pain and motor
      dysfunction in a number of medical conditions. A probe will be inserted percutaneously at the
      target anterior femoral cutaneous nerve and infrapatellar branch of the saphenous nerve
      guided by ultrasound visualization to accurately determine the location of the nerve and to
      account for adjacent neurovascular structures and variations in anatomical structures. The
      target locations are drawn directly on the patients' skin prior to treatment along which a
      dose of local anesthetic will be injected subcutaneously before treatment. Cryoneurolysis at
      each target site requires 2-4 freeze cycles with a duration of 3 mins, and with thaw cycles
      between 20-40 seconds. A temperature probe will be inserted adjacent to the target nerve and
      cryoneurolysis-probe to ensure a controlled cooling effect and to control nerve damage. The
      sham intervention includes a similar procedure but using a sham probe.

      GLA:D. SHAM and CRYO will both participate in the GLA:D program, which is a standard
      education and exercise program for patients with osteoarthritis in Denmark. The program is
      performed in groups and with the supervision of an experienced physiotherapist specialized in
      training of musculoskeletal disorders and has a duration of 8 weeks.

      STATISTICAL METHODS The treatment groups will be examined for comparability based on baseline
      demographic and prognostic measures. An Intention-To-Treat (ITT) analysis will be used for
      all allocated patients and a mixed effects model will be used on the continuous outcome
      measures to determine the effects of cryoneurolysis treatment from baseline to post treatment
      and follow-ups [Between groups factor: CRYO vs SHAM, within groups factor: time]. The model
      will use robust estimation methods to account for outliers. Finally, a multiple imputation
      approach will be used in case of missing data. All P-values < 0.05 will be considered
      statistically significant.

      ETHICS AND SIGNIFICANCE The project will be conducted according to the declaration of
      Helsinki and will be registered in ClinicalTrials.gov. The Project has been approved by the
      Regional Committee on Health Research Ethics for Southern Denmark (S-20180089).

      Cryoneurolysis could potentially provide an effective, safe and minimally invasive option to
      treat pain in OA patients. The potential benefits include increased functional capacity and
      quality of life as a result of significant pain relief and improved benefits of physical
      exercise, ultimately postponing or making surgical intervention unnecessary. Finally, an
      important perspective, is the application of cryoneurolysis in other areas - such as managing
      pain, related to surgery, to improve rehabilitation.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in NRS knee pain intensity score
time frame: Change in NRS pain score, between baseline and two weeks post surgery
description: NRS consists of a numerical, from 0 to 10, anchored by two verbal descriptors, "no pain" for the score of zero and "worst pain imaginable" for the score of 10. NRS is a self-reported tool where the respondent is asked their current pain intensity.
measure: Change in Pain location
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: Pain location as drawn by the patient.
measure: Change in Functional Performance Evaluated by the 30 second chair-stand test.
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: The outcome is the total number of complete chair stands performed for the duration of the task (one chair stand represents a stand followed by a sit movement).
measure: Change in use of Analgesics
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: Use of analgesics from medical records
measure: Number of Adverse effects
time frame: Reported adverse effects 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: Pre-defined and unexpected adverse effects
measure: Change in Pain type
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: Change in pain type using prespecified pain definitions
measure: Change in Functional Performance Evaluated by the 40m fast-paced walk test.
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: The outcome is expressed as speed. i.e. walking distance (40m) divided by the time to perform the task (s).
measure: Change in Functional Performance Evaluated by the 9 step stair test.
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: The outcome is the total time to perform the task (s).
measure: Change in Functional Performance Evaluated by Maximum Voluntary Contraction
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: As measured in moment force of the knee extensors (Nm)
measure: Change in Quality of Life using the Quality of Life questionnaire (EQ5D)
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: EQ5D consists of 5 subscales; Mobility, Self-care, Usual activities, Pain/Discomfort and Anxiety / depression. An health state score is obtained based on the responses from 1-5 in each subscale, from which a single index value is calculated representing patients' overall health state.
measure: Change in self-rated health using the Quality of Life questionnaire (EQ5D)
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: EQ5D includes a so called EQ VAS score which is the patients' self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled "the best health you can imagine" and "the worst health you can imagine".
measure: Change in the subscale "Pain" using the Knee injury and Osteoarthritis Score (KOOS score)
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.
measure: Change in the subscale "other Symptoms" using the Knee injury and Osteoarthritis Score (KOOS score)
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.
measure: Change in the subscale "Function in daily living (ADL)" using the Knee injury and Osteoarthritis Score (KOOS score)
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.
measure: Change in the subscale "Function in sport and recreation (Sport/Rec)" using the Knee injury and Osteoarthritis Score (KOOS score)
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.
measure: Change in the subscale "Knee related Quality of Life (QoL)" using the Knee injury and Osteoarthritis Score (KOOS score)
time frame: Change between baseline, 2 weeks post cryoneurolysis, post GLA;D and at 6, 12 and 24 month follow-up.
description: KOOS consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) us calculated for each subscale.
arm group label: CRYO
arm group type: Experimental
description: Subjected to Cryoneurolysis treatment and Neuromuscular training (GLA:D).
arm group label: SHAM
arm group type: Sham Comparator
description: Subjected to similar procedures as CRYO, but without freezing temperatures. Subjected to Neuromuscular training (GLA:D).
intervention type: Device
intervention name: Cryoneurolysis
description: A cryoprobe will be inserted percutaneously and freeze the target nerves (infrapatellar branch of the saphenous nerve & anterior femoral cutaneous nerve) guided by ultrasound visualization.
arm group label: CRYO
other name: Cryoablation
intervention type: Other
intervention name: Neuromuscular exercise (GLA:D)
description: The GLA:D program, is a standard education and exercise program for patients with osteoarthritis in Denmark. The program is performed in groups and with the supervision of an experienced physiotherapist specialized in training of musculoskeletal disorders.
arm group label: CRYO
arm group label: SHAM
intervention type: Device
intervention name: Sham
description: The sham intervention includes a similar procedure but without freezing temperatures.
arm group label: SHAM
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bibi (Valgerdur) Gram, PhD
role: Study Director
affiliation: Hospital of South West Jutland
last name: Carsten Kock-Jensen, MD
role: Study Director
affiliation: Hospital of South West Jutland
last name: Niels-Peter B Nielsen, PhD
role: Principal Investigator
affiliation: Hospital of South West Jutland
facility: 
country: Denmark
citation: SUNDERLAND S. A classification of peripheral nerve injuries producing loss of function. Brain. 1951 Dec;74(4):491-516. doi: 10.1093/brain/74.4.491. No abstract available.
PMID: 14895767
citation: Ilfeld BM, Preciado J, Trescot AM. Novel cryoneurolysis device for the treatment of sensory and motor peripheral nerves. Expert Rev Med Devices. 2016 Aug;13(8):713-25. doi: 10.1080/17434440.2016.1204229. Epub 2016 Jul 13.
PMID: 27333989
citation: Radnovich R, Scott D, Patel AT, Olson R, Dasa V, Segal N, Lane NE, Shrock K, Naranjo J, Darr K, Surowitz R, Choo J, Valadie A, Harrell R, Wei N, Metyas S. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. Osteoarthritis Cartilage. 2017 Aug;25(8):1247-1256. doi: 10.1016/j.joca.2017.03.006. Epub 2017 Mar 20.
PMID: 28336454
citation: Trescot AM. Cryoanalgesia in interventional pain management. Pain Physician. 2003 Jul;6(3):345-60.
PMID: 16880882
citation: Skou ST, Roos EM. Good Life with osteoArthritis in Denmark (GLA:D): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide. BMC Musculoskelet Disord. 2017 Feb 7;18(1):72. doi: 10.1186/s12891-017-1439-y.
PMID: 28173795
citation: Dasa V, Lensing G, Parsons M, Harris J, Volaufova J, Bliss R. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. Knee. 2016 Jun;23(3):523-8. doi: 10.1016/j.knee.2016.01.011. Epub 2016 Feb 10.
PMID: 26875052
citation: Lewis GN, Rice DA, McNair PJ, Kluger M. Predictors of persistent pain after total knee arthroplasty: a systematic review and meta-analysis. Br J Anaesth. 2015 Apr;114(4):551-61. doi: 10.1093/bja/aeu441. Epub 2014 Dec 26.
PMID: 25542191
citation: O'Brien T, Breivik H. The impact of chronic pain-European patients' perspective over 12 months. Scand J Pain. 2012 Jan 1;3(1):23-29. doi: 10.1016/j.sjpain.2011.11.004.
PMID: 29913762
citation: Ageberg E, Link A, Roos EM. Feasibility of neuromuscular training in patients with severe hip or knee OA: the individualized goal-based NEMEX-TJR training program. BMC Musculoskelet Disord. 2010 Jun 17;11:126. doi: 10.1186/1471-2474-11-126.
PMID: 20565735
responsible party type: Principal Investigator
investigator affiliation: Hospital of South West Jutland
investigator full name: Niels-Peter Brøchner Nielsen, PhD
investigator title: Post doc, Research employee
mesh term: Osteoarthritis
mesh term: Osteoarthritis, Knee
mesh term: Chronic Pain
sharing ipd: Undecided