<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/NCT03015961</url>
  </required_header>
  <id_info>
    <org_study_id>402-C-409</org_study_id>
    <nct_id>NCT03015961</nct_id>
  </id_info>
  <brief_title>Phase 4, Controlled Study in Adult Subjects Undergoing Primary, 1-2 Level, Open Lumbar Spinal Fusion Surgery</brief_title>
  <official_title>A Multicenter, Randomized, Double-Blind, Controlled Study of EXPAREL for Postsurgical Pain Management in Subjects Undergoing Open Lumbar Spinal Fusion Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pacira Pharmaceuticals, Inc</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Pacira Pharmaceuticals, Inc</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>
      Primary Objective: The primary objective of this study is to compare postsurgical pain&#xD;
      control following local infiltration analgesia (LIA) with EXPAREL admixed with bupivacaine&#xD;
      HCl versus LIA with bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal&#xD;
      fusion surgery.&#xD;
&#xD;
      Secondary Objectives: The secondary objectives of this study are to compare additional&#xD;
      efficacy, safety, and health economic outcomes following LIA with EXPAREL admixed with&#xD;
      bupivacaine HCl versus LIA with bupivacaine HCl in adult subjects undergoing open lumbar&#xD;
      posterior spinal fusion surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 4, multicenter, randomized, double-blind, controlled study in 38 adult&#xD;
      subjects undergoing primary, 1-2 level, open lumbar spinal fusion surgery under general&#xD;
      anesthesia.&#xD;
&#xD;
      Subjects will be screened within 30 days prior to study drug administration and at least one&#xD;
      day prior to surgery. During the screening visit, subjects will be assessed for past or&#xD;
      present neurologic, cardiac, and general medical conditions that in the opinion of the&#xD;
      Investigator would preclude them from study participation. After the informed consent form&#xD;
      (ICF) is signed, a medical history, surgical history, physical examination, 12-lead&#xD;
      electrocardiogram (ECG), vital sign measurements, select clinical laboratory evaluations,&#xD;
      urine drug screen, alcohol breath test, and urine pregnancy test for women of childbearing&#xD;
      potential will be conducted. Study drug, approximately 1-2 mL every 1.0-1.5 cm, will be&#xD;
      administered using 20- or 22-gauge needles prior to wound closure.&#xD;
&#xD;
      Administration Instructions/Procedures&#xD;
&#xD;
      Study drug should be injected in the prescribed locations based on the areas of highest nerve&#xD;
      density. Study drug will be administered using syringes with 20- or 22-gauge needles prior to&#xD;
      wound closure. The Investigator must document the size of the incision. Each infiltration&#xD;
      site should be spaced 1.0-1.5 cm apart and should deliver approximately 1-2 mL into both deep&#xD;
      and superficial areas (para-spinous fascia, muscle, and subcutaneous layers). Total volume&#xD;
      administered will be depended on the number of levels of dissection, as described below.&#xD;
      Following infiltration, the tissue should visibly expand with minimal leakage.&#xD;
&#xD;
      Total Volume of Expansion&#xD;
&#xD;
      The Investigator must document the total volume used for each surgery.&#xD;
&#xD;
        1. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 20&#xD;
           mL normal saline = total volume of 60 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 40 mL&#xD;
           normal saline = total volume of 60 mL&#xD;
&#xD;
        2. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 50&#xD;
           mL normal saline = total volume of 90 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 70 mL&#xD;
           normal saline = total volume of 90 mL&#xD;
&#xD;
      Drains may be used at the surgeon's discretion. In addition to LIA, all study participants&#xD;
      will receive a standardized approach for managing postsurgical pain that includes a scheduled&#xD;
      multimodal pain regimen including adjunctive analgesics, non-steroidal anti-inflammatory&#xD;
      drugs (NSAIDs). Rescue analgesics will be available as needed.&#xD;
&#xD;
      Postsurgical clinical assessments will include pain intensity scores using a 10-cm visual&#xD;
      analog scale (VAS) (see Appendix 1); overall benefit of analgesia score (OBAS) questionnaire&#xD;
      (see Appendix 2); total postsurgical opioid consumption; predefined opioid-related AEs; and&#xD;
      nurse's satisfaction with overall analgesia (see Appendix 3).&#xD;
&#xD;
      Adverse events will be recorded from the time the ICF is signed through Day 30. If a cardiac&#xD;
      AE (e.g., chest pain [angina, myocardial infarction], abnormal/irregular heart rate&#xD;
      [bradycardia, tachycardia, extrasystoles], or shortness of breath), neurological AE (e.g.,&#xD;
      altered mental status/altered sensorium, dizziness, dysarthria, hyperesthesia, metallic&#xD;
      taste, peroral numbness, seizure, tinnitus, tremors, visual disturbance, muscular twitching&#xD;
      or rigidity beyond 72 hours postdose, or tingling/paresthesia beyond 72 hours postdose), or&#xD;
      serious AE (SAE) occurs during the study a 12-lead ECG, vital signs, and any appropriate&#xD;
      clinical laboratory tests should be conducted.&#xD;
&#xD;
      Postsurgical health economic outcome assessments will include hospital length of stay (LOS),&#xD;
      use of skilled nursing facility, hospital readmissions, and use of other health services&#xD;
      following discharge (phone calls related to postsurgical pain, unscheduled visits related to&#xD;
      postsurgical pain, and visits to emergency department) through Day 30.&#xD;
&#xD;
      A follow-up visit will be scheduled for all subjects on postsurgical Day 14. A follow-up&#xD;
      phone call will be made on Day 30 to all subjects who received study drug to assess for&#xD;
      adverse events (AEs).&#xD;
&#xD;
      Number of Subjects (Planned):&#xD;
&#xD;
      Approximately 194 subjects are planned for enrollment in this study in order to have at least&#xD;
      184 evaluable subjects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow enrollment&#xD;
  </why_stopped>
  <start_date type="Actual">February 21, 2017</start_date>
  <completion_date type="Actual">October 30, 2017</completion_date>
  <primary_completion_date type="Actual">October 30, 2017</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores From 0 to 72 Hours</measure>
    <time_frame>0-72 hours</time_frame>
    <description>AUC of VAS pain intensity scores from 0 to 72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, &quot;How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now.&quot; AUC curve is derived using the trapezoidal rule (see formula below) on the pain scores. AUC start with the first pain assessment obtained after surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery. Note t1 is pain score collected after surgery.)</description>
  </primary_outcome>
  <other_outcome>
    <measure>Percentage of Opioid-Free Patients</measure>
    <time_frame>0-24, 0-48, 0-72 hours</time_frame>
    <description>Percentage of opioid-free patients through 24, 48 and 72 hours post-surgery</description>
  </other_outcome>
  <other_outcome>
    <measure>Area Under the Curve (AUC) of the Visual Analog Scale (VAS) Pain Intensity Scores From 24-48 and 48-72 Hours Postsurgery</measure>
    <time_frame>24-48 hours, 48-72 hours</time_frame>
    <description>AUC of the VAS pain intensity scores from 24-48 and 48-72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, &quot;How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now.&quot; AUC from 24-48 hours start with the pain assessment obtained at 24 hours post-surgery and use all subsequent pain assessments up to 48 hours post-surgery. AUC from 48-72 hours start with the pain assessment obtained at 48 hours post-surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery.)</description>
  </other_outcome>
  <other_outcome>
    <measure>Total Opioid Consumption Through 48 Hours Postsurgery</measure>
    <time_frame>0-48 hours</time_frame>
    <description>Total Opioid Consumption Through 48 Hours Postsurgery</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">38</enrollment>
  <condition>Postoperative Pain Management</condition>
  <arm_group>
    <arm_group_label>EXPAREL admixed with bupivacaine HCl</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>EXPAREL 266 mg + bupivacaine HCl</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bupivacaine HCl</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Bupivacaine HCl</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EXPAREL and bupivacaine HCl</intervention_name>
    <description>Drug: EXPAREL EXPAREL and bupivacaine HCl&#xD;
Other Name: bupivacaine liposome injectable suspension Drug: Bupivacaine Single dose of bupivacaine HCl 0.5%&#xD;
Other Name: bupivacaine HCl</description>
    <arm_group_label>EXPAREL admixed with bupivacaine HCl</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupivacaine HCl</intervention_name>
    <description>Drug: Bupivacaine Single dose of bupivacaine HCl 0.5%&#xD;
Other Name: bupivacaine HCl</description>
    <arm_group_label>Bupivacaine HCl</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female, at least 18 years of age at screening.&#xD;
&#xD;
          2. Primary surgical indication is lumbar pain, radiculopathy, disc degeneration, disc&#xD;
             herniation, foraminal stenosis, or 1-2 level spondylolisthesis or deformity.&#xD;
&#xD;
          3. Scheduled to undergo primary, 1-2 level, open lumbar spinal fusion surgery under&#xD;
             general anesthesia.&#xD;
&#xD;
          4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.&#xD;
&#xD;
          5. Female subjects must be surgically sterile; or at least 2 years postmenopausal; or&#xD;
             have a monogamous partner who is surgically sterile; or practicing double-barrier&#xD;
             contraception; or practicing abstinence (must agree to use double-barrier&#xD;
             contraception in the event of sexual activity); or using an insertable, injectable, or&#xD;
             transdermal, contraceptive approved by the FDA for greater than 2 months prior to&#xD;
             screening. All women of childbearing potential (ie, premenopausal without permanent&#xD;
             sterilization) must commit to the use of an acceptable form of birth control for the&#xD;
             duration of the study and for 30 days after completion of the study.&#xD;
&#xD;
          6. Able to provide informed consent, adhere to the study visit schedule, and complete all&#xD;
             study assessments.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Currently pregnant, nursing, or planning to become pregnant during the study or within&#xD;
             1 month after study drug administration.&#xD;
&#xD;
          2. Serious spinal conditions (to include cauda equina syndrome, infection, tumor,&#xD;
             fracture, or severe osteoporosis [ie, if taking Bisphosphonate or TNF-α blockers]).&#xD;
&#xD;
          3. Planned anterior or lateral incisions&#xD;
&#xD;
          4. Previous spinal surgery at the same level other than microdiscectomy or&#xD;
             hemilaminectomy (eg, bi-lateral laminectomy, fusion).&#xD;
&#xD;
          5. Planned concurrent surgical procedure.&#xD;
&#xD;
          6. Identification of a dural tear during surgery will be an intra-operative exclusion&#xD;
             unless it is well repaired (no evidence of cerebrospinal fluid [CSF] leak with&#xD;
             Valsalva and no plan to restrict activity post-operatively). Any injury to the nerve&#xD;
             root occurring during surgery will also be considered an intra-operative exclusion.&#xD;
&#xD;
          7. Concurrent painful physical condition that may require analgesic treatment (such as an&#xD;
             NSAID or opioid) in the postsurgical period for pain that is not strictly related to&#xD;
             the spinal surgery and which may confound the postsurgical assessments.&#xD;
&#xD;
          8. Comorbidity impacting current physical function or Investigator opinion that it may&#xD;
             impact postsurgical rehabilitation.&#xD;
&#xD;
          9. Allergy, hypersensitivity, or contraindication to any of the study medications (ie,&#xD;
             bupivacaine, oxycodone, morphine, hydromorphone, gabapentin, acetaminophen, or&#xD;
             cyclobenzaprine) for which an alternative medication is not provided in the protocol.&#xD;
&#xD;
         10. Use of any of the following medications within the times specified before surgery:&#xD;
             long-acting opioid medication (eg, morphine including MS Contin®, hydromorphone&#xD;
             [Dilaudid®], oxycodone [Oxycontin®], methadone) daily for more than 3 months duration&#xD;
             or within 3 days of surgery. Patients receiving short-acting opioids or NSAIDs should&#xD;
             be at a steady or plateau dose. Such patients should require or receive no more than&#xD;
             40 mg morphine (oral) equivalents (eg, approximately 5 mg oxycodone) within 24 hours&#xD;
             of surgery.&#xD;
&#xD;
         11. Initiation of treatment with any of the following medications within 1 month of study&#xD;
             drug administration or if the medication(s) are being given to control pain: selective&#xD;
             serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors&#xD;
             (SNRIs), or duloxetine (Cymbalta®). If a subject is taking one of these medications&#xD;
             for a reason other than pain control, he or she must be on a stable dose for at least&#xD;
             1 month prior to study drug administration.&#xD;
&#xD;
         12. Current use of systemic glucocorticosteroids within 1 month of enrollment in this&#xD;
             study.&#xD;
&#xD;
         13. Use of dexmedetomidine HCl (Precedex®) within 3 days of study drug administration.&#xD;
&#xD;
         14. History of coronary or vascular stent placed within the past 3 months (may be extended&#xD;
             to 1 year if medically indicated per physician discretion).&#xD;
&#xD;
         15. Have been treated for a deep vein thrombosis, pulmonary embolism, myocardial&#xD;
             infarction, or ischemic stroke within the past 6 months (may be extended to 1 year if&#xD;
             medically indicated per physician discretion).&#xD;
&#xD;
         16. Severely impaired renal (eg, serum creatinine clearance ≤ 30) or hepatic function (eg,&#xD;
             serum aspartate aminotransferase [AST] level &gt;3 times the upper limit of normal [ULN]&#xD;
             or serum alanine aminotransferase [ALT] level &gt;3 x ULN).&#xD;
&#xD;
         17. Any neurologic or psychiatric disorder that might impact postsurgical pain or&#xD;
             interfere with study assessments.&#xD;
&#xD;
         18. Malignancy in the last 2 years, per physician discretion.&#xD;
&#xD;
         19. History of misuse, abuse, or dependence on opioid analgesics, other prescription&#xD;
             drugs, illicit drugs, or alcohol as defined in DSM-IV. Dependence or chronic opioid&#xD;
             use will be defined as use of more than 30 morphine equivalents per day during the&#xD;
             prior 90 days.&#xD;
&#xD;
         20. Failure to pass the alcohol breath test or urine drug screen positive for illicit&#xD;
             drugs.&#xD;
&#xD;
         21. Body weight &lt;50 kg (110 pounds) or a body mass index &gt;44 kg/m2.&#xD;
&#xD;
         22. Subjects receiving Worker's compensation for a disability or who are involved in&#xD;
             litigation.&#xD;
&#xD;
         23. Previous participation in an EXPAREL study.&#xD;
&#xD;
         24. Administration of an investigational drug within 30 days or 5 elimination half-lives&#xD;
             of such investigational drug, whichever is longer, prior to study drug administration,&#xD;
             or planned administration of another investigational product or procedure during the&#xD;
             subject's participation in this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>OrthoArizona</name>
      <address>
        <city>Gilbert</city>
        <state>Arizona</state>
        <zip>85295</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph's Hospital</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UC Davis</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beaumont Health</name>
      <address>
        <city>Troy</city>
        <state>Michigan</state>
        <zip>48085</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington Univ</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Icahn School of Medicine</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>OrthoCarolina</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State Univ</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Thomas Jefferson University of Neurosurgery</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Texas Spine Institute</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78731</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor Scott &amp; White</name>
      <address>
        <city>Temple</city>
        <state>Texas</state>
        <zip>76508</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Univ of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Colonial Orthopaedics</name>
      <address>
        <city>Colonial Heights</city>
        <state>Virginia</state>
        <zip>23834</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Virginia University Hospitals</name>
      <address>
        <city>Morgantown</city>
        <state>West Virginia</state>
        <zip>26506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>November 14, 2016</study_first_submitted>
  <study_first_submitted_qc>January 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 10, 2017</study_first_posted>
  <results_first_submitted>September 18, 2020</results_first_submitted>
  <results_first_submitted_qc>October 12, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">October 13, 2021</results_first_posted>
  <last_update_submitted>October 12, 2021</last_update_submitted>
  <last_update_submitted_qc>October 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 13, 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>Bupivacaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>August 2, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/61/NCT03015961/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 5, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/61/NCT03015961/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited between February 21, 2017 and October 30, 2017 at 15 sites in the United States. The study was terminated due to low enrollment.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>EXPAREL Admixed With Bupivacaine HCl</title>
          <description>Local infiltration analgesia with EXPAREL (bupivacaine liposome injectable suspension) 266 mg/20 mL admixed with bupivacaine HCl 0.5% 20 mL and expanded with 20 mL (1-level procedures) or 50 mL (2-level procedures) normal saline</description>
        </group>
        <group group_id="P2">
          <title>Bupivacaine HCl</title>
          <description>Local infiltration analgesia with bupivacaine hydrochloride (HCl) 0.5% 20 mL expanded with 40 mL (1-level procedures) or 70 mL (2-level procedures) normal saline</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All randomized subjects. The study was terminated; no efficacy outcomes were analyzed.</population>
      <group_list>
        <group group_id="B1">
          <title>EXPAREL Admixed With Bupivacaine HCl</title>
          <description>Local infiltration analgesia with EXPAREL (bupivacaine liposome injectable suspension) 266 mg/20 mL admixed with bupivacaine HCl 0.5% 20 mL and expanded with 20 mL (1-level procedures) or 50 mL (2-level procedures) normal saline</description>
        </group>
        <group group_id="B2">
          <title>Bupivacaine HCl</title>
          <description>Local infiltration analgesia with bupivacaine HCl 0.5% 20 mL expanded with 40 mL (1-level procedures) or 70 mL (2-level procedures) normal saline</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="18"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="38"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>year</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57.3" spread="12.13"/>
                    <measurement group_id="B2" value="61.6" spread="9.33"/>
                    <measurement group_id="B3" value="59.5" spread="10.81"/>
                  </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>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="16"/>
                  </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="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="36"/>
                  </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="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</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>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="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="37"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores From 0 to 72 Hours</title>
        <description>AUC of VAS pain intensity scores from 0 to 72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, &quot;How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now.&quot; AUC curve is derived using the trapezoidal rule (see formula below) on the pain scores. AUC start with the first pain assessment obtained after surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery. Note t1 is pain score collected after surgery.)</description>
        <time_frame>0-72 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EXPAREL Admixed With Bupivacaine HCl</title>
            <description>Local infiltration analgesia with EXPAREL (bupivacaine liposome injectable suspension) 266 mg/20 mL admixed with bupivacaine HCl 0.5% 20 mL and expanded with 20 mL (1-level procedures) or 50 mL (2-level procedures) normal saline</description>
          </group>
          <group group_id="O2">
            <title>Bupivacaine HCl</title>
            <description>Local infiltration analgesia with bupivacaine HCl 0.5% 20 mL expanded with 40 mL (1-level procedures) or 70 mL (2-level procedures) normal saline</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores From 0 to 72 Hours</title>
          <description>AUC of VAS pain intensity scores from 0 to 72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, &quot;How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now.&quot; AUC curve is derived using the trapezoidal rule (see formula below) on the pain scores. AUC start with the first pain assessment obtained after surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery. Note t1 is pain score collected after surgery.)</description>
          <units>score on a scale*hours</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="342.8" lower_limit="1" upper_limit="624"/>
                    <measurement group_id="O2" value="369.0" lower_limit="96" upper_limit="718"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Percentage of Opioid-Free Patients</title>
        <description>Percentage of opioid-free patients through 24, 48 and 72 hours post-surgery</description>
        <time_frame>0-24, 0-48, 0-72 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EXPAREL Admixed With Bupivacaine HCl</title>
            <description>Local infiltration analgesia with EXPAREL (bupivacaine liposome injectable suspension) 266 mg/20 mL admixed with bupivacaine HCl 0.5% 20 mL and expanded with 20 mL (1-level procedures) or 50 mL (2-level procedures) normal saline</description>
          </group>
          <group group_id="O2">
            <title>Bupivacaine HCl</title>
            <description>Local infiltration analgesia with bupivacaine HCl 0.5% 20 mL expanded with 40 mL (1-level procedures) or 70 mL (2-level procedures) normal saline</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Opioid-Free Patients</title>
          <description>Percentage of opioid-free patients through 24, 48 and 72 hours post-surgery</description>
          <units>percentage of opioid-free patients</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>0-24 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.11"/>
                    <measurement group_id="O2" value="11.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>0-48 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.11"/>
                    <measurement group_id="O2" value="5.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>0-72 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.11"/>
                    <measurement group_id="O2" value="5.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Area Under the Curve (AUC) of the Visual Analog Scale (VAS) Pain Intensity Scores From 24-48 and 48-72 Hours Postsurgery</title>
        <description>AUC of the VAS pain intensity scores from 24-48 and 48-72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, &quot;How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now.&quot; AUC from 24-48 hours start with the pain assessment obtained at 24 hours post-surgery and use all subsequent pain assessments up to 48 hours post-surgery. AUC from 48-72 hours start with the pain assessment obtained at 48 hours post-surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery.)</description>
        <time_frame>24-48 hours, 48-72 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EXPAREL Admixed With Bupivacaine HCl</title>
            <description>Local infiltration analgesia with EXPAREL (bupivacaine liposome injectable suspension) 266 mg/20 mL admixed with bupivacaine HCl 0.5% 20 mL and expanded with 20 mL (1-level procedures) or 50 mL (2-level procedures) normal saline</description>
          </group>
          <group group_id="O2">
            <title>Bupivacaine HCl</title>
            <description>Local infiltration analgesia with bupivacaine HCl 0.5% 20 mL expanded with 40 mL (1-level procedures) or 70 mL (2-level procedures) normal saline</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve (AUC) of the Visual Analog Scale (VAS) Pain Intensity Scores From 24-48 and 48-72 Hours Postsurgery</title>
          <description>AUC of the VAS pain intensity scores from 24-48 and 48-72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, &quot;How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now.&quot; AUC from 24-48 hours start with the pain assessment obtained at 24 hours post-surgery and use all subsequent pain assessments up to 48 hours post-surgery. AUC from 48-72 hours start with the pain assessment obtained at 48 hours post-surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery.)</description>
          <units>score on a scale*hours</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>24-48 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97.3" lower_limit="0" upper_limit="185"/>
                    <measurement group_id="O2" value="98.1" lower_limit="14" upper_limit="225"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>48-72 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="86.8" lower_limit="0" upper_limit="187"/>
                    <measurement group_id="O2" value="90.6" lower_limit="8" upper_limit="162"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Total Opioid Consumption Through 48 Hours Postsurgery</title>
        <description>Total Opioid Consumption Through 48 Hours Postsurgery</description>
        <time_frame>0-48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EXPAREL Admixed With Bupivacaine HCl</title>
            <description>Local infiltration analgesia with EXPAREL (bupivacaine liposome injectable suspension) 266 mg/20 mL admixed with bupivacaine HCl 0.5% 20 mL and expanded with 20 mL (1-level procedures) or 50 mL (2-level procedures) normal saline</description>
          </group>
          <group group_id="O2">
            <title>Bupivacaine HCl</title>
            <description>Local infiltration analgesia with bupivacaine HCl 0.5% 20 mL expanded with 40 mL (1-level procedures) or 70 mL (2-level procedures) normal saline</description>
          </group>
        </group_list>
        <measure>
          <title>Total Opioid Consumption Through 48 Hours Postsurgery</title>
          <description>Total Opioid Consumption Through 48 Hours Postsurgery</description>
          <units>MED, 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="18"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="103.6" spread="101.55"/>
                    <measurement group_id="O2" value="90.8" spread="100.58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the time informed consent form is signed to Day 30</time_frame>
      <desc>An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg, abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov.</desc>
      <group_list>
        <group group_id="E1">
          <title>EXPAREL Admixed With Bupivacaine HCl</title>
          <description>Local infiltration analgesia with EXPAREL (bupivacaine liposome injectable suspension) 266 mg/20 mL admixed with bupivacaine HCl 0.5% 20 mL and expanded with 20 mL (1-level procedures) or 50 mL (2-level procedures) normal saline</description>
        </group>
        <group group_id="E2">
          <title>Bupivacaine HCl</title>
          <description>Local infiltration analgesia with bupivacaine HCl 0.5% 20 mL expanded with 40 mL (1-level procedures) or 70 mL (2-level procedures) normal saline</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 19.1</default_vocab>
        <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="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Intervertebral disc protrusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>2</frequency_threshold>
        <default_vocab>MedDRA 19.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Diplopia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Vessel puncture site bruise</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Incision site pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Agitation postoperative</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Anaemia postoperative</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Postoperative fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Procedural pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Blood glucose increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Blood magnesium decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Blood pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Electrocardiogram T wave abnormal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pedal pulse decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Muscle tightness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Radiculopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Facial spasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Mental status changes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Apnoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="20"/>
              </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>Results conducted at Site shall not be published before 1st multicenter publication by Sponsor but can proceed if there is no such publication ≤18 months after study completion/termination at all sites and all data have been received. Before submitting manuscript/materials to an outside person/entity, site shall give Sponsor 60 days to review and comment. Site shall, upon request, further delay publication/presentation for ≤120 days to allow Sponsor to protect its interests in Inventions.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>This study was terminated early due to low enrollment; small sample sizes make data interpretation difficult.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Pacira Medical Information</name_or_title>
      <organization>Pacira Pharmaceuticals, Inc.</organization>
      <phone>1-855-793-9727</phone>
      <email>MedInfo@pacira.com</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/NCT03015961
org study id: 402-C-409
nct id: NCT03015961
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Primary Objective: The primary objective of this study is to compare postsurgical pain
      control following local infiltration analgesia (LIA) with EXPAREL admixed with bupivacaine
      HCl versus LIA with bupivacaine HCl in adult subjects undergoing open lumbar posterior spinal
      fusion surgery.

      Secondary Objectives: The secondary objectives of this study are to compare additional
      efficacy, safety, and health economic outcomes following LIA with EXPAREL admixed with
      bupivacaine HCl versus LIA with bupivacaine HCl in adult subjects undergoing open lumbar
      posterior spinal fusion surgery.
This is a Phase 4, multicenter, randomized, double-blind, controlled study in 38 adult
      subjects undergoing primary, 1-2 level, open lumbar spinal fusion surgery under general
      anesthesia.

      Subjects will be screened within 30 days prior to study drug administration and at least one
      day prior to surgery. During the screening visit, subjects will be assessed for past or
      present neurologic, cardiac, and general medical conditions that in the opinion of the
      Investigator would preclude them from study participation. After the informed consent form
      (ICF) is signed, a medical history, surgical history, physical examination, 12-lead
      electrocardiogram (ECG), vital sign measurements, select clinical laboratory evaluations,
      urine drug screen, alcohol breath test, and urine pregnancy test for women of childbearing
      potential will be conducted. Study drug, approximately 1-2 mL every 1.0-1.5 cm, will be
      administered using 20- or 22-gauge needles prior to wound closure.

      Administration Instructions/Procedures

      Study drug should be injected in the prescribed locations based on the areas of highest nerve
      density. Study drug will be administered using syringes with 20- or 22-gauge needles prior to
      wound closure. The Investigator must document the size of the incision. Each infiltration
      site should be spaced 1.0-1.5 cm apart and should deliver approximately 1-2 mL into both deep
      and superficial areas (para-spinous fascia, muscle, and subcutaneous layers). Total volume
      administered will be depended on the number of levels of dissection, as described below.
      Following infiltration, the tissue should visibly expand with minimal leakage.

      Total Volume of Expansion

      The Investigator must document the total volume used for each surgery.

        1. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 20
           mL normal saline = total volume of 60 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 40 mL
           normal saline = total volume of 60 mL

        2. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 50
           mL normal saline = total volume of 90 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 70 mL
           normal saline = total volume of 90 mL

      Drains may be used at the surgeon's discretion. In addition to LIA, all study participants
      will receive a standardized approach for managing postsurgical pain that includes a scheduled
      multimodal pain regimen including adjunctive analgesics, non-steroidal anti-inflammatory
      drugs (NSAIDs). Rescue analgesics will be available as needed.

      Postsurgical clinical assessments will include pain intensity scores using a 10-cm visual
      analog scale (VAS) (see Appendix 1); overall benefit of analgesia score (OBAS) questionnaire
      (see Appendix 2); total postsurgical opioid consumption; predefined opioid-related AEs; and
      nurse's satisfaction with overall analgesia (see Appendix 3).

      Adverse events will be recorded from the time the ICF is signed through Day 30. If a cardiac
      AE (e.g., chest pain [angina, myocardial infarction], abnormal/irregular heart rate
      [bradycardia, tachycardia, extrasystoles], or shortness of breath), neurological AE (e.g.,
      altered mental status/altered sensorium, dizziness, dysarthria, hyperesthesia, metallic
      taste, peroral numbness, seizure, tinnitus, tremors, visual disturbance, muscular twitching
      or rigidity beyond 72 hours postdose, or tingling/paresthesia beyond 72 hours postdose), or
      serious AE (SAE) occurs during the study a 12-lead ECG, vital signs, and any appropriate
      clinical laboratory tests should be conducted.

      Postsurgical health economic outcome assessments will include hospital length of stay (LOS),
      use of skilled nursing facility, hospital readmissions, and use of other health services
      following discharge (phone calls related to postsurgical pain, unscheduled visits related to
      postsurgical pain, and visits to emergency department) through Day 30.

      A follow-up visit will be scheduled for all subjects on postsurgical Day 14. A follow-up
      phone call will be made on Day 30 to all subjects who received study drug to assess for
      adverse events (AEs).

      Number of Subjects (Planned):

      Approximately 194 subjects are planned for enrollment in this study in order to have at least
      184 evaluable subjects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores From 0 to 72 Hours
time frame: 0-72 hours
description: AUC of VAS pain intensity scores from 0 to 72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, "How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now." AUC curve is derived using the trapezoidal rule (see formula below) on the pain scores. AUC start with the first pain assessment obtained after surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery. Note t1 is pain score collected after surgery.)
measure: Percentage of Opioid-Free Patients
time frame: 0-24, 0-48, 0-72 hours
description: Percentage of opioid-free patients through 24, 48 and 72 hours post-surgery
measure: Area Under the Curve (AUC) of the Visual Analog Scale (VAS) Pain Intensity Scores From 24-48 and 48-72 Hours Postsurgery
time frame: 24-48 hours, 48-72 hours
description: AUC of the VAS pain intensity scores from 24-48 and 48-72 hours postsurgery. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, "How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now." AUC from 24-48 hours start with the pain assessment obtained at 24 hours post-surgery and use all subsequent pain assessments up to 48 hours post-surgery. AUC from 48-72 hours start with the pain assessment obtained at 48 hours post-surgery and use all subsequent pain assessments up to 72 hours post-surgery. (Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery.)
measure: Total Opioid Consumption Through 48 Hours Postsurgery
time frame: 0-48 hours
description: Total Opioid Consumption Through 48 Hours Postsurgery
arm group label: EXPAREL admixed with bupivacaine HCl
arm group type: Active Comparator
description: EXPAREL 266 mg + bupivacaine HCl
arm group label: Bupivacaine HCl
arm group type: Placebo Comparator
description: Bupivacaine HCl
intervention type: Drug
intervention name: EXPAREL and bupivacaine HCl
description: Drug: EXPAREL EXPAREL and bupivacaine HCl
Other Name: bupivacaine liposome injectable suspension Drug: Bupivacaine Single dose of bupivacaine HCl 0.5%
Other Name: bupivacaine HCl
arm group label: EXPAREL admixed with bupivacaine HCl
intervention type: Drug
intervention name: Bupivacaine HCl
description: Drug: Bupivacaine Single dose of bupivacaine HCl 0.5%
Other Name: bupivacaine HCl
arm group label: Bupivacaine HCl
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
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country: United States
responsible party type: Sponsor
mesh term: Pain, Postoperative
mesh term: Bupivacaine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This study was terminated early due to low enrollment; small sample sizes make data interpretation difficult.
point of contact: 