<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/NCT03792828</url>
  </required_header>
  <id_info>
    <org_study_id>SNUBMC_20181128</org_study_id>
    <nct_id>NCT03792828</nct_id>
  </id_info>
  <brief_title>Pre-emptive Effect of Duloxetine in the Second Knee in Staged Total Knee Arthroplasty</brief_title>
  <official_title>Pre-emptive Effect of Duloxetine in the Second Knee in Staged Total Knee Arthroplasty: A Randomized Controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seoul National University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Seoul National University Hospital</source>
  <oversight_info>
    <has_dmc>No</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>
      In Korea, the interval between knee arthroplasties is usually 1 week. According to previous&#xD;
      studies, when total knee arthroplasty was performed at 1-week intervals, total bleeding was&#xD;
      reduced and the period of hospital stay was shortened.&#xD;
&#xD;
      However, if stepwise total knee arthroplasty is performed at intervals of one week, the pain&#xD;
      is greater after the second operation, and the reason for this phenomenon is known to be due&#xD;
      to central sensitization and opioid resistance.&#xD;
&#xD;
      Therefore, the investigators aim to confirm whether Duloxetine reduces the central&#xD;
      sensitization as previously known and affects the pain control after the second operation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Degenerative arthritis of the knee is one of the most common arthritis. Currently, total knee&#xD;
      arthroplasty is the most commonly used surgical procedure. The degenerative changes of the&#xD;
      knee are often seen on both sides, and bilateral total knee arthroplasty is usually&#xD;
      performed. In the past, bilateral total knee arthroplasty was performed at the same time.&#xD;
      When bilateral total knee arthroplasty was performed simultaneously, the complications such&#xD;
      as increased mortality occurred. So, it is common to perform bilateral total knee&#xD;
      arthroplasty in a stepwise manner.&#xD;
&#xD;
      In Korea, the interval between knee arthroplasties is usually 1 week. According to previous&#xD;
      studies, when total knee arthroplasty was performed at 1-week intervals, total blood loss was&#xD;
      reduced and the period of hospital stay was shortened. However, if stepwise total knee&#xD;
      arthroplasty is performed at intervals of one week, the pain is greater after the second&#xD;
      operation, and the reason for this phenomenon is known to be due to central sensitization and&#xD;
      opioid resistance.&#xD;
&#xD;
      Therefore, the investigators aim to 1) whether the pain is greater than the first operation&#xD;
      at the second operation in the control group. 2) whether the pre-operative and post-operative&#xD;
      duloxetine use causes the pre-analgesic effect on the second operation. 3) whether the&#xD;
      central sensitization, clinical score, and painkiller usage are different by comparing&#xD;
      duloxetine-treated group and control group.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 2019</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">October 2019</primary_completion_date>
  <phase>Phase 4</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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pain VAS</measure>
    <time_frame>day 7 (inpatient)</time_frame>
    <description>Pain VAS(11-point numeric scale: 0-11) at rest, maximal knee flexion and maximal knee extension</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Central censitization</measure>
    <time_frame>Preop. day 1, 2, 7 (inpatient) , Postop. 6 week, 3 month</time_frame>
    <description>DN4 (Douleur Neuropathique 4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Opioid consumption</measure>
    <time_frame>Preop. day 1, 2, 7 (inpatient) , Postop. 6 week, 3 month</time_frame>
    <description>Opioid conversion to Morphine IV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain VAS</measure>
    <time_frame>Preop. day 1, 2 (inpatient) , Postop. 6 week, 3 month</time_frame>
    <description>Pain VAS(11-point numeric scale: 0-11) at rest, maximal knee flexion and maximal knee extension</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">90</enrollment>
  <condition>Knee Osteoarthritis</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Duloxetine HCl 30mg is not used.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Duloxetine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One capsule of Duloxetine HCl 30mg (Duroceptol) is taken orally and daily from the day before the first operation to seven days after the second operation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Duloxetine HCl 30mg</intervention_name>
    <description>In the duloxetine group, one capsule of Duloxetine HCl 30mg (Duroceptol) is taken orally and daily from the day before the first operation to seven days after the second operation. In the control group, the patients can take painkillers except duloxetine.</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Duloxetine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Candidate for staged bilateral total knee replacement arthroplasty due to&#xD;
             osteoarthritis of the knee.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergic reaction to duloxetine&#xD;
&#xD;
          -  Secondary arthritis (ex. Rheumatic arthritis, traumatic arthritis, septic arthritis)&#xD;
&#xD;
          -  History of major operation(ex. Arthroscopic knee arthroplasty, osteotomy, open&#xD;
             reduction, and internal fixation)&#xD;
&#xD;
          -  History of manic or bipolar disorder, epilepsy, increased intraocular pressure or risk&#xD;
             of acute angle-closure glaucoma, liver disease, moderate renal disease (CLcr &lt;&#xD;
             30ml/min), severe heart disease, uncontrolled hypertension, unregulated narrow-angle&#xD;
             glaucoma&#xD;
&#xD;
          -  Known congenital or acquired coagulopathy&#xD;
&#xD;
          -  Known genetic disorders such as fulminant intolerance / glucose-galactose uptake&#xD;
             disorder/sucrose isoleucetase deficiency&#xD;
&#xD;
          -  Taken MAO inhibitor, anti-depressants, diuretics, duloxetine&#xD;
&#xD;
          -  Refuse to participate in the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Seung-Baik Kang, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>SMG-SNU Boramae Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Seung-Baik Kang, MD, PhD</last_name>
    <phone>+82-870-3931</phone>
    <email>ossbkang@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>JoungYoup Shin, MD</last_name>
    <phone>+82-10-5310-7133</phone>
    <email>sjy820828@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Seoul National University Boramae Medical Center</name>
      <address>
        <city>Seoul</city>
        <zip>07061</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <contact>
      <last_name>Seung-Baik Kang, MD, PhD</last_name>
      <phone>+82-2-870-3931</phone>
      <email>ossbkang@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Seung-Baik Kang, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Chong Bum Chang, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Moon Jong Chang, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Joung Youp Shin, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Whang Kim, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dong Whan Suh, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jong Byung Oh, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Shin HJ, Kim EY, Na HS, Kim TK, Kim MH, Do SH. Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial. Br J Anaesth. 2016 Oct;117(4):497-503. doi: 10.1093/bja/aew227. Epub 2016 Oct 17.</citation>
    <PMID>28077538</PMID>
  </reference>
  <reference>
    <citation>Scott CE, Murray RC, MacDonald DJ, Biant LC. Staged bilateral total knee replacement: changes in expectations and outcomes between the first and second operations. Bone Joint J. 2014 Jun;96-B(6):752-8. doi: 10.1302/0301-620X.96B6.32793.</citation>
    <PMID>24891574</PMID>
  </reference>
  <reference>
    <citation>Hussain N, Chien T, Hussain F, Bookwala A, Simunovic N, Shetty V, Bhandari M. Simultaneous versus staged bilateral total knee arthroplasty: a meta-analysis evaluating mortality, peri-operative complications and infection rates. HSS J. 2013 Feb;9(1):50-9. doi: 10.1007/s11420-012-9315-7. Epub 2013 Jan 24.</citation>
    <PMID>24426845</PMID>
  </reference>
  <reference>
    <citation>Sun J, Li L, Yuan S, Zhou Y. Analysis of Early Postoperative Pain in the First and Second Knee in Staged Bilateral Total Knee Arthroplasty: A Retrospective Controlled Study. PLoS One. 2015 Jun 11;10(6):e0129973. doi: 10.1371/journal.pone.0129973. eCollection 2015.</citation>
    <PMID>26068371</PMID>
  </reference>
  <reference>
    <citation>Kumar V, Bin Abd Razak HR, Chong HC, Tan AH. Functional Outcomes of the Second Surgery Are Similar to the First in Asians Undergoing Staged-Bilateral Total Knee Arthroplasty. Ann Acad Med Singap. 2015 Nov;44(11):514-8.</citation>
    <PMID>27089957</PMID>
  </reference>
  <reference>
    <citation>Onutu AH. Duloxetine, an antidepressant with analgesic properties - a preliminary analysis. Rom J Anaesth Intensive Care. 2015 Oct;22(2):123-128.</citation>
    <PMID>28913467</PMID>
  </reference>
  <reference>
    <citation>Forster MC, Bauze AJ, Bailie AG, Falworth MS, Oakeshott RD. A retrospective comparative study of bilateral total knee replacement staged at a one-week interval. J Bone Joint Surg Br. 2006 Aug;88(8):1006-10. doi: 10.1302/0301-620X.88B8.17862.</citation>
    <PMID>16877597</PMID>
  </reference>
  <reference>
    <citation>Kim MH, Nahm FS, Kim TK, Chang MJ, Do SH. Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: clinical evidence of enhanced pain sensitivity after surgical injury. Pain. 2014 Jan;155(1):22-27. doi: 10.1016/j.pain.2013.08.027. Epub 2013 Aug 30.</citation>
    <PMID>23994101</PMID>
  </reference>
  <reference>
    <citation>YaDeau JT, Brummett CM, Mayman DJ, Lin Y, Goytizolo EA, Padgett DE, Alexiades MM, Kahn RL, Jules-Elysee KM, Fields KG, Goon AK, Gadulov Y, Westrich G. Duloxetine and Subacute Pain after Knee Arthroplasty when Added to a Multimodal Analgesic Regimen: A Randomized, Placebo-controlled, Triple-blinded Trial. Anesthesiology. 2016 Sep;125(3):561-72. doi: 10.1097/ALN.0000000000001228.</citation>
    <PMID>27387351</PMID>
  </reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>November 28, 2018</study_first_submitted>
  <study_first_submitted_qc>January 1, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 3, 2019</study_first_posted>
  <last_update_submitted>January 1, 2019</last_update_submitted>
  <last_update_submitted_qc>January 1, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 3, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Seoul National University Hospital</investigator_affiliation>
    <investigator_full_name>Seung-Baik Kang</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>total knee replacement arthroplasty</keyword>
  <keyword>total knee arthroplasty</keyword>
  <keyword>central censitization</keyword>
  <keyword>duloxetine</keyword>
  <keyword>serotonin-norepinephrine reuptake inhibitors</keyword>
  <keyword>pre-emptive effect</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Duloxetine Hydrochloride</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03792828
org study id: SNUBMC_20181128
nct id: NCT03792828
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In Korea, the interval between knee arthroplasties is usually 1 week. According to previous
      studies, when total knee arthroplasty was performed at 1-week intervals, total bleeding was
      reduced and the period of hospital stay was shortened.

      However, if stepwise total knee arthroplasty is performed at intervals of one week, the pain
      is greater after the second operation, and the reason for this phenomenon is known to be due
      to central sensitization and opioid resistance.

      Therefore, the investigators aim to confirm whether Duloxetine reduces the central
      sensitization as previously known and affects the pain control after the second operation.
Degenerative arthritis of the knee is one of the most common arthritis. Currently, total knee
      arthroplasty is the most commonly used surgical procedure. The degenerative changes of the
      knee are often seen on both sides, and bilateral total knee arthroplasty is usually
      performed. In the past, bilateral total knee arthroplasty was performed at the same time.
      When bilateral total knee arthroplasty was performed simultaneously, the complications such
      as increased mortality occurred. So, it is common to perform bilateral total knee
      arthroplasty in a stepwise manner.

      In Korea, the interval between knee arthroplasties is usually 1 week. According to previous
      studies, when total knee arthroplasty was performed at 1-week intervals, total blood loss was
      reduced and the period of hospital stay was shortened. However, if stepwise total knee
      arthroplasty is performed at intervals of one week, the pain is greater after the second
      operation, and the reason for this phenomenon is known to be due to central sensitization and
      opioid resistance.

      Therefore, the investigators aim to 1) whether the pain is greater than the first operation
      at the second operation in the control group. 2) whether the pre-operative and post-operative
      duloxetine use causes the pre-analgesic effect on the second operation. 3) whether the
      central sensitization, clinical score, and painkiller usage are different by comparing
      duloxetine-treated group and control group.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Pain VAS
time frame: day 7 (inpatient)
description: Pain VAS(11-point numeric scale: 0-11) at rest, maximal knee flexion and maximal knee extension
measure: Central censitization
time frame: Preop. day 1, 2, 7 (inpatient) , Postop. 6 week, 3 month
description: DN4 (Douleur Neuropathique 4)
measure: Opioid consumption
time frame: Preop. day 1, 2, 7 (inpatient) , Postop. 6 week, 3 month
description: Opioid conversion to Morphine IV
measure: Pain VAS
time frame: Preop. day 1, 2 (inpatient) , Postop. 6 week, 3 month
description: Pain VAS(11-point numeric scale: 0-11) at rest, maximal knee flexion and maximal knee extension
arm group label: Control
arm group type: Active Comparator
description: Duloxetine HCl 30mg is not used.
arm group label: Duloxetine
arm group type: Experimental
description: One capsule of Duloxetine HCl 30mg (Duroceptol) is taken orally and daily from the day before the first operation to seven days after the second operation.
intervention type: Drug
intervention name: Duloxetine HCl 30mg
description: In the duloxetine group, one capsule of Duloxetine HCl 30mg (Duroceptol) is taken orally and daily from the day before the first operation to seven days after the second operation. In the control group, the patients can take painkillers except duloxetine.
arm group label: Control
arm group label: Duloxetine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: Seung-Baik Kang, MD, PhD
role: Principal Investigator
affiliation: SMG-SNU Boramae Medical Center
last name: Seung-Baik Kang, MD, PhD
phone: +82-870-3931
email: ossbkang@gmail.com
last name: JoungYoup Shin, MD
phone: +82-10-5310-7133
email: sjy820828@gmail.com
facility: 
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Korea, Republic of
citation: Shin HJ, Kim EY, Na HS, Kim TK, Kim MH, Do SH. Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial. Br J Anaesth. 2016 Oct;117(4):497-503. doi: 10.1093/bja/aew227. Epub 2016 Oct 17.
PMID: 28077538
citation: Scott CE, Murray RC, MacDonald DJ, Biant LC. Staged bilateral total knee replacement: changes in expectations and outcomes between the first and second operations. Bone Joint J. 2014 Jun;96-B(6):752-8. doi: 10.1302/0301-620X.96B6.32793.
PMID: 24891574
citation: Hussain N, Chien T, Hussain F, Bookwala A, Simunovic N, Shetty V, Bhandari M. Simultaneous versus staged bilateral total knee arthroplasty: a meta-analysis evaluating mortality, peri-operative complications and infection rates. HSS J. 2013 Feb;9(1):50-9. doi: 10.1007/s11420-012-9315-7. Epub 2013 Jan 24.
PMID: 24426845
citation: Sun J, Li L, Yuan S, Zhou Y. Analysis of Early Postoperative Pain in the First and Second Knee in Staged Bilateral Total Knee Arthroplasty: A Retrospective Controlled Study. PLoS One. 2015 Jun 11;10(6):e0129973. doi: 10.1371/journal.pone.0129973. eCollection 2015.
PMID: 26068371
citation: Kumar V, Bin Abd Razak HR, Chong HC, Tan AH. Functional Outcomes of the Second Surgery Are Similar to the First in Asians Undergoing Staged-Bilateral Total Knee Arthroplasty. Ann Acad Med Singap. 2015 Nov;44(11):514-8.
PMID: 27089957
citation: Onutu AH. Duloxetine, an antidepressant with analgesic properties - a preliminary analysis. Rom J Anaesth Intensive Care. 2015 Oct;22(2):123-128.
PMID: 28913467
citation: Forster MC, Bauze AJ, Bailie AG, Falworth MS, Oakeshott RD. A retrospective comparative study of bilateral total knee replacement staged at a one-week interval. J Bone Joint Surg Br. 2006 Aug;88(8):1006-10. doi: 10.1302/0301-620X.88B8.17862.
PMID: 16877597
citation: Kim MH, Nahm FS, Kim TK, Chang MJ, Do SH. Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: clinical evidence of enhanced pain sensitivity after surgical injury. Pain. 2014 Jan;155(1):22-27. doi: 10.1016/j.pain.2013.08.027. Epub 2013 Aug 30.
PMID: 23994101
citation: YaDeau JT, Brummett CM, Mayman DJ, Lin Y, Goytizolo EA, Padgett DE, Alexiades MM, Kahn RL, Jules-Elysee KM, Fields KG, Goon AK, Gadulov Y, Westrich G. Duloxetine and Subacute Pain after Knee Arthroplasty when Added to a Multimodal Analgesic Regimen: A Randomized, Placebo-controlled, Triple-blinded Trial. Anesthesiology. 2016 Sep;125(3):561-72. doi: 10.1097/ALN.0000000000001228.
PMID: 27387351
responsible party type: Principal Investigator
investigator affiliation: Seoul National University Hospital
investigator full name: Seung-Baik Kang
investigator title: Professor
mesh term: Osteoarthritis
mesh term: Osteoarthritis, Knee
mesh term: Duloxetine Hydrochloride