<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/NCT03235739</url>
  </required_header>
  <id_info>
    <org_study_id>17-765</org_study_id>
    <nct_id>NCT03235739</nct_id>
  </id_info>
  <brief_title>Ancillary Effects of Oral Naloxegol (Movantik)</brief_title>
  <official_title>Ancillary Effects of Oral Naloxegol (Movantik)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Cleveland Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Cleveland Clinic</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to find out whether oral Naloxegol can reduce the side effects&#xD;
      of opioid painkillers following surgery. This study aims to explore whether Naloxegol can&#xD;
      similarly reduce opioid-induced side effects in post-surgical patients. About 130 surgery&#xD;
      patients will participate in this study which is being conducted at Cleveland Clinic Main&#xD;
      Campus.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Opioids are the gold standard for postoperative pain management, but they have been shown to&#xD;
      produce uncomfortable side effects such as urinary retention (an inability to completely&#xD;
      empty the bladder), constipation and nausea/vomiting. Clinical evidence demonstrates that&#xD;
      Naloxegol can safely and effectively block these undesirable side effects while maintaining&#xD;
      the painkilling effects of opioids in outpatients suffering from opioid-induced constipation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Actual">May 23, 2022</completion_date>
  <primary_completion_date type="Actual">May 31, 2021</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>Effect of Naloxegol on reversing opioid-related side effects in patients recovering from elective primary hip surgery under spinal anesthesia who will be randomly assigned to oral Naloxegol or placebo for two postoperative days or until the date of discharge, whichever occurs earlier. The design will be a randomized, double-blind, placebo-controlled trial of oral Naloxegol in adults having elective primary hip or knee surgery under spinal anesthesia. The study will be performed at the Cleveland Clinic hospitals.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Residual Urine Volume</measure>
    <time_frame>from Postoperative days 1 to POD 2 or until day of discharge whichever occurs first</time_frame>
    <description>Residual urine volume in the bladder as assessed by bladder scan</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Side Effects of Naloxegol on Other Opioid Related Side Effects</measure>
    <time_frame>Postoperative days 1-2 or until day of discharge whichever occurs first</time_frame>
    <description>Opioid-related Symptom Distress Scale (ORSDS) is a 4 point-scale that evaluates three symptom distress dimensions (frequency, severity, bothersomeness) for opioid-related side effects. The 12 elements of the ORSDS are nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness, lightheaded, fatigue, feeling confused, itchiness, dry mouth, and headache. The ORSDS questionnaire was administered by a trained investigator on first and second postoperative days while patients remained hospitalized. We reported the average ORSDS score from all 12 elements, which ranged from 0 to 4 and higher scores represent worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for Indwelling Urinary Catheterization</measure>
    <time_frame>Postoperative days 1-2 or until day of discharge whichever occurs first</time_frame>
    <description>Number of patients receiving Naloxegol requiring indwelling urinary catheters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Recovery</measure>
    <time_frame>Postoperative Days 2 or discharge day whichever was earlier</time_frame>
    <description>Quality of recovery is a validated scoring system that quantifies patients' early postoperative health status with range of 0-150 where higher score means better quality of recovery. We used the 15-question version, the QoR-15</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">136</enrollment>
  <condition>Pain, Postoperative</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Arm</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naloxegol 25 MG</intervention_name>
    <description>Oral Naloxegol 25 MG</description>
    <arm_group_label>Treatment Arm</arm_group_label>
    <other_name>Movantik</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>matching oral placebo</description>
    <arm_group_label>Placebo Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
          2. Female or male aged at least 18 years&#xD;
&#xD;
          3. American Society of Anesthesiologists physical status 1-4;&#xD;
&#xD;
          4. Scheduled for elective primary hip or knee surgery under spinal anesthesia;&#xD;
&#xD;
          5. Expected to receive intravenous patient-controlled analgesia (IV PCA)&#xD;
&#xD;
          6. Expected to have significant postoperative pain&#xD;
&#xD;
          7. Negative pregnancy test&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Severe hepatic impairment, with/or twice the upper normal levels of liver enzymes&#xD;
&#xD;
          2. Severe renal impairment, or creatinine level &gt; 2.0&#xD;
&#xD;
          3. History of bladder cancer&#xD;
&#xD;
          4. Patients receiving perioperative regional anesthesia blocks&#xD;
&#xD;
          5. Presence of a sacral nerve stimulator&#xD;
&#xD;
          6. Medications (anticholinergic agents such as antihistamines, phenothiazines,&#xD;
             antidepressants, antipsychotics), conditions or comorbidity causing urinary retention&#xD;
&#xD;
          7. Patient with requirement of urinary catheter insertion before or immediately&#xD;
             post-surgery due to immobility&#xD;
&#xD;
          8. Urinary Tract Infections and other urogenital comorbidity (incontinence,&#xD;
             cysto-ureteric reflux, known bladder retention) or conditions which can cause urinary&#xD;
             retention&#xD;
&#xD;
          9. Severe peptic ulcer disease, diverticular disease, infiltrative gastrointestinal tract&#xD;
             malignancies, or peritoneal metastases&#xD;
&#xD;
         10. Patients with known or suspected disruption of blood brain barrier, which may include&#xD;
             but not limited to: Alzheimer's disease, stroke, poliomyelitis, cerebral palsy,&#xD;
             multiple sclerosis, spinal lesions, and Parkinson's disease&#xD;
&#xD;
         11. Gastrointestinal obstruction/Gastrointestinal perforation&#xD;
&#xD;
         12. Strong CYP3A4 inhibitors (some antibiotics, antifungals, protease inhibitors, and&#xD;
             antidepressants), Strong CYP3A4 inducers, Other opioid antagonists&#xD;
&#xD;
         13. Hypersensitivity to MOVANTIK (naloxegol) or any of its excipients&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mehmet A Turan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Cleveland Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Cleveland Clinic Foundation</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 18, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <results_first_submitted>September 14, 2022</results_first_submitted>
  <results_first_submitted_qc>August 14, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">September 5, 2023</results_first_posted>
  <last_update_submitted>August 14, 2023</last_update_submitted>
  <last_update_submitted_qc>August 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Cleveland Clinic</investigator_affiliation>
    <investigator_full_name>Alparslan Turan</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </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>Naloxegol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Data to be provided in aggregate without patient identifiers</ipd_description>
  </patient_data>
  <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>November 26, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT03235739/Prot_SAP_006.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 23, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT03235739/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>of 508 patients screened, 136 patients meet all inclusion and exclusion criteria and gave consent to the study. 136 patients were randomized.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Treatment-Naloxegol</title>
          <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Naloxegol 25 MG: Oral Naloxegol 25 MG</description>
        </group>
        <group group_id="P2">
          <title>Placebo Arm</title>
          <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Placebo: matching 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="69"/>
                <participants group_id="P2" count="67"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="67"/>
                <participants group_id="P2" count="64"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </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="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment-Naloxegol</title>
          <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Naloxegol 25 MG: Oral Naloxegol 25 MG</description>
        </group>
        <group group_id="B2">
          <title>Placebo Arm</title>
          <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Placebo: matching 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="67"/>
            <count group_id="B2" value="64"/>
            <count group_id="B3" value="131"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64" spread="13"/>
                    <measurement group_id="B2" value="62" spread="11"/>
                    <measurement group_id="B3" value="63" spread="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="64"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Caucasian</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59"/>
                    <measurement group_id="B2" value="57"/>
                    <measurement group_id="B3" value="116"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>African American</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ASA status</title>
          <description>ASA Physical Status Classification System, where lower number means better condition. I means a normal healthy patient and VI means a declared brain-dead patient whose organs are being removed for donor purposes</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="52"/>
                    <measurement group_id="B2" value="46"/>
                    <measurement group_id="B3" value="98"/>
                  </measurement_list>
                </category>
                <category>
                  <title>4</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Apfel PONV score</title>
          <description>Apfel Score for Postoperative Nausea and Vomiting. The EMR- based risk scoring tool was integrated into all preanesthetic assessments and allowed for the assignment of low, moderate, or high risk of PONV. Low risk was defined as an Apfel score of 0 to1, medium risk was defined as an Apfel score of 2, and high risk was defined as an Apfel score of 3 or greater. The minimum of the score is 0 and maximum score is 4.</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2" lower_limit="2" upper_limit="3"/>
                    <measurement group_id="B2" value="2" lower_limit="2" upper_limit="3"/>
                    <measurement group_id="B3" value="2" lower_limit="2" upper_limit="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Chronic opioid use</title>
          <description>Chronic opioid use will be defined as opioid use for more than 30 consecutive days, at a daily dose of 15 mg or more of morphine or equivalent, within the 3 months before surgery.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Surgery type</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hip</title>
                  <measurement_list>
                    <measurement group_id="B1" value="67"/>
                    <measurement group_id="B2" value="64"/>
                    <measurement group_id="B3" value="131"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Knee</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>Surgery duration</title>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.6" lower_limit="2.9" upper_limit="4.7"/>
                    <measurement group_id="B2" value="3.5" lower_limit="2.9" upper_limit="4.5"/>
                    <measurement group_id="B3" value="3.6" lower_limit="2.9" upper_limit="4.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Medical history</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Kidney disease</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>chronic pulmonary disease</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>obstructive sleep apnea</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>diabetes mellitus</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>myocardial infarction</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ischemic Heart Disease</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>neurological disease</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>chronic pain</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>current smoker</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>drug user</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>alcohol abuse</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>cancer</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="64"/>
                    <count group_id="B3" value="131"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Anesthesia type</title>
          <population>one patient was missing on anesthesia type information</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="63"/>
                    <count group_id="B3" value="130"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>General anesthesia</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="45"/>
                    <measurement group_id="B3" value="91"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Spinal anesthesia</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intraoperative colloids, ml</title>
          <population>one patient was missing on colloids information</population>
          <units>ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="63"/>
                    <count group_id="B3" value="130"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0" lower_limit="0" upper_limit="500"/>
                    <measurement group_id="B2" value="0" lower_limit="0" upper_limit="250"/>
                    <measurement group_id="B3" value="0" lower_limit="0" upper_limit="300"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intraoperative crystalloids</title>
          <population>one patient was missing on crystalloids</population>
          <units>ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="63"/>
                    <count group_id="B3" value="130"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2000" lower_limit="1400" upper_limit="2700"/>
                    <measurement group_id="B2" value="1800" lower_limit="1400" upper_limit="2700"/>
                    <measurement group_id="B3" value="1900" lower_limit="1400" upper_limit="2700"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intraoperative RBC</title>
          <population>one patient was missing</population>
          <units>cc</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="63"/>
                    <count group_id="B3" value="130"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="B2" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="B3" value="0" lower_limit="0" upper_limit="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intraoperative platelets</title>
          <population>one patient was missing</population>
          <units>cc</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="63"/>
                    <count group_id="B3" value="130"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="B2" value="0" lower_limit="0" upper_limit="0"/>
                    <measurement group_id="B3" value="0" lower_limit="0" upper_limit="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>intraoperative Urine</title>
          <population>one patient was missing</population>
          <units>cc</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="63"/>
                    <count group_id="B3" value="130"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0" lower_limit="0" upper_limit="420"/>
                    <measurement group_id="B2" value="0" lower_limit="0" upper_limit="460"/>
                    <measurement group_id="B3" value="0" lower_limit="0" upper_limit="420"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intraoperative opioid use</title>
          <population>one patient was missing</population>
          <units>mg</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="67"/>
                    <count group_id="B2" value="63"/>
                    <count group_id="B3" value="130"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20" lower_limit="5" upper_limit="30.3"/>
                    <measurement group_id="B2" value="20" lower_limit="7.5" upper_limit="25.3"/>
                    <measurement group_id="B3" value="20" lower_limit="5" upper_limit="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Residual Urine Volume</title>
        <description>Residual urine volume in the bladder as assessed by bladder scan</description>
        <time_frame>from Postoperative days 1 to POD 2 or until day of discharge whichever occurs first</time_frame>
        <population>17 patients were completely missing on urine residual. Multiple imputation was used solely for estimating the treatment effect on urinal residual. The summary statistics of urine residual for each day was reported based on original data.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment-Naloxegol</title>
            <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Naloxegol 25 MG: Oral Naloxegol 25 MG</description>
          </group>
          <group group_id="O2">
            <title>Placebo Arm</title>
            <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Placebo: matching oral placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Residual Urine Volume</title>
          <description>Residual urine volume in the bladder as assessed by bladder scan</description>
          <population>17 patients were completely missing on urine residual. Multiple imputation was used solely for estimating the treatment effect on urinal residual. The summary statistics of urine residual for each day was reported based on original data.</population>
          <units>ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="59"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1 AM</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="40"/>
                    <count group_id="O2" value="46"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="62" lower_limit="5" upper_limit="187"/>
                    <measurement group_id="O2" value="114" lower_limit="13" upper_limit="247"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 1 PM</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="41"/>
                    <count group_id="O2" value="43"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48" lower_limit="0" upper_limit="206"/>
                    <measurement group_id="O2" value="31" lower_limit="0" upper_limit="169"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 2 AM</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="39"/>
                    <count group_id="O2" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32" lower_limit="0" upper_limit="152"/>
                    <measurement group_id="O2" value="28" lower_limit="0" upper_limit="122"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 2 PM</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="32"/>
                    <count group_id="O2" value="37"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="0" upper_limit="122"/>
                    <measurement group_id="O2" value="28" lower_limit="0" upper_limit="66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>multiple imputation for longitudinal data was conducted to impute the missing data for the primary outcome. The final results were obtained from pooling results from 10 imputed complete case data set.</non_inferiority_desc>
            <p_value>0.84</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>geometric mean ratio</param_type>
            <param_value>0.90</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.32</ci_lower_limit>
            <ci_upper_limit>2.55</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A sensitivity analysis using complete case analysis</non_inferiority_desc>
            <p_value>0.73</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>geometric mean ratio</param_type>
            <param_value>0.82</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.26</ci_lower_limit>
            <ci_upper_limit>2.56</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Side Effects of Naloxegol on Other Opioid Related Side Effects</title>
        <description>Opioid-related Symptom Distress Scale (ORSDS) is a 4 point-scale that evaluates three symptom distress dimensions (frequency, severity, bothersomeness) for opioid-related side effects. The 12 elements of the ORSDS are nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness, lightheaded, fatigue, feeling confused, itchiness, dry mouth, and headache. The ORSDS questionnaire was administered by a trained investigator on first and second postoperative days while patients remained hospitalized. We reported the average ORSDS score from all 12 elements, which ranged from 0 to 4 and higher scores represent worse outcome.</description>
        <time_frame>Postoperative days 1-2 or until day of discharge whichever occurs first</time_frame>
        <population>some patients were missing on this outcome at repeated measurements. A mixed effects model assuming auto-regressive correlation structure and the outcome was log-transformed</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment-Naloxegol</title>
            <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Naloxegol 25 MG: Oral Naloxegol 25 MG</description>
          </group>
          <group group_id="O2">
            <title>Placebo Arm</title>
            <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Placebo: matching oral placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Side Effects of Naloxegol on Other Opioid Related Side Effects</title>
          <description>Opioid-related Symptom Distress Scale (ORSDS) is a 4 point-scale that evaluates three symptom distress dimensions (frequency, severity, bothersomeness) for opioid-related side effects. The 12 elements of the ORSDS are nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness, lightheaded, fatigue, feeling confused, itchiness, dry mouth, and headache. The ORSDS questionnaire was administered by a trained investigator on first and second postoperative days while patients remained hospitalized. We reported the average ORSDS score from all 12 elements, which ranged from 0 to 4 and higher scores represent worse outcome.</description>
          <population>some patients were missing on this outcome at repeated measurements. A mixed effects model assuming auto-regressive correlation structure and the outcome was log-transformed</population>
          <units>log(score on a scale)</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="66"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="66"/>
                    <count group_id="O2" value="61"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.53" lower_limit="0.34" upper_limit="0.79"/>
                    <measurement group_id="O2" value="0.45" lower_limit="0.31" upper_limit="0.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="54"/>
                    <count group_id="O2" value="52"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.34" lower_limit="0.2" upper_limit="0.64"/>
                    <measurement group_id="O2" value="0.34" lower_limit="0.13" upper_limit="0.62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.91</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>geometric mean ratio</param_type>
            <param_value>1.02</param_value>
            <ci_percent>98.3</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.63</ci_lower_limit>
            <ci_upper_limit>1.67</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Need for Indwelling Urinary Catheterization</title>
        <description>Number of patients receiving Naloxegol requiring indwelling urinary catheters</description>
        <time_frame>Postoperative days 1-2 or until day of discharge whichever occurs first</time_frame>
        <population>Our final analyzed study population had 131 patients since 5 patients did not complete (due to withdrawal or not receiving any treatment) the study thus were removed from the final analysis. Among 131 patients, 4 patients were missing from this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment-Naloxegol</title>
            <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Naloxegol 25 MG: Oral Naloxegol 25 MG</description>
          </group>
          <group group_id="O2">
            <title>Placebo Arm</title>
            <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Placebo: matching oral placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Need for Indwelling Urinary Catheterization</title>
          <description>Number of patients receiving Naloxegol requiring indwelling urinary catheters</description>
          <population>Our final analyzed study population had 131 patients since 5 patients did not complete (due to withdrawal or not receiving any treatment) the study thus were removed from the final analysis. Among 131 patients, 4 patients were missing from this analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="65"/>
                <count group_id="O2" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.012</p_value>
            <method>Chi-squared</method>
            <param_type>Risk Ratio (RR)</param_type>
            <param_value>2.58</param_value>
            <ci_percent>98.3</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.98</ci_lower_limit>
            <ci_upper_limit>6.80</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Quality of Recovery</title>
        <description>Quality of recovery is a validated scoring system that quantifies patients' early postoperative health status with range of 0-150 where higher score means better quality of recovery. We used the 15-question version, the QoR-15</description>
        <time_frame>Postoperative Days 2 or discharge day whichever was earlier</time_frame>
        <population>We only had a total of 131 patients in our final analysis since 5 patients were removed from the final analysis due to not completing the study (withdrawal or not receiving any treatment). Among 131 patients, 9 patients were missing from this analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment-Naloxegol</title>
            <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Naloxegol 25 MG: Oral Naloxegol 25 MG</description>
          </group>
          <group group_id="O2">
            <title>Placebo Arm</title>
            <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Placebo: matching oral placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Quality of Recovery</title>
          <description>Quality of recovery is a validated scoring system that quantifies patients' early postoperative health status with range of 0-150 where higher score means better quality of recovery. We used the 15-question version, the QoR-15</description>
          <population>We only had a total of 131 patients in our final analysis since 5 patients were removed from the final analysis due to not completing the study (withdrawal or not receiving any treatment). Among 131 patients, 9 patients were missing from this analysis</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="63"/>
                <count group_id="O2" value="59"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="119" lower_limit="103" upper_limit="131"/>
                    <measurement group_id="O2" value="123" lower_limit="115" upper_limit="133"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.08</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>median of differences</param_type>
            <param_value>-5</param_value>
            <ci_percent>98.3</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-12</ci_lower_limit>
            <ci_upper_limit>2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>until discharge from hospital, an average of 2 day, up to 3 days</time_frame>
      <desc>Adverse events of particular interest are:&#xD;
Opioid withdrawal: hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability&#xD;
Severe abdominal pain (&gt;8/10) and/or diarrhea&#xD;
Gastrointestinal perforation</desc>
      <group_list>
        <group group_id="E1">
          <title>Treatment-Naloxegol</title>
          <description>Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Naloxegol 25 MG: Oral Naloxegol 25 MG</description>
        </group>
        <group group_id="E2">
          <title>Placebo Arm</title>
          <description>Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first&#xD;
Placebo: matching oral placebo</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="67"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="67"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Troponin elevation and ST elevation</sub_title>
                <description>Patient was transferred to coronary ICU for further care. A heparin infusion was initiated. A left heart cath is planned for 5/31/2018.&#xD;
Reported to PI. Not related to study medication. Continue to follow patient status.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="67"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="64"/>
              </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="67"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There IS 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>Alparslan Turan, MD</name_or_title>
      <organization>Cleveland Clinic</organization>
      <phone>216-4459857</phone>
      <email>turana@ccf.org</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/NCT03235739
org study id: 17-765
nct id: NCT03235739
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to find out whether oral Naloxegol can reduce the side effects
      of opioid painkillers following surgery. This study aims to explore whether Naloxegol can
      similarly reduce opioid-induced side effects in post-surgical patients. About 130 surgery
      patients will participate in this study which is being conducted at Cleveland Clinic Main
      Campus.
Opioids are the gold standard for postoperative pain management, but they have been shown to
      produce uncomfortable side effects such as urinary retention (an inability to completely
      empty the bladder), constipation and nausea/vomiting. Clinical evidence demonstrates that
      Naloxegol can safely and effectively block these undesirable side effects while maintaining
      the painkilling effects of opioids in outpatients suffering from opioid-induced constipation.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Effect of Naloxegol on reversing opioid-related side effects in patients recovering from elective primary hip surgery under spinal anesthesia who will be randomly assigned to oral Naloxegol or placebo for two postoperative days or until the date of discharge, whichever occurs earlier. The design will be a randomized, double-blind, placebo-controlled trial of oral Naloxegol in adults having elective primary hip or knee surgery under spinal anesthesia. The study will be performed at the Cleveland Clinic hospitals.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Residual Urine Volume
time frame: from Postoperative days 1 to POD 2 or until day of discharge whichever occurs first
description: Residual urine volume in the bladder as assessed by bladder scan
measure: Side Effects of Naloxegol on Other Opioid Related Side Effects
time frame: Postoperative days 1-2 or until day of discharge whichever occurs first
description: Opioid-related Symptom Distress Scale (ORSDS) is a 4 point-scale that evaluates three symptom distress dimensions (frequency, severity, bothersomeness) for opioid-related side effects. The 12 elements of the ORSDS are nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness, lightheaded, fatigue, feeling confused, itchiness, dry mouth, and headache. The ORSDS questionnaire was administered by a trained investigator on first and second postoperative days while patients remained hospitalized. We reported the average ORSDS score from all 12 elements, which ranged from 0 to 4 and higher scores represent worse outcome.
measure: Need for Indwelling Urinary Catheterization
time frame: Postoperative days 1-2 or until day of discharge whichever occurs first
description: Number of patients receiving Naloxegol requiring indwelling urinary catheters
measure: Quality of Recovery
time frame: Postoperative Days 2 or discharge day whichever was earlier
description: Quality of recovery is a validated scoring system that quantifies patients' early postoperative health status with range of 0-150 where higher score means better quality of recovery. We used the 15-question version, the QoR-15
arm group label: Treatment Arm
arm group type: Experimental
description: Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first
arm group label: Placebo Arm
arm group type: Placebo Comparator
description: Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first
intervention type: Drug
intervention name: Naloxegol 25 MG
description: Oral Naloxegol 25 MG
arm group label: Treatment Arm
other name: Movantik
intervention type: Drug
intervention name: Placebo
description: matching oral placebo
arm group label: Placebo Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mehmet A Turan, MD
role: Principal Investigator
affiliation: The Cleveland Clinic
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The Cleveland Clinic
investigator full name: Alparslan Turan
investigator title: Principal Investigator
mesh term: Pain, Postoperative
mesh term: Naloxegol
sharing ipd: No
ipd description: Data to be provided in aggregate without patient identifiers
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 