<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/NCT04471233</url>
  </required_header>
  <id_info>
    <org_study_id>20-0139</org_study_id>
    <nct_id>NCT04471233</nct_id>
  </id_info>
  <brief_title>Influence of Patient Sex on Pain Control and Multimodal Analgesia in Total Knee Arthroplasty</brief_title>
  <official_title>Influence of Patient Sex on Pain Control and Multimodal Analgesia in Total Knee Arthroplasty</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwell Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwell Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to examine the influence of sex on postoperative pain, following&#xD;
      total knee arthroplasty (TKA). Patients will first be stratified by sex and then be&#xD;
      randomized into one of two multimodal analgesic regimen (MAR), which differ in presence of&#xD;
      pregabalin. We hypothesize that that acute postoperative pain scores are different over time&#xD;
      between males and females and between multimodal analgesic regimens following TKA.&#xD;
      Investigators will be blinded to which multimodal group patients are in. Patients will&#xD;
      complete surveys in the office, during their hospital stay, and at followup intervals for up&#xD;
      to six months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The overall goal of this study is to better understand the influence of patient-sex on&#xD;
      postoperative pain perception in men versus women following total knee arthroplasty (TKA)&#xD;
      utilizing two different multimodal analgesia regimens.&#xD;
&#xD;
      Pregabalin is a neuromuscular antagonist of voltage gated calcium channels at the&#xD;
      post-synaptic dorsal horns in the spinal cord and brain. It binds to the alpha-2-delta&#xD;
      subunit and interrupts pain signal transmission. The use of pregabalin as part of multimodal&#xD;
      pain control has been associated with a decrease in postoperative opioid use.&#xD;
&#xD;
      This will be a randomized, single-blinded control trial in which patients either will or will&#xD;
      not receive pregabalin as part of their multimodal analgesia regimen following TKA. It will&#xD;
      be performed at a single institution, with multiple tertiary academic centers.&#xD;
&#xD;
      Patients will first be grouped according to their sex, then randomized into one of two arms:&#xD;
&#xD;
        1. Multimodal analgesia regimen including pregabalin;&#xD;
&#xD;
        2. Multimodal analgesia regimen not including pregabalin.&#xD;
&#xD;
      For the intervention group, patient will be provided with an oral preoperative pregabalin&#xD;
      dose of 150mg on the day of surgery. Patient will continue pregabalin 75mg two times a day,&#xD;
      for two weeks postoperatively. For both both groups, the operative technique and additional&#xD;
      perioperative analgesic modalities will follow a standard protocol.&#xD;
&#xD;
      Primary Endpoint: Acute postoperative pain difference (up to 72 hours), measured by 100mm&#xD;
      visual analogue scale (VAS) while at rest and mobilization, between males and females and&#xD;
      between multimodal analgesic regimens in patients undergoing TKA.&#xD;
&#xD;
      Secondary Endpoints:&#xD;
&#xD;
        -  Pain control measured by 100mm visual analogue scale (VAS) while at rest and&#xD;
           mobilization.&#xD;
&#xD;
        -  Pain control additionally measured by morphine equivalent units (MEq).&#xD;
&#xD;
        -  Number of postoperative days to opioid cessation.&#xD;
&#xD;
        -  Pain measured by Knee Injury and Osteoarthritis Outcome Score (KOOS).&#xD;
&#xD;
        -  Physical function measured by KOOS, physical component summary (PCS-12) of VR-12.&#xD;
&#xD;
        -  Mental health measured by mental component summary (MCS-12) of VR-12.&#xD;
&#xD;
        -  Safety will be tracked by adverse reactions reported or observed by investigators. These&#xD;
           will be collected via patient communication and review of the medical record.&#xD;
&#xD;
        -  Additionally, severity of common short-term postoperative complications like nausea,&#xD;
           vomiting, dizziness, and sedation will be assessed by 100mm VAS.&#xD;
&#xD;
      The study recruitment phase is estimated to last for 6 months. Subject followup is 6 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 9, 2020</start_date>
  <completion_date type="Anticipated">September 2023</completion_date>
  <primary_completion_date type="Anticipated">July 2023</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>
    <intervention_model_description>Intervention is preoperative and 14 days postoperatively. Patients will be assigned to either multimodal analgesia regimen. No crossing over of patients will occur.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Care providers, and investigators will all be blinded to patient group identity.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Assess influence of sex and multimodal analgesia regimens on acute postoperative pain scores at 48 hours postoperatively, in patients undergoing TKA.</measure>
    <time_frame>48 hours</time_frame>
    <description>Pain control measured by 100mm visual analogue scale (VAS) while at rest 48 hours after the procedure.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assess how sex differences and multimodal analgesia regimens influence physical function</measure>
    <time_frame>26 weeks</time_frame>
    <description>-Pain measured by Knee Injury and Osteoarthritis Outcome Score (KOOS) of week 4, week 12, week 26 postoperatively, compared to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess how sex differences and multimodal analgesia regimens influence postoperative narcotic medication use</measure>
    <time_frame>72 hours</time_frame>
    <description>Pain control additionally measured by morphine equivalent units (MEq) for 24, 48, and 72 hours after the end of the procedure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess how sex differences and multimodal analgesia regimens influence postoperative narcotic medication cessation</measure>
    <time_frame>2 weeks</time_frame>
    <description>-Number of postoperative days to opioid cessation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess how sex differences and multimodal analgesia regimens influence chronic postoperative pain</measure>
    <time_frame>26 weeks</time_frame>
    <description>-Chronic: Pain control measured by 100mm visual analogue scale (VAS) (0 corresponding to no pain and 100 corresponding to worst possible pain) while at rest and mobilization at week 1, week 2, week 4-6, week 12, week 26 postoperatively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess how sex differences and multimodal analgesia regimens influence mental health</measure>
    <time_frame>week 26</time_frame>
    <description>-Mental health measured by mental component summary (MCS-12) of VR-12 of week 2, week 4, week 12, week 26 postoperatively, compared to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess how sex differences and multimodal analgesia regimens influence physical function</measure>
    <time_frame>26 weeks</time_frame>
    <description>-Physical function measured physical component summary (PCS-12) of Veterans Rand-12 (VR-12) at week 2, week 4, week 12, week 26 postoperatively, compared to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess how sex differences and multimodal analgesia regimens influence range of motion (ROM)</measure>
    <time_frame>26 weeks</time_frame>
    <description>Range of Motion (ROM) of week 2, week 4, week 12, week 26 postoperatively, compared to baseline.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Knee Osteoarthritis</condition>
  <condition>Pain, Postoperative</condition>
  <arm_group>
    <arm_group_label>Multimodal analgesia regimen including pregabalin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>For the pregabalin group, patient will be provided with an oral preoperative pregabalin dose of 150mg on the day of surgery. Patient will continue pregabalin 75mg two times a day, for two weeks postoperatively. For both the intervention and control groups, the operative technique and additional perioperative analgesic modalities will follow a standard protocol</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Multimodal analgesia regimen not including pregabalin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>For the non-pregabalin group, patient will be undergo total knee arthroplasty with the same operative technique and additional perioperative analgesic modalities will follow a standard protocol</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Multimodal analgesia including pregabalin</intervention_name>
    <description>Standardized protocol for our institution with multiple medications used for pain (NSAIDs, opioids, dexamethasone) and non-narcotic spinal. Patient will be provided with an preoperative pregabalin dose and will continue medication two weeks postoperatively.</description>
    <arm_group_label>Multimodal analgesia regimen including pregabalin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Multimodal analgesia not including pregabalin</intervention_name>
    <description>Standardized protocol for our institution with multiple medications used for pain (NSAIDs, opioids, dexamethasone) and non-narcotic spinal.</description>
    <arm_group_label>Multimodal analgesia regimen not including pregabalin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of signed and dated informed consent form&#xD;
&#xD;
          2. Stated willingness to comply with all study procedures and availability for the&#xD;
             duration of the study&#xD;
&#xD;
          3. Male or female, age 18-80&#xD;
&#xD;
          4. Undergoing primary unilateral TKA for primary osteoarthritis&#xD;
&#xD;
          5. English speaking&#xD;
&#xD;
          6. Patients whose primary residence is in a home and not a facility or rehabilitation&#xD;
             center.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Chronic (&gt;6 months) use of neuromodulators pregabalin or gabapentin.&#xD;
&#xD;
          2. Pregnancy or lactation&#xD;
&#xD;
          3. Prior history of adverse reactions to pregabalin&#xD;
&#xD;
          4. Coexisting chronic pain condition rated ≥50mm on 100-mm VAS requiring narcotics.&#xD;
&#xD;
          5. Coexisting condition leading to sedation or dizziness&#xD;
&#xD;
          6. Kidney disease&#xD;
&#xD;
          7. History of angioedema&#xD;
&#xD;
          8. History of depression with suicidal ideation.&#xD;
&#xD;
          9. Extensive history of opioid/ substance use and/or abuse.&#xD;
&#xD;
         10. Receiving active or maintenance treatment for cancer or solid organ and/or marrow&#xD;
             transplant.&#xD;
&#xD;
         11. Patient staying less than one night in the hospital.&#xD;
&#xD;
         12. Patients with a history of chronic obstructive pulmonary disease (COPD) with&#xD;
             supplementary oxygen requirements.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Eligibility will be based on biological sex</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jonathan Danoff, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwell Health</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Caroline Aprigliano</last_name>
    <phone>5166400317</phone>
    <email>caprigliano@northwell.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Northwell Health Orthopedic Institute at Great Neck</name>
      <address>
        <city>Great Neck</city>
        <state>New York</state>
        <zip>11021</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cesar Iturriaga</last_name>
      <phone>718-470-7320</phone>
      <email>citurriaga@northwell.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013 Jul;111(1):52-8. doi: 10.1093/bja/aet127.</citation>
    <PMID>23794645</PMID>
  </reference>
  <reference>
    <citation>Berkley KJ. Sex differences in pain. Behav Brain Sci. 1997 Sep;20(3):371-80; discussion 435-513. doi: 10.1017/s0140525x97221485.</citation>
    <PMID>10097000</PMID>
  </reference>
  <results_reference>
    <citation>Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol. 2008;83:1-10. doi: 10.1016/S0074-7742(08)00001-9.</citation>
    <PMID>18929073</PMID>
  </results_reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>May 21, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 15, 2020</study_first_posted>
  <last_update_submitted>February 7, 2023</last_update_submitted>
  <last_update_submitted_qc>February 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pain, Postoperative</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pregabalin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04471233
org study id: 20-0139
nct id: NCT04471233
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of this study is to examine the influence of sex on postoperative pain, following
      total knee arthroplasty (TKA). Patients will first be stratified by sex and then be
      randomized into one of two multimodal analgesic regimen (MAR), which differ in presence of
      pregabalin. We hypothesize that that acute postoperative pain scores are different over time
      between males and females and between multimodal analgesic regimens following TKA.
      Investigators will be blinded to which multimodal group patients are in. Patients will
      complete surveys in the office, during their hospital stay, and at followup intervals for up
      to six months.
The overall goal of this study is to better understand the influence of patient-sex on
      postoperative pain perception in men versus women following total knee arthroplasty (TKA)
      utilizing two different multimodal analgesia regimens.

      Pregabalin is a neuromuscular antagonist of voltage gated calcium channels at the
      post-synaptic dorsal horns in the spinal cord and brain. It binds to the alpha-2-delta
      subunit and interrupts pain signal transmission. The use of pregabalin as part of multimodal
      pain control has been associated with a decrease in postoperative opioid use.

      This will be a randomized, single-blinded control trial in which patients either will or will
      not receive pregabalin as part of their multimodal analgesia regimen following TKA. It will
      be performed at a single institution, with multiple tertiary academic centers.

      Patients will first be grouped according to their sex, then randomized into one of two arms:

        1. Multimodal analgesia regimen including pregabalin;

        2. Multimodal analgesia regimen not including pregabalin.

      For the intervention group, patient will be provided with an oral preoperative pregabalin
      dose of 150mg on the day of surgery. Patient will continue pregabalin 75mg two times a day,
      for two weeks postoperatively. For both both groups, the operative technique and additional
      perioperative analgesic modalities will follow a standard protocol.

      Primary Endpoint: Acute postoperative pain difference (up to 72 hours), measured by 100mm
      visual analogue scale (VAS) while at rest and mobilization, between males and females and
      between multimodal analgesic regimens in patients undergoing TKA.

      Secondary Endpoints:

        -  Pain control measured by 100mm visual analogue scale (VAS) while at rest and
           mobilization.

        -  Pain control additionally measured by morphine equivalent units (MEq).

        -  Number of postoperative days to opioid cessation.

        -  Pain measured by Knee Injury and Osteoarthritis Outcome Score (KOOS).

        -  Physical function measured by KOOS, physical component summary (PCS-12) of VR-12.

        -  Mental health measured by mental component summary (MCS-12) of VR-12.

        -  Safety will be tracked by adverse reactions reported or observed by investigators. These
           will be collected via patient communication and review of the medical record.

        -  Additionally, severity of common short-term postoperative complications like nausea,
           vomiting, dizziness, and sedation will be assessed by 100mm VAS.

      The study recruitment phase is estimated to last for 6 months. Subject followup is 6 months.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Intervention is preoperative and 14 days postoperatively. Patients will be assigned to either multimodal analgesia regimen. No crossing over of patients will occur.
primary purpose: Treatment
masking: Triple (Care Provider, Investigator, Outcomes Assessor)
masking description: Care providers, and investigators will all be blinded to patient group identity.
measure: Assess influence of sex and multimodal analgesia regimens on acute postoperative pain scores at 48 hours postoperatively, in patients undergoing TKA.
time frame: 48 hours
description: Pain control measured by 100mm visual analogue scale (VAS) while at rest 48 hours after the procedure.
measure: Assess how sex differences and multimodal analgesia regimens influence physical function
time frame: 26 weeks
description: -Pain measured by Knee Injury and Osteoarthritis Outcome Score (KOOS) of week 4, week 12, week 26 postoperatively, compared to baseline.
measure: Assess how sex differences and multimodal analgesia regimens influence postoperative narcotic medication use
time frame: 72 hours
description: Pain control additionally measured by morphine equivalent units (MEq) for 24, 48, and 72 hours after the end of the procedure.
measure: Assess how sex differences and multimodal analgesia regimens influence postoperative narcotic medication cessation
time frame: 2 weeks
description: -Number of postoperative days to opioid cessation.
measure: Assess how sex differences and multimodal analgesia regimens influence chronic postoperative pain
time frame: 26 weeks
description: -Chronic: Pain control measured by 100mm visual analogue scale (VAS) (0 corresponding to no pain and 100 corresponding to worst possible pain) while at rest and mobilization at week 1, week 2, week 4-6, week 12, week 26 postoperatively.
measure: Assess how sex differences and multimodal analgesia regimens influence mental health
time frame: week 26
description: -Mental health measured by mental component summary (MCS-12) of VR-12 of week 2, week 4, week 12, week 26 postoperatively, compared to baseline.
measure: Assess how sex differences and multimodal analgesia regimens influence physical function
time frame: 26 weeks
description: -Physical function measured physical component summary (PCS-12) of Veterans Rand-12 (VR-12) at week 2, week 4, week 12, week 26 postoperatively, compared to baseline.
measure: Assess how sex differences and multimodal analgesia regimens influence range of motion (ROM)
time frame: 26 weeks
description: Range of Motion (ROM) of week 2, week 4, week 12, week 26 postoperatively, compared to baseline.
arm group label: Multimodal analgesia regimen including pregabalin
arm group type: Experimental
description: For the pregabalin group, patient will be provided with an oral preoperative pregabalin dose of 150mg on the day of surgery. Patient will continue pregabalin 75mg two times a day, for two weeks postoperatively. For both the intervention and control groups, the operative technique and additional perioperative analgesic modalities will follow a standard protocol
arm group label: Multimodal analgesia regimen not including pregabalin
arm group type: Active Comparator
description: For the non-pregabalin group, patient will be undergo total knee arthroplasty with the same operative technique and additional perioperative analgesic modalities will follow a standard protocol
intervention type: Other
intervention name: Multimodal analgesia including pregabalin
description: Standardized protocol for our institution with multiple medications used for pain (NSAIDs, opioids, dexamethasone) and non-narcotic spinal. Patient will be provided with an preoperative pregabalin dose and will continue medication two weeks postoperatively.
arm group label: Multimodal analgesia regimen including pregabalin
intervention type: Other
intervention name: Multimodal analgesia not including pregabalin
description: Standardized protocol for our institution with multiple medications used for pain (NSAIDs, opioids, dexamethasone) and non-narcotic spinal.
arm group label: Multimodal analgesia regimen not including pregabalin
criteria: 
gender: All
gender based: Yes
gender description: Eligibility will be based on biological sex
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Jonathan Danoff, MD
role: Principal Investigator
affiliation: Northwell Health
last name: Caroline Aprigliano
phone: 5166400317
email: caprigliano@northwell.edu
facility: 
status: Recruiting
contact: 
country: United States
citation: Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013 Jul;111(1):52-8. doi: 10.1093/bja/aet127.
PMID: 23794645
citation: Berkley KJ. Sex differences in pain. Behav Brain Sci. 1997 Sep;20(3):371-80; discussion 435-513. doi: 10.1017/s0140525x97221485.
PMID: 10097000
citation: Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol. 2008;83:1-10. doi: 10.1016/S0074-7742(08)00001-9.
PMID: 18929073
responsible party type: Sponsor
mesh term: Pain, Postoperative
mesh term: Pregabalin
sharing ipd: No