<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/NCT03020966</url>
  </required_header>
  <id_info>
    <org_study_id>2016-209</org_study_id>
    <nct_id>NCT03020966</nct_id>
  </id_info>
  <brief_title>IV vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty</brief_title>
  <acronym>IV Tylenol</acronym>
  <official_title>IV vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: a Randomized, Blinded Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital for Special Surgery, New York</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Mallinckrodt</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital for Special Surgery, New York</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine how well two different methods of administrating&#xD;
      Tylenol reduce pain and improve patient satisfaction after total hip replacement (THR)&#xD;
      surgery. The methods of administration are orally, via a pill that is to be swallowed, and&#xD;
      intravenously. Our aim is to determine whether oral or intravenous administration of Tylenol&#xD;
      will reduce opioid consumption and opioid-related side effects after THR.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A) Opioid use after THA. Opioid use after THA can be 90 mg (+/-79) in morphine equivalents&#xD;
      when using epidural bupivacaine / hydromorphone and multimodal analgesia. Less than 1/3 of&#xD;
      this was via the epidural (26/90 mg). Patients reported ORSDS composite scores of 0.58&#xD;
&#xD;
      B) IV vs oral acetaminophen. The therapeutic blood concentration of acetaminophen for pain&#xD;
      relief is 10 mcg/ml.&#xD;
&#xD;
      After an oral, single dose: In 24 fasting adult subjects, the maximal blood concentration&#xD;
      (Cmax) of 7.7 to 17.6 mcg/mL occurred within 1 hour following a single 1000-mg dose of oral&#xD;
      acetaminophen (liquid or caplet). Acetaminophen crosses the blood-brain barrier. Central&#xD;
      diffusion to the brain and spinal fluid occurs within 15 to 45 minutes with maximum&#xD;
      cerebrospinal fluid concentrations occurring at 2 to 4 hours. [Product Information:&#xD;
      TYLENOL(R) oral, acetaminophen oral. McNeil Consumer Healthcare, Skillman, NJ, 2010].&#xD;
&#xD;
      In a randomized, double-blind, placebo-controlled, single-dose study, acetaminophen 1,000 mg&#xD;
      provided significantly greater efficacy in treating postsurgical dental pain compared with&#xD;
      acetaminophen 650 mg and placebo.&#xD;
&#xD;
      Oral, multiple-dose, immediate-release, elderly patients: In 12 very elderly patients (mean&#xD;
      age, 89 years), the Cmax was 23.9 mcg/mL following the administration of acetaminophen 1000&#xD;
      mg orally 3 times daily for 5 days.&#xD;
&#xD;
      In adult subjects, the mean Cmax was 28 +/- 21 mcg/mL at the end of a 15-minute IV infusion&#xD;
      of acetaminophen 1000 mg. [Product Information: OFIRMEV(TM) intravenous infusion,&#xD;
      acetaminophen intravenous infusion. Cadence Pharmaceuticals Inc., San Diego, CA, 2010].&#xD;
&#xD;
      The oral medication has an excellent absorption and at least 85% bioavailability, but peak&#xD;
      concentration occurs later than the IV, and the therapeutic blood concentration for pain&#xD;
      relief (10mcg/ml) may not be achieved after one oral dose (7-17mcg/ml).A full stomach delays&#xD;
      the absorption. With multiple doses, in elderly patients, or with renal/ liver failure, the&#xD;
      blood concentration is higher.&#xD;
&#xD;
      Epidural bupivacaine / clonidine (Liu). Pain scores (NRS) after THA with activity on POD1 can&#xD;
      be 3.4 mean (2.6 SD) when using epidural bupivacaine / clonidine and multimodal analgesia.&#xD;
&#xD;
      Low-opioid protocol (oxycodone may be too strong for some; cannot use Vicodin due to&#xD;
      acetaminophen) Choice of instruments (CAM, ORSDS, Pain OUT). The ORSDS is a 4-point scale&#xD;
      that evaluates 12 symptoms (nausea, vomiting, constipation, difficulty passing urine,&#xD;
      difficulty concentrating, drowsiness or difficulty staying awake, feeling lightheaded or&#xD;
      dizzy, feeling confused, feelings of general fatigue or weakness, itchiness, dry mouth and&#xD;
      headache) via 3 symptom distress dimensions (frequency, severity, bothersomeness). It is&#xD;
      validated for use after orthopaedic surgery, specifically including TKA patients receiving&#xD;
      epidural analgesia and femoral nerve blockade.&#xD;
&#xD;
      Patients can meet criteria for delirium by CAM by having acute onset of inattention as well&#xD;
      as either disorganized thinking or altered level of consciousness.Patients without acute&#xD;
      onset can also meet criteria for delirium if inattention, disorganized thinking and altered&#xD;
      level of consciousness are all present, with at least one factor judged to be fluctuating.&#xD;
      CAM has been widely applied and has been specifically used to evaluate elderly TKA patients&#xD;
      receiving epidural analgesia and femoral nerve blockade.&#xD;
&#xD;
      The Patient Outcome Questionnaire by the American Pain society is used for quality&#xD;
      improvement, and measures 6 aspects of quality, including (1) pain severity and relief; (2)&#xD;
      impact of pain on activity, sleep, and negative emotions; (3) side effects of treatment; (4)&#xD;
      helpfulness of information about pain treatment; (5) ability to participate in pain treatment&#xD;
      decisions; and (6) use of nonpharmacological strategies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 16, 2017</start_date>
  <completion_date type="Actual">June 16, 2019</completion_date>
  <primary_completion_date type="Actual">June 16, 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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pain With Physical Therapy on Post-operative Day 1</measure>
    <time_frame>24 hours after the operation (post-operative day 1)</time_frame>
    <description>Numerical rating scale of pain on a scale of 0-10, with 0 representing the minimum value of no pain and 10, representing the maximum, defined as being pain as bad as imaginable.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Opioid Use</measure>
    <time_frame>Day of surgery to post-operative day 3</time_frame>
    <description>Oral morphine equivalents, cumulative, POD 0-3. Recorded in Medication Usage Database.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Opioid Side Effects</measure>
    <time_frame>24 hours after surgery (Post-operative day 1)</time_frame>
    <description>The Opioid-Related Symptom Distress Scale (ORSDS) is a Likert scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 12 symptoms. Frequency is rated on a 4-point scale (1= 'Rarely', 4= 'Almost constantly'). Severity is rated on a 4-point scale (1= 'Slightly', 4= 'Very'). Bothersomeness is rated on a 5-point scale (0.8= 'Not at all', 4.0= 'Very much'). The symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite ORSDS score is the average of 12 symptom-specific scores.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">154</enrollment>
  <condition>Pain, Postoperative</condition>
  <condition>Opioid Use</condition>
  <arm_group>
    <arm_group_label>Oral Tylenol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intravenous Tylenol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen</intervention_name>
    <description>Oral acetaminophen, intravenous placebo</description>
    <arm_group_label>Oral Tylenol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen</intervention_name>
    <description>Intravenous acetaminophen, oral placebo</description>
    <arm_group_label>Intravenous Tylenol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Adult&#xD;
&#xD;
          -  Scheduled for an elective primary THA with a participating surgeon,&#xD;
&#xD;
          -  Planned for Combined Spinal Epidural anesthesia (CSE) and Patient Controlled Epidural&#xD;
             Analgesia (PCEA)&#xD;
&#xD;
          -  English-speaking&#xD;
&#xD;
          -  Patients that did not receive pre-operative opioids&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Hepatic or renal insufficiency, as defined by abnormal readings on liver and kidney&#xD;
             functioning tests.&#xD;
&#xD;
          -  Hypersensitivity or contraindication to protocol medication&#xD;
&#xD;
          -  Contraindication for CSE and PCEA&#xD;
&#xD;
          -  Incapable to provide consent/answer questions in English&#xD;
&#xD;
          -  Revision or urgent surgery&#xD;
&#xD;
          -  Receiving Periarticular Injections&#xD;
&#xD;
          -  History of opioid use&#xD;
&#xD;
          -  Patients on disability or worker's compensation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jacques Ya Deau, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital for Special Surgery, New York</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital for Special Surgery</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10021</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Jules-Elysee KM, Goon AK, Westrich GH, Padgett DE, Mayman DJ, Ranawat AS, Ranawat CS, Lin Y, Kahn RL, Bhagat DD, Goytizolo EA, Ma Y, Reid SC, Curren J, YaDeau JT. Patient-controlled epidural analgesia or multimodal pain regimen with periarticular injection after total hip arthroplasty: a randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am. 2015 May 20;97(10):789-98. doi: 10.2106/JBJS.N.00698.</citation>
    <PMID>25995489</PMID>
  </reference>
  <reference>
    <citation>Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther. 2007 Jun;81(6):840-8. doi: 10.1038/sj.clpt.6100121. Epub 2007 Mar 21.</citation>
    <PMID>17377528</PMID>
  </reference>
  <reference>
    <citation>Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012 Sep;12(7):523-32. doi: 10.1111/j.1533-2500.2012.00556.x. Epub 2012 Apr 24.</citation>
    <PMID>22524979</PMID>
  </reference>
  <reference>
    <citation>Qi DS, May LG, Zimmerman B, Peng P, Atillasoy E, Brown JD, Cooper SA. A randomized, double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg for the treatment of postsurgical dental pain. Clin Ther. 2012 Dec;34(12):2247-2258.e3. doi: 10.1016/j.clinthera.2012.11.003. Epub 2012 Nov 28.</citation>
    <PMID>23200183</PMID>
  </reference>
  <reference>
    <citation>Liu SS, Bae JJ, Bieltz M, Wukovits B, Ma Y. A prospective survey of patient-controlled epidural analgesia with bupivacaine and clonidine after total hip replacement: a pre- and postchange comparison with bupivacaine and hydromorphone in 1,000 patients. Anesth Analg. 2011 Nov;113(5):1213-7. doi: 10.1213/ANE.0b013e318228fc8b. Epub 2011 Aug 4.</citation>
    <PMID>21821512</PMID>
  </reference>
  <reference>
    <citation>Yadeau JT, Liu SS, Rade MC, Marcello D, Liguori GA. Performance characteristics and validation of the Opioid-Related Symptom Distress Scale for evaluation of analgesic side effects after orthopedic surgery. Anesth Analg. 2011 Aug;113(2):369-77. doi: 10.1213/ANE.0b013e31821ae3f7. Epub 2011 Apr 27.</citation>
    <PMID>21525182</PMID>
  </reference>
  <reference>
    <citation>Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990 Dec 15;113(12):941-8. doi: 10.7326/0003-4819-113-12-941.</citation>
    <PMID>2240918</PMID>
  </reference>
  <reference>
    <citation>Rade MC, Yadeau JT, Ford C, Reid MC. Postoperative delirium in elderly patients after elective hip or knee arthroplasty performed under regional anesthesia. HSS J. 2011 Jul;7(2):151-6. doi: 10.1007/s11420-011-9195-2. Epub 2011 Feb 11.</citation>
    <PMID>22754416</PMID>
  </reference>
  <reference>
    <citation>Gordon DB, Polomano RC, Pellino TA, Turk DC, McCracken LM, Sherwood G, Paice JA, Wallace MS, Strassels SA, Farrar JT. Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R) for quality improvement of pain management in hospitalized adults: preliminary psychometric evaluation. J Pain. 2010 Nov;11(11):1172-86. doi: 10.1016/j.jpain.2010.02.012. Epub 2010 Apr 18.</citation>
    <PMID>20400379</PMID>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 13, 2017</study_first_posted>
  <results_first_submitted>March 26, 2021</results_first_submitted>
  <results_first_submitted_qc>August 9, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">August 10, 2021</results_first_posted>
  <last_update_submitted>August 9, 2021</last_update_submitted>
  <last_update_submitted_qc>August 9, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 10, 2021</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>Acetaminophen</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 28, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/66/NCT03020966/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Oral Tylenol</title>
          <description>Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo&#xD;
Acetaminophen: Oral acetaminophen, intravenous placebo</description>
        </group>
        <group group_id="P2">
          <title>Intravenous Tylenol</title>
          <description>Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo&#xD;
Acetaminophen: Intravenous acetaminophen, oral placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="77"/>
                <participants group_id="P2" count="77"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="75"/>
                <participants group_id="P2" count="77"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Oral Tylenol</title>
          <description>Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo&#xD;
Acetaminophen: Oral acetaminophen, intravenous placebo</description>
        </group>
        <group group_id="B2">
          <title>Intravenous Tylenol</title>
          <description>Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo&#xD;
Acetaminophen: Intravenous acetaminophen, oral placebo</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="77"/>
            <count group_id="B2" value="77"/>
            <count group_id="B3" value="154"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                    <measurement group_id="B2" value="39"/>
                    <measurement group_id="B3" value="79"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="37"/>
                    <measurement group_id="B2" value="38"/>
                    <measurement group_id="B3" value="75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <description>This table is intended to report the mean age rage and standard deviation of both study arms.</description>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65" spread="10"/>
                    <measurement group_id="B2" value="63" spread="10"/>
                    <measurement group_id="B3" value="64" spread="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <description>This table is intended to report the how many participants were initially enrolled in each arm of the study and if they were Male or Female.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                    <measurement group_id="B2" value="49"/>
                    <measurement group_id="B3" value="91"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="74"/>
                    <measurement group_id="B2" value="75"/>
                    <measurement group_id="B3" value="149"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="70"/>
                    <measurement group_id="B2" value="69"/>
                    <measurement group_id="B3" value="139"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="77"/>
                    <measurement group_id="B2" value="77"/>
                    <measurement group_id="B3" value="154"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Pain With Physical Therapy on Post-operative Day 1</title>
        <description>Numerical rating scale of pain on a scale of 0-10, with 0 representing the minimum value of no pain and 10, representing the maximum, defined as being pain as bad as imaginable.</description>
        <time_frame>24 hours after the operation (post-operative day 1)</time_frame>
        <population>Three patients withdrew from the protocol, but were followed using intention-to-treat principles. One patient did not wish to answer the postoperative questions, 1 could not swallow the pills, and 1 received a different anesthetic/analgesic protocol due to pre-existing expectations.</population>
        <group_list>
          <group group_id="O1">
            <title>Oral Tylenol</title>
            <description>Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo&#xD;
Acetaminophen: Oral acetaminophen, intravenous placebo</description>
          </group>
          <group group_id="O2">
            <title>Intravenous Tylenol</title>
            <description>Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo&#xD;
Acetaminophen: Intravenous acetaminophen, oral placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Pain With Physical Therapy on Post-operative Day 1</title>
          <description>Numerical rating scale of pain on a scale of 0-10, with 0 representing the minimum value of no pain and 10, representing the maximum, defined as being pain as bad as imaginable.</description>
          <population>Three patients withdrew from the protocol, but were followed using intention-to-treat principles. One patient did not wish to answer the postoperative questions, 1 could not swallow the pills, and 1 received a different anesthetic/analgesic protocol due to pre-existing expectations.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="75"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.6" spread="2.4"/>
                    <measurement group_id="O2" value="3.9" spread="2.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Opioid Use</title>
        <description>Oral morphine equivalents, cumulative, POD 0-3. Recorded in Medication Usage Database.</description>
        <time_frame>Day of surgery to post-operative day 3</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Oral Tylenol</title>
            <description>Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo&#xD;
Acetaminophen: Oral acetaminophen, intravenous placebo</description>
          </group>
          <group group_id="O2">
            <title>Intravenous Tylenol</title>
            <description>Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo&#xD;
Acetaminophen: Intravenous acetaminophen, oral placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Opioid Use</title>
          <description>Oral morphine equivalents, cumulative, POD 0-3. Recorded in Medication Usage Database.</description>
          <units>Oral Morphine Equivalent (mg)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="65"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="108" spread="63"/>
                    <measurement group_id="O2" value="121" spread="71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Opioid Side Effects</title>
        <description>The Opioid-Related Symptom Distress Scale (ORSDS) is a Likert scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 12 symptoms. Frequency is rated on a 4-point scale (1= 'Rarely', 4= 'Almost constantly'). Severity is rated on a 4-point scale (1= 'Slightly', 4= 'Very'). Bothersomeness is rated on a 5-point scale (0.8= 'Not at all', 4.0= 'Very much'). The symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite ORSDS score is the average of 12 symptom-specific scores.</description>
        <time_frame>24 hours after surgery (Post-operative day 1)</time_frame>
        <population>Three patients withdrew from the protocol, but were followed using intention-to-treat principles. One patient did not wish to answer the postoperative questions, 1 could not swallow the pills, and 1 received a different anesthetic/analgesic protocol due to pre-existing expectations. In addition, ORSDS on POD 1 was not recorded for two patients who were lost to follow up.</population>
        <group_list>
          <group group_id="O1">
            <title>Oral Tylenol</title>
            <description>Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo&#xD;
Acetaminophen: Oral acetaminophen, intravenous placebo</description>
          </group>
          <group group_id="O2">
            <title>Intravenous Tylenol</title>
            <description>Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo&#xD;
Acetaminophen: Intravenous acetaminophen, oral placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Opioid Side Effects</title>
          <description>The Opioid-Related Symptom Distress Scale (ORSDS) is a Likert scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 12 symptoms. Frequency is rated on a 4-point scale (1= 'Rarely', 4= 'Almost constantly'). Severity is rated on a 4-point scale (1= 'Slightly', 4= 'Very'). Bothersomeness is rated on a 5-point scale (0.8= 'Not at all', 4.0= 'Very much'). The symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite ORSDS score is the average of 12 symptom-specific scores.</description>
          <population>Three patients withdrew from the protocol, but were followed using intention-to-treat principles. One patient did not wish to answer the postoperative questions, 1 could not swallow the pills, and 1 received a different anesthetic/analgesic protocol due to pre-existing expectations. In addition, ORSDS on POD 1 was not recorded for two patients who were lost to follow up.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="74"/>
                <count group_id="O2" value="75"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.4" spread="0.3"/>
                    <measurement group_id="O2" value="0.3" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 days</time_frame>
      <desc>Patients with a high likelihood to experience serious adverse effects, have pre-existing conditions which may put the patient at risk for adverse effects, or have contradictions to the medications in this study were not enrolled. The likelihood of serious risks occurring is low since the required doses are not high enough to cause adverse liver damage. Furthermore, the dosage of acetaminophen will be closely monitored.</desc>
      <group_list>
        <group group_id="E1">
          <title>Oral Tylenol</title>
          <description>Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo&#xD;
Acetaminophen: Oral acetaminophen, intravenous placebo</description>
        </group>
        <group group_id="E2">
          <title>Intravenous Tylenol</title>
          <description>Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo&#xD;
Acetaminophen: Intravenous acetaminophen, oral placebo</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="75"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="76"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="75"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="76"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="75"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="76"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Jacques Yadeau</name_or_title>
      <organization>Hospital for Special Surgery</organization>
      <phone>(212) 774-2224</phone>
      <email>Yadeauj@hss.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03020966
org study id: 2016-209
nct id: NCT03020966
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this study is to determine how well two different methods of administrating
      Tylenol reduce pain and improve patient satisfaction after total hip replacement (THR)
      surgery. The methods of administration are orally, via a pill that is to be swallowed, and
      intravenously. Our aim is to determine whether oral or intravenous administration of Tylenol
      will reduce opioid consumption and opioid-related side effects after THR.
A) Opioid use after THA. Opioid use after THA can be 90 mg (+/-79) in morphine equivalents
      when using epidural bupivacaine / hydromorphone and multimodal analgesia. Less than 1/3 of
      this was via the epidural (26/90 mg). Patients reported ORSDS composite scores of 0.58

      B) IV vs oral acetaminophen. The therapeutic blood concentration of acetaminophen for pain
      relief is 10 mcg/ml.

      After an oral, single dose: In 24 fasting adult subjects, the maximal blood concentration
      (Cmax) of 7.7 to 17.6 mcg/mL occurred within 1 hour following a single 1000-mg dose of oral
      acetaminophen (liquid or caplet). Acetaminophen crosses the blood-brain barrier. Central
      diffusion to the brain and spinal fluid occurs within 15 to 45 minutes with maximum
      cerebrospinal fluid concentrations occurring at 2 to 4 hours. [Product Information:
      TYLENOL(R) oral, acetaminophen oral. McNeil Consumer Healthcare, Skillman, NJ, 2010].

      In a randomized, double-blind, placebo-controlled, single-dose study, acetaminophen 1,000 mg
      provided significantly greater efficacy in treating postsurgical dental pain compared with
      acetaminophen 650 mg and placebo.

      Oral, multiple-dose, immediate-release, elderly patients: In 12 very elderly patients (mean
      age, 89 years), the Cmax was 23.9 mcg/mL following the administration of acetaminophen 1000
      mg orally 3 times daily for 5 days.

      In adult subjects, the mean Cmax was 28 +/- 21 mcg/mL at the end of a 15-minute IV infusion
      of acetaminophen 1000 mg. [Product Information: OFIRMEV(TM) intravenous infusion,
      acetaminophen intravenous infusion. Cadence Pharmaceuticals Inc., San Diego, CA, 2010].

      The oral medication has an excellent absorption and at least 85% bioavailability, but peak
      concentration occurs later than the IV, and the therapeutic blood concentration for pain
      relief (10mcg/ml) may not be achieved after one oral dose (7-17mcg/ml).A full stomach delays
      the absorption. With multiple doses, in elderly patients, or with renal/ liver failure, the
      blood concentration is higher.

      Epidural bupivacaine / clonidine (Liu). Pain scores (NRS) after THA with activity on POD1 can
      be 3.4 mean (2.6 SD) when using epidural bupivacaine / clonidine and multimodal analgesia.

      Low-opioid protocol (oxycodone may be too strong for some; cannot use Vicodin due to
      acetaminophen) Choice of instruments (CAM, ORSDS, Pain OUT). The ORSDS is a 4-point scale
      that evaluates 12 symptoms (nausea, vomiting, constipation, difficulty passing urine,
      difficulty concentrating, drowsiness or difficulty staying awake, feeling lightheaded or
      dizzy, feeling confused, feelings of general fatigue or weakness, itchiness, dry mouth and
      headache) via 3 symptom distress dimensions (frequency, severity, bothersomeness). It is
      validated for use after orthopaedic surgery, specifically including TKA patients receiving
      epidural analgesia and femoral nerve blockade.

      Patients can meet criteria for delirium by CAM by having acute onset of inattention as well
      as either disorganized thinking or altered level of consciousness.Patients without acute
      onset can also meet criteria for delirium if inattention, disorganized thinking and altered
      level of consciousness are all present, with at least one factor judged to be fluctuating.
      CAM has been widely applied and has been specifically used to evaluate elderly TKA patients
      receiving epidural analgesia and femoral nerve blockade.

      The Patient Outcome Questionnaire by the American Pain society is used for quality
      improvement, and measures 6 aspects of quality, including (1) pain severity and relief; (2)
      impact of pain on activity, sleep, and negative emotions; (3) side effects of treatment; (4)
      helpfulness of information about pain treatment; (5) ability to participate in pain treatment
      decisions; and (6) use of nonpharmacological strategies.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Pain With Physical Therapy on Post-operative Day 1
time frame: 24 hours after the operation (post-operative day 1)
description: Numerical rating scale of pain on a scale of 0-10, with 0 representing the minimum value of no pain and 10, representing the maximum, defined as being pain as bad as imaginable.
measure: Opioid Use
time frame: Day of surgery to post-operative day 3
description: Oral morphine equivalents, cumulative, POD 0-3. Recorded in Medication Usage Database.
measure: Opioid Side Effects
time frame: 24 hours after surgery (Post-operative day 1)
description: The Opioid-Related Symptom Distress Scale (ORSDS) is a Likert scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 12 symptoms. Frequency is rated on a 4-point scale (1= 'Rarely', 4= 'Almost constantly'). Severity is rated on a 4-point scale (1= 'Slightly', 4= 'Very'). Bothersomeness is rated on a 5-point scale (0.8= 'Not at all', 4.0= 'Very much'). The symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite ORSDS score is the average of 12 symptom-specific scores.
arm group label: Oral Tylenol
arm group type: Experimental
description: Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo
arm group label: Intravenous Tylenol
arm group type: Experimental
description: Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo
intervention type: Drug
intervention name: Acetaminophen
description: Oral acetaminophen, intravenous placebo
arm group label: Oral Tylenol
intervention type: Drug
intervention name: Acetaminophen
description: Intravenous acetaminophen, oral placebo
arm group label: Intravenous Tylenol
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Jacques Ya Deau, MD, PhD
role: Principal Investigator
affiliation: Hospital for Special Surgery, New York
facility: 
country: United States
citation: Jules-Elysee KM, Goon AK, Westrich GH, Padgett DE, Mayman DJ, Ranawat AS, Ranawat CS, Lin Y, Kahn RL, Bhagat DD, Goytizolo EA, Ma Y, Reid SC, Curren J, YaDeau JT. Patient-controlled epidural analgesia or multimodal pain regimen with periarticular injection after total hip arthroplasty: a randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am. 2015 May 20;97(10):789-98. doi: 10.2106/JBJS.N.00698.
PMID: 25995489
citation: Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther. 2007 Jun;81(6):840-8. doi: 10.1038/sj.clpt.6100121. Epub 2007 Mar 21.
PMID: 17377528
citation: Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012 Sep;12(7):523-32. doi: 10.1111/j.1533-2500.2012.00556.x. Epub 2012 Apr 24.
PMID: 22524979
citation: Qi DS, May LG, Zimmerman B, Peng P, Atillasoy E, Brown JD, Cooper SA. A randomized, double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg for the treatment of postsurgical dental pain. Clin Ther. 2012 Dec;34(12):2247-2258.e3. doi: 10.1016/j.clinthera.2012.11.003. Epub 2012 Nov 28.
PMID: 23200183
citation: Liu SS, Bae JJ, Bieltz M, Wukovits B, Ma Y. A prospective survey of patient-controlled epidural analgesia with bupivacaine and clonidine after total hip replacement: a pre- and postchange comparison with bupivacaine and hydromorphone in 1,000 patients. Anesth Analg. 2011 Nov;113(5):1213-7. doi: 10.1213/ANE.0b013e318228fc8b. Epub 2011 Aug 4.
PMID: 21821512
citation: Yadeau JT, Liu SS, Rade MC, Marcello D, Liguori GA. Performance characteristics and validation of the Opioid-Related Symptom Distress Scale for evaluation of analgesic side effects after orthopedic surgery. Anesth Analg. 2011 Aug;113(2):369-77. doi: 10.1213/ANE.0b013e31821ae3f7. Epub 2011 Apr 27.
PMID: 21525182
citation: Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990 Dec 15;113(12):941-8. doi: 10.7326/0003-4819-113-12-941.
PMID: 2240918
citation: Rade MC, Yadeau JT, Ford C, Reid MC. Postoperative delirium in elderly patients after elective hip or knee arthroplasty performed under regional anesthesia. HSS J. 2011 Jul;7(2):151-6. doi: 10.1007/s11420-011-9195-2. Epub 2011 Feb 11.
PMID: 22754416
citation: Gordon DB, Polomano RC, Pellino TA, Turk DC, McCracken LM, Sherwood G, Paice JA, Wallace MS, Strassels SA, Farrar JT. Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R) for quality improvement of pain management in hospitalized adults: preliminary psychometric evaluation. J Pain. 2010 Nov;11(11):1172-86. doi: 10.1016/j.jpain.2010.02.012. Epub 2010 Apr 18.
PMID: 20400379
responsible party type: Sponsor
mesh term: Pain, Postoperative
mesh term: Acetaminophen
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 