<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/NCT04461028</url>
  </required_header>
  <id_info>
    <org_study_id>832346</org_study_id>
    <nct_id>NCT04461028</nct_id>
  </id_info>
  <brief_title>Liposomal Bupivacaine in Shoulder Arthroscopy</brief_title>
  <official_title>The Effect of Liposomal Bupivacaine on the Quality of Recovery in Patients Undergoing Shoulder Arthroscopy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      The research study is being conducted to see if using the liposomal Bupivacaine for the&#xD;
      Interscalene block will improve the patient pain control and the whole patient's experience&#xD;
      48 hours after surgery when compared to using the regular Marcaine (bupivacaine&#xD;
      hydrochloride) in addition to the dexamethasone.&#xD;
&#xD;
      All preoperative, surgical, post-operative care in the recovery room, and discharge&#xD;
      instructions will be the same as any other patient undergoing this surgery.&#xD;
&#xD;
      Study procedures:&#xD;
&#xD;
        1. After obtaining informed consent, an anesthesiologist will receive an envelope with&#xD;
           result of randomization. Patients will receive a single injection interscalene nerve&#xD;
           block prior to surgery&#xD;
&#xD;
        2. Patients will be randomized to one of two groups:&#xD;
&#xD;
             -  GROUP 1 liposomal Bupivacaine - will receive a 20 ml mixture of 10 ml of Liposomal&#xD;
                Bupivacaine 1.3% and 10 ml of Bupivacaine HCl 0.5%.&#xD;
&#xD;
             -  GROUP 2 Bupivacaine with dexamethasone - will receive 20 ml of Bupivacaine HCl 0.5%&#xD;
                with 4 mg of preservative-free dexamethasone.&#xD;
&#xD;
      4. Patients will undergo general endotracheal anesthesia with inhaled anesthetic&#xD;
      (Sevoflurane) for a goal MAC 1.0. Other than the aforementioned interscalene nerve block,&#xD;
      patients will not receive any other local anesthetic.&#xD;
&#xD;
      5. Patients will receive a multimodal analgesic and antiemetic regimen standardized for&#xD;
      shoulder arthroscopies at our institution. Preoperatively, all patients will receive 300 mg&#xD;
      of gabapentin and 1,000 mg of acetaminophen orally. Intraoperatively, patients will receive 4&#xD;
      mg of ondansetron and 15 mg of ketorolac intravenously. Postoperatively, patients will remain&#xD;
      on an oral regimen of 300 mg of gabapentin three times daily for one week, and 1,000 mg of&#xD;
      acetaminophen and 10 mg of ketorolac every 8 hours for 48 hours after surgery.&#xD;
&#xD;
      6. Additional intraoperative or postoperative opioid analgesics will be administered as&#xD;
      needed. Patients with a history of PONV or otherwise deemed high risk for PONV by the&#xD;
      attending anesthesiologist will receive a scopolamine patch before induction of general&#xD;
      anesthesia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Shoulder arthroscopy is one of the most commonly performed ambulatory orthopedic procedures&#xD;
      in the United States. However, despite advances in arthroscopic technique, significant&#xD;
      postoperative pain remains a major challenge in the perioperative period. Regional anesthesia&#xD;
      has played a key part in alleviating postoperative pain, particularly the use of single-shot&#xD;
      interscalene nerve blocks. However, single-shot blocks are limited by their relatively short&#xD;
      duration of action. The use of continuous peripheral nerve catheters is often limited by&#xD;
      institutional resources.&#xD;
&#xD;
      As such, adjuvants can be added to the local anesthetic solution to help prolong the&#xD;
      single-shot block. Whereas a long-acting local anesthetic such as Bupivacaine HCl can provide&#xD;
      analgesia for 8-12 hours when deposited perineurally, the addition of adjuvants such as 4 mg&#xD;
      preservative-free dexamethasone has been shown to prolong blocks for up to 24 hours.&#xD;
&#xD;
      Liposomal Bupivacaine (Exparel®, Pacira Pharmaceuticals, Parsippany, NJ) is a novel&#xD;
      formulation of Bupivacaine that was approved for interscalene nerve blocks in April 2018.8 By&#xD;
      incorporating Bupivacaine within a multivesicular liposomal suspension (DepoFoam®) that&#xD;
      causes a slow release of the drug, it is purported to extend a nerve block's analgesic effect&#xD;
      to at least 72 hours.9 10 ml of Liposomal Bupivacaine 1.3% (133 mg) is recommended for&#xD;
      interscalene blocks; this solution is also often mixed with Bupivacaine HCl to complement&#xD;
      early analgesia.&#xD;
&#xD;
      To our knowledge, no study has evaluated the effect of Liposomal Bupivacaine in the context&#xD;
      of postoperative quality of recovery. Given the well-known postoperative pain and functional&#xD;
      limitations of shoulder arthroscopy, the postoperative Quality of Recovery (QoR) scale is an&#xD;
      appropriate tool to capture these outcomes. This scale assesses patient recovery in multiple&#xD;
      domains, including physiological, nociceptive, activities of daily living, cognition and&#xD;
      patient satisfaction. To date, the QoR scale has been used in over 100 perioperative studies&#xD;
      and has been repeatedly validated in the postoperative setting, including ambulatory&#xD;
      orthopedic procedures. As they have been validated over the years, the QoR has been&#xD;
      correlated to quality of life and patient satisfaction with pain management after surgery,&#xD;
      two key components of a successful ambulatory procedure.&#xD;
&#xD;
      Therefore, we propose a prospective randomized controlled clinical trial aiming to evaluate&#xD;
      the effect of Liposomal Bupivacaine in this context. We hypothesize that using Liposomal&#xD;
      Bupivacaine will improve the quality of recovery in patients undergoing shoulder arthroscopy&#xD;
      for rotator cuff repair when compared to using Bupivicaine HCl 0.5% with preservative-free&#xD;
      dexamethasone.&#xD;
&#xD;
      Study Objectives:&#xD;
&#xD;
      We seek to determine if Liposomal Bupivacaine 1.3% will improve the quality of recovery, as&#xD;
      measured by QoR-15 scores, in patients undergoing shoulder arthroscopy for rotator cuff&#xD;
      repair when compared to Bupivacaine HCl 0.5% with 4 mg of preservative-free dexamethasone as&#xD;
      an additive.&#xD;
&#xD;
      Primary Outcome:&#xD;
&#xD;
      The primary outcome will be defined as the QoR-15 score at 48 hours after surgery.&#xD;
&#xD;
      Secondary Outcomes:&#xD;
&#xD;
      Secondary outcomes will include QoR-15 scores at 24 hours and 1 week after surgery, patient&#xD;
      reported pain scores and opioid use at 24, 48, and 72 hours after surgery, PACU length of&#xD;
      stay, and PACU opioids and antiemetics given.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
      This is a prospective, randomized, controlled blinded clinical trial with a parallel design&#xD;
      and an allocation ratio of 1:1 for the treatment groups.&#xD;
&#xD;
      Recruitment:&#xD;
&#xD;
      Patients will be identified from the surgical schedule the day before surgery and will be&#xD;
      contacted by one of the study investigators to scan for eligibility for enrollment.&#xD;
&#xD;
      Patients will be consented the morning of their surgery by one of the study investigators or&#xD;
      the research coordinator. Study aims and procedures will be explained to patients and all&#xD;
      questions will be answered. There is no formal recruitment script, but the informed consent&#xD;
      form will be carefully reviewed with the patient to ensure adequate comprehension.&#xD;
&#xD;
      Randomization:&#xD;
&#xD;
      A computer-generated randomization table will be used for patient allocation to one of the&#xD;
      two study groups; either the Liposomal Bupivacaine group or the Bupivacaine HCl with&#xD;
      dexamethasone group. Randomization will be done in blocks of 10 patients each.&#xD;
&#xD;
      Study procedures:&#xD;
&#xD;
      After obtaining informed consent, patients will receive a single injection interscalene nerve&#xD;
      block prior to surgery. Patients will be randomized to one of two groups: the Liposomal&#xD;
      Bupivacaine or Bupivacaine with dexamethasone groups. The Liposomal Bupivacaine group will&#xD;
      receive a 20 ml mixture of 10 ml of Liposomal Bupivacaine 1.3% and 10 ml of Bupivacaine HCl&#xD;
      0.5%. The Bupivacaine with dexamethasone group will receive 20 ml of Bupivacaine HCl 0.2%&#xD;
      with 4 mg of preservative-free dexamethasone. The research assistant collecting the data as&#xD;
      well the patient will be blinded to the nature of the group assignments.&#xD;
&#xD;
      Prior to the nerve block, a block time out will be performed according to standard operating&#xD;
      procedures with the attending anesthesiologist present. Patients will be monitored during&#xD;
      block performance with standard ASA monitors. All patients will receive 2 L of continuous&#xD;
      oxygen via nasal cannula. 1-2 mg midazolam will be titrated to sedative effect. All blocks&#xD;
      will be done under ultrasound guidance using Sonosite S (Bothell, WA) machines with a high&#xD;
      frequency linear probe (6-13 MHz). The block will be performed with strict adherence to&#xD;
      sterile technique. After an optimal interscalene &quot;stop-sign&quot; view is obtained, a 21-guage&#xD;
      needle will be inserted in-plane and the local anesthetic will be deposited with a focus on&#xD;
      the C5 nerve root.&#xD;
&#xD;
      Patients will then undergo general endotracheal anesthesia with inhaled anesthetic&#xD;
      (Sevoflurane) for a goal MAC 1.0. Other than the aforementioned interscalene nerve block,&#xD;
      patients will not receive any other local anesthetic. Patients will receive a multimodal&#xD;
      analgesic and antiemetic regimen standardized for these surgeries at this institution.&#xD;
&#xD;
      Preoperatively, all patients will receive 300 mg of gabapentin and 1,000 mg of acetaminophen&#xD;
      orally. Intraoperatively, patients will receive 4 mg of ondansetron and 15 mg of ketorolac&#xD;
      intravenously. Postoperatively, patients will remain on an oral regimen of 300 mg of&#xD;
      gabapentin three times daily for one week, and 1,000 mg of acetaminophen and 10 mg of&#xD;
      ketorolac every 8 hours for 48 hours after surgery. Additional intraoperative or&#xD;
      postoperative opioid analgesics will be administered as needed. Patients with a history of&#xD;
      PONV or otherwise deemed high risk for PONV by the attending anesthesiologist will receive a&#xD;
      scopolamine patch before induction of general anesthesia.&#xD;
&#xD;
      Data Collection:&#xD;
&#xD;
      Basic demographic data (age, gender, ethnicity) and associated diagnoses such as depression&#xD;
      and anxiety will be collected preoperatively. A QoR-15 will be assessed at 24 and 48 hours&#xD;
      and 1 week after surgery. Patients will also be sent home with a pain diary to determine pain&#xD;
      scores and the amount of pain pills taken for 72 hours after surgery. Other data to be&#xD;
      collected will include PACU length of stay and any PACU medications (particularly opioids and&#xD;
      rescue antiemetics) given. Opioids will be converted to morphine equivalent doses. The&#xD;
      research assistant collecting data will be blinded to the nature of the group assignments.&#xD;
&#xD;
      Study Duration:&#xD;
&#xD;
      We plan to begin enrollment pending IRB approval. The length of participation for each&#xD;
      patient will be 1-week in total after surgery.&#xD;
&#xD;
      Statistical Analysis:&#xD;
&#xD;
      Statistical analyses will be performed using STATA 15 statistical software (College Station,&#xD;
      TX). Demographic or other categorical data will be analyzed using student's T test or&#xD;
      Fisher's exact test as appropriate. Repeated measurements (QoR-15 scores, pain scores) will&#xD;
      be analyzed by repeated measures ANOVA or ANOVA on ranks, with further paired comparisons at&#xD;
      each time interval performed using the t-test or Mann-Whitney U-test as appropriate. Normally&#xD;
      distributed data will be presented as means ± SE of the mean (SEM), non-normally distributed&#xD;
      data will be presented as medians ± quartiles (interquartile range) and categorical data will&#xD;
      be presented as raw data and as frequencies. The alpha level for all analyses will be set as&#xD;
      P&lt;0.05.&#xD;
&#xD;
      Sample size:&#xD;
&#xD;
      Average QOR-15 scores at time point of 24hrs is 112 ± 19 Myles 2016 . A clinically meaningful&#xD;
      differences in the QOR-15 scale is 8.0.Myles 2016 Our sample size calculation to detect a&#xD;
      8-point difference in the QOR-15 scale (p&lt;0.05) is 71 patients in each group (alpha=0.05,&#xD;
      power=80%). We will inflate our sample size by 10% to account for any missing data or any&#xD;
      withdrawal from the study; therefore, our estimated sample size will be 78 patients per group&#xD;
      for a total number of patients of 156. Statistical analyses will be performed using STATA 13&#xD;
      statistical software (Dallas, TX).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 21, 2019</start_date>
  <completion_date type="Anticipated">May 21, 2028</completion_date>
  <primary_completion_date type="Anticipated">May 21, 2028</primary_completion_date>
  <phase>Phase 3</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>Randomization between Group 1 and Group 2</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
    <masking_description>The research assistant collecting the data as well the patient will be blinded to the nature of the group assignments.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Quality of Recovery</measure>
    <time_frame>48 Hours</time_frame>
    <description>The primary outcome will be defined as the Quality of Recovery (QoR-15) score at 48 hours after surgery. There are 15 questions assessed on a scale of 0-10, 10 being the better outcome.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quality of Recovery</measure>
    <time_frame>24 hours</time_frame>
    <description>The secondary outcome will be defined as the Quality of Recovery (QoR-15) score at 24 hours after surgery. There are 15 questions assessed on a scale of 0-10, 10 being the better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Recovery</measure>
    <time_frame>1 Week</time_frame>
    <description>The secondary outcome will be defined as the Quality of Recovery (QoR-15) score at 1 week after surgery. There are 15 questions assessed on a scale of 0-10, 10 being the better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain scores</measure>
    <time_frame>72 hours</time_frame>
    <description>Patient reported pain scores on a scale of 0(no pain)-10(extreme pain),</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Opioid Use</measure>
    <time_frame>72 hours</time_frame>
    <description>Patient reported opioid use for 72 hours.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PACU LOS</measure>
    <time_frame>1 Day</time_frame>
    <description>PACU length of stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PACU Medications</measure>
    <time_frame>1 Day</time_frame>
    <description>Measurement of opioid given to patient at PACU in morphine equivalents.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Rotator Cuff Tears</condition>
  <arm_group>
    <arm_group_label>GROUP 1 Liposomal Bupivacaine</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Will receive a 20 ml mixture of 10 ml of Liposomal Bupivacaine 1.3% and 10 ml of Bupivacaine HCl 0.5%.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>GROUP 2 Bupivacaine with dexamethasone</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Will receive 20 ml of Bupivacaine HCl 0.5% with 4 mg of preservative-free dexamethasone.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liposomal bupivacaine</intervention_name>
    <description>20 ml mixture of 10 ml of Liposomal Bupivacaine 1.3% and 10 ml of Bupivacaine HCl 0.5%.</description>
    <arm_group_label>GROUP 1 Liposomal Bupivacaine</arm_group_label>
    <other_name>Exparel</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupivacaine with Dexamethasone Solution</intervention_name>
    <description>20 ml of Bupivacaine HCl 0.5% with 4 mg of preservative-free dexamethasone.</description>
    <arm_group_label>GROUP 2 Bupivacaine with dexamethasone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  physical ASA status I-III&#xD;
&#xD;
          -  age greater than 18 years&#xD;
&#xD;
          -  mental competency&#xD;
&#xD;
          -  ability to provide informed consent for the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  severe pulmonary disease including chronic obstructive pulmonary disease(COPD)&#xD;
&#xD;
          -  home oxygen use&#xD;
&#xD;
          -  a preexisting chronic pain syndrome (defined as daily opioid intake for more than&#xD;
             three months prior to surgery)&#xD;
&#xD;
          -  allergies to any of the study medications or any of the medications in the multimodal&#xD;
             analgesic regimen&#xD;
&#xD;
          -  an inability to receive a nerve block due to anticoagulation status infection&#xD;
&#xD;
          -  nerve injury&#xD;
&#xD;
          -  patient refusal.&#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>Nabil M Elkassabany, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pennsylvania</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Nabil M Elkassabany, MD</last_name>
    <phone>2156623761</phone>
    <email>Nabil.Elkassabany@pennmedicine.upenn.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Penn Presbyterian Medical Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Nabil M Elkassabany</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Lu F Cai</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Warrender WJ, Syed UAM, Hammoud S, Emper W, Ciccotti MG, Abboud JA, Freedman KB. Pain Management After Outpatient Shoulder Arthroscopy: A Systematic Review of Randomized Controlled Trials. Am J Sports Med. 2017 Jun;45(7):1676-1686. doi: 10.1177/0363546516667906. Epub 2016 Oct 13.</citation>
    <PMID>27729319</PMID>
  </reference>
  <reference>
    <citation>Uquillas CA, Capogna BM, Rossy WH, Mahure SA, Rokito AS. Postoperative pain control after arthroscopic rotator cuff repair. J Shoulder Elbow Surg. 2016 Jul;25(7):1204-13. doi: 10.1016/j.jse.2016.01.026. Epub 2016 Apr 11.</citation>
    <PMID>27079219</PMID>
  </reference>
  <reference>
    <citation>Hughes MS, Matava MJ, Wright RW, Brophy RH, Smith MV. Interscalene brachial plexus block for arthroscopic shoulder surgery: a systematic review. J Bone Joint Surg Am. 2013 Jul 17;95(14):1318-24. doi: 10.2106/JBJS.L.01116. No abstract available.</citation>
    <PMID>23864181</PMID>
  </reference>
  <reference>
    <citation>Pehora C, Pearson AM, Kaushal A, Crawford MW, Johnston B. Dexamethasone as an adjuvant to peripheral nerve block. Cochrane Database Syst Rev. 2017 Nov 9;11(11):CD011770. doi: 10.1002/14651858.CD011770.pub2.</citation>
    <PMID>29121400</PMID>
  </reference>
  <reference>
    <citation>Kahn RL, Cheng J, Gadulov Y, Fields KG, YaDeau JT, Gulotta LV. Perineural Low-Dose Dexamethasone Prolongs Interscalene Block Analgesia With Bupivacaine Compared With Systemic Dexamethasone: A Randomized Trial. Reg Anesth Pain Med. 2018 Aug;43(6):572-579. doi: 10.1097/AAP.0000000000000817.</citation>
    <PMID>29889698</PMID>
  </reference>
  <reference>
    <citation>Holland D, Amadeo RJJ, Wolfe S, Girling L, Funk F, Collister M, Czaplinski E, Ferguson C, Leiter J, Old J, MacDonald P, Dufault B, Mutter TC. Effect of dexamethasone dose and route on the duration of interscalene brachial plexus block for outpatient arthroscopic shoulder surgery: a randomized controlled trial. Can J Anaesth. 2018 Jan;65(1):34-45. doi: 10.1007/s12630-017-0989-7. Epub 2017 Nov 10.</citation>
    <PMID>29127558</PMID>
  </reference>
  <reference>
    <citation>Tandoc MN, Fan L, Kolesnikov S, Kruglov A, Nader ND. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth. 2011 Oct;25(5):704-9. doi: 10.1007/s00540-011-1180-x. Epub 2011 Jun 17.</citation>
    <PMID>21681533</PMID>
  </reference>
  <reference>
    <citation>Balocco AL, Van Zundert PGE, Gan SS, Gan TJ, Hadzic A. Extended release bupivacaine formulations for postoperative analgesia: an update. Curr Opin Anaesthesiol. 2018 Oct;31(5):636-642. doi: 10.1097/ACO.0000000000000648.</citation>
    <PMID>30074492</PMID>
  </reference>
  <reference>
    <citation>Viscusi ER. Liposomal drug delivery for postoperative pain management. Reg Anesth Pain Med. 2005 Sep-Oct;30(5):491-6. doi: 10.1016/j.rapm.2005.05.001. No abstract available.</citation>
    <PMID>16135355</PMID>
  </reference>
  <reference>
    <citation>Bowyer A, Jakobsson J, Ljungqvist O, Royse C. A review of the scope and measurement of postoperative quality of recovery. Anaesthesia. 2014 Nov;69(11):1266-78. doi: 10.1111/anae.12730. Epub 2014 Jun 2.</citation>
    <PMID>24888412</PMID>
  </reference>
  <reference>
    <citation>Myles PS. Measuring quality of recovery in perioperative clinical trials. Curr Opin Anaesthesiol. 2018 Aug;31(4):396-401. doi: 10.1097/ACO.0000000000000612.</citation>
    <PMID>29846193</PMID>
  </reference>
  <reference>
    <citation>Chazapis M, Walker EM, Rooms MA, Kamming D, Moonesinghe SR. Measuring quality of recovery-15 after day case surgery. Br J Anaesth. 2016 Feb;116(2):241-8. doi: 10.1093/bja/aev413.</citation>
    <PMID>26787793</PMID>
  </reference>
  <reference>
    <citation>Myles PS, Hunt JO, Nightingale CE, Fletcher H, Beh T, Tanil D, Nagy A, Rubinstein A, Ponsford JL. Development and psychometric testing of a quality of recovery score after general anesthesia and surgery in adults. Anesth Analg. 1999 Jan;88(1):83-90. doi: 10.1097/00000539-199901000-00016.</citation>
    <PMID>9895071</PMID>
  </reference>
  <reference>
    <citation>Stark PA, Myles PS, Burke JA. Development and psychometric evaluation of a postoperative quality of recovery score: the QoR-15. Anesthesiology. 2013 Jun;118(6):1332-40. doi: 10.1097/ALN.0b013e318289b84b.</citation>
    <PMID>23411725</PMID>
  </reference>
  <reference>
    <citation>Myles PS, Reeves MD, Anderson H, Weeks AM. Measurement of quality of recovery in 5672 patients after anaesthesia and surgery. Anaesth Intensive Care. 2000 Jun;28(3):276-80. doi: 10.1177/0310057X0002800304.</citation>
    <PMID>10853209</PMID>
  </reference>
  <reference>
    <citation>Myles PS, Myles DB, Galagher W, Chew C, MacDonald N, Dennis A. Minimal Clinically Important Difference for Three Quality of Recovery Scales. Anesthesiology. 2016 Jul;125(1):39-45. doi: 10.1097/ALN.0000000000001158.</citation>
    <PMID>27159009</PMID>
  </reference>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>October 11, 2019</study_first_submitted>
  <study_first_submitted_qc>July 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 8, 2020</study_first_posted>
  <last_update_submitted>October 29, 2021</last_update_submitted>
  <last_update_submitted_qc>October 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pennsylvania</investigator_affiliation>
    <investigator_full_name>Nabil Elkassabany</investigator_full_name>
    <investigator_title>Physician</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rotator Cuff Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Bupivacaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04461028
org study id: 832346
nct id: NCT04461028
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Background:

      The research study is being conducted to see if using the liposomal Bupivacaine for the
      Interscalene block will improve the patient pain control and the whole patient's experience
      48 hours after surgery when compared to using the regular Marcaine (bupivacaine
      hydrochloride) in addition to the dexamethasone.

      All preoperative, surgical, post-operative care in the recovery room, and discharge
      instructions will be the same as any other patient undergoing this surgery.

      Study procedures:

        1. After obtaining informed consent, an anesthesiologist will receive an envelope with
           result of randomization. Patients will receive a single injection interscalene nerve
           block prior to surgery

        2. Patients will be randomized to one of two groups:

             -  GROUP 1 liposomal Bupivacaine - will receive a 20 ml mixture of 10 ml of Liposomal
                Bupivacaine 1.3% and 10 ml of Bupivacaine HCl 0.5%.

             -  GROUP 2 Bupivacaine with dexamethasone - will receive 20 ml of Bupivacaine HCl 0.5%
                with 4 mg of preservative-free dexamethasone.

      4. Patients will undergo general endotracheal anesthesia with inhaled anesthetic
      (Sevoflurane) for a goal MAC 1.0. Other than the aforementioned interscalene nerve block,
      patients will not receive any other local anesthetic.

      5. Patients will receive a multimodal analgesic and antiemetic regimen standardized for
      shoulder arthroscopies at our institution. Preoperatively, all patients will receive 300 mg
      of gabapentin and 1,000 mg of acetaminophen orally. Intraoperatively, patients will receive 4
      mg of ondansetron and 15 mg of ketorolac intravenously. Postoperatively, patients will remain
      on an oral regimen of 300 mg of gabapentin three times daily for one week, and 1,000 mg of
      acetaminophen and 10 mg of ketorolac every 8 hours for 48 hours after surgery.

      6. Additional intraoperative or postoperative opioid analgesics will be administered as
      needed. Patients with a history of PONV or otherwise deemed high risk for PONV by the
      attending anesthesiologist will receive a scopolamine patch before induction of general
      anesthesia.
Background:

      Shoulder arthroscopy is one of the most commonly performed ambulatory orthopedic procedures
      in the United States. However, despite advances in arthroscopic technique, significant
      postoperative pain remains a major challenge in the perioperative period. Regional anesthesia
      has played a key part in alleviating postoperative pain, particularly the use of single-shot
      interscalene nerve blocks. However, single-shot blocks are limited by their relatively short
      duration of action. The use of continuous peripheral nerve catheters is often limited by
      institutional resources.

      As such, adjuvants can be added to the local anesthetic solution to help prolong the
      single-shot block. Whereas a long-acting local anesthetic such as Bupivacaine HCl can provide
      analgesia for 8-12 hours when deposited perineurally, the addition of adjuvants such as 4 mg
      preservative-free dexamethasone has been shown to prolong blocks for up to 24 hours.

      Liposomal Bupivacaine (Exparel®, Pacira Pharmaceuticals, Parsippany, NJ) is a novel
      formulation of Bupivacaine that was approved for interscalene nerve blocks in April 2018.8 By
      incorporating Bupivacaine within a multivesicular liposomal suspension (DepoFoam®) that
      causes a slow release of the drug, it is purported to extend a nerve block's analgesic effect
      to at least 72 hours.9 10 ml of Liposomal Bupivacaine 1.3% (133 mg) is recommended for
      interscalene blocks; this solution is also often mixed with Bupivacaine HCl to complement
      early analgesia.

      To our knowledge, no study has evaluated the effect of Liposomal Bupivacaine in the context
      of postoperative quality of recovery. Given the well-known postoperative pain and functional
      limitations of shoulder arthroscopy, the postoperative Quality of Recovery (QoR) scale is an
      appropriate tool to capture these outcomes. This scale assesses patient recovery in multiple
      domains, including physiological, nociceptive, activities of daily living, cognition and
      patient satisfaction. To date, the QoR scale has been used in over 100 perioperative studies
      and has been repeatedly validated in the postoperative setting, including ambulatory
      orthopedic procedures. As they have been validated over the years, the QoR has been
      correlated to quality of life and patient satisfaction with pain management after surgery,
      two key components of a successful ambulatory procedure.

      Therefore, we propose a prospective randomized controlled clinical trial aiming to evaluate
      the effect of Liposomal Bupivacaine in this context. We hypothesize that using Liposomal
      Bupivacaine will improve the quality of recovery in patients undergoing shoulder arthroscopy
      for rotator cuff repair when compared to using Bupivicaine HCl 0.5% with preservative-free
      dexamethasone.

      Study Objectives:

      We seek to determine if Liposomal Bupivacaine 1.3% will improve the quality of recovery, as
      measured by QoR-15 scores, in patients undergoing shoulder arthroscopy for rotator cuff
      repair when compared to Bupivacaine HCl 0.5% with 4 mg of preservative-free dexamethasone as
      an additive.

      Primary Outcome:

      The primary outcome will be defined as the QoR-15 score at 48 hours after surgery.

      Secondary Outcomes:

      Secondary outcomes will include QoR-15 scores at 24 hours and 1 week after surgery, patient
      reported pain scores and opioid use at 24, 48, and 72 hours after surgery, PACU length of
      stay, and PACU opioids and antiemetics given.

      Methods:

      Study Design:

      This is a prospective, randomized, controlled blinded clinical trial with a parallel design
      and an allocation ratio of 1:1 for the treatment groups.

      Recruitment:

      Patients will be identified from the surgical schedule the day before surgery and will be
      contacted by one of the study investigators to scan for eligibility for enrollment.

      Patients will be consented the morning of their surgery by one of the study investigators or
      the research coordinator. Study aims and procedures will be explained to patients and all
      questions will be answered. There is no formal recruitment script, but the informed consent
      form will be carefully reviewed with the patient to ensure adequate comprehension.

      Randomization:

      A computer-generated randomization table will be used for patient allocation to one of the
      two study groups; either the Liposomal Bupivacaine group or the Bupivacaine HCl with
      dexamethasone group. Randomization will be done in blocks of 10 patients each.

      Study procedures:

      After obtaining informed consent, patients will receive a single injection interscalene nerve
      block prior to surgery. Patients will be randomized to one of two groups: the Liposomal
      Bupivacaine or Bupivacaine with dexamethasone groups. The Liposomal Bupivacaine group will
      receive a 20 ml mixture of 10 ml of Liposomal Bupivacaine 1.3% and 10 ml of Bupivacaine HCl
      0.5%. The Bupivacaine with dexamethasone group will receive 20 ml of Bupivacaine HCl 0.2%
      with 4 mg of preservative-free dexamethasone. The research assistant collecting the data as
      well the patient will be blinded to the nature of the group assignments.

      Prior to the nerve block, a block time out will be performed according to standard operating
      procedures with the attending anesthesiologist present. Patients will be monitored during
      block performance with standard ASA monitors. All patients will receive 2 L of continuous
      oxygen via nasal cannula. 1-2 mg midazolam will be titrated to sedative effect. All blocks
      will be done under ultrasound guidance using Sonosite S (Bothell, WA) machines with a high
      frequency linear probe (6-13 MHz). The block will be performed with strict adherence to
      sterile technique. After an optimal interscalene "stop-sign" view is obtained, a 21-guage
      needle will be inserted in-plane and the local anesthetic will be deposited with a focus on
      the C5 nerve root.

      Patients will then undergo general endotracheal anesthesia with inhaled anesthetic
      (Sevoflurane) for a goal MAC 1.0. Other than the aforementioned interscalene nerve block,
      patients will not receive any other local anesthetic. Patients will receive a multimodal
      analgesic and antiemetic regimen standardized for these surgeries at this institution.

      Preoperatively, all patients will receive 300 mg of gabapentin and 1,000 mg of acetaminophen
      orally. Intraoperatively, patients will receive 4 mg of ondansetron and 15 mg of ketorolac
      intravenously. Postoperatively, patients will remain on an oral regimen of 300 mg of
      gabapentin three times daily for one week, and 1,000 mg of acetaminophen and 10 mg of
      ketorolac every 8 hours for 48 hours after surgery. Additional intraoperative or
      postoperative opioid analgesics will be administered as needed. Patients with a history of
      PONV or otherwise deemed high risk for PONV by the attending anesthesiologist will receive a
      scopolamine patch before induction of general anesthesia.

      Data Collection:

      Basic demographic data (age, gender, ethnicity) and associated diagnoses such as depression
      and anxiety will be collected preoperatively. A QoR-15 will be assessed at 24 and 48 hours
      and 1 week after surgery. Patients will also be sent home with a pain diary to determine pain
      scores and the amount of pain pills taken for 72 hours after surgery. Other data to be
      collected will include PACU length of stay and any PACU medications (particularly opioids and
      rescue antiemetics) given. Opioids will be converted to morphine equivalent doses. The
      research assistant collecting data will be blinded to the nature of the group assignments.

      Study Duration:

      We plan to begin enrollment pending IRB approval. The length of participation for each
      patient will be 1-week in total after surgery.

      Statistical Analysis:

      Statistical analyses will be performed using STATA 15 statistical software (College Station,
      TX). Demographic or other categorical data will be analyzed using student's T test or
      Fisher's exact test as appropriate. Repeated measurements (QoR-15 scores, pain scores) will
      be analyzed by repeated measures ANOVA or ANOVA on ranks, with further paired comparisons at
      each time interval performed using the t-test or Mann-Whitney U-test as appropriate. Normally
      distributed data will be presented as means ± SE of the mean (SEM), non-normally distributed
      data will be presented as medians ± quartiles (interquartile range) and categorical data will
      be presented as raw data and as frequencies. The alpha level for all analyses will be set as
      P<0.05.

      Sample size:

      Average QOR-15 scores at time point of 24hrs is 112 ± 19 Myles 2016 . A clinically meaningful
      differences in the QOR-15 scale is 8.0.Myles 2016 Our sample size calculation to detect a
      8-point difference in the QOR-15 scale (p<0.05) is 71 patients in each group (alpha=0.05,
      power=80%). We will inflate our sample size by 10% to account for any missing data or any
      withdrawal from the study; therefore, our estimated sample size will be 78 patients per group
      for a total number of patients of 156. Statistical analyses will be performed using STATA 13
      statistical software (Dallas, TX).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomization between Group 1 and Group 2
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
masking description: The research assistant collecting the data as well the patient will be blinded to the nature of the group assignments.
measure: Quality of Recovery
time frame: 48 Hours
description: The primary outcome will be defined as the Quality of Recovery (QoR-15) score at 48 hours after surgery. There are 15 questions assessed on a scale of 0-10, 10 being the better outcome.
measure: Quality of Recovery
time frame: 24 hours
description: The secondary outcome will be defined as the Quality of Recovery (QoR-15) score at 24 hours after surgery. There are 15 questions assessed on a scale of 0-10, 10 being the better outcome.
measure: Quality of Recovery
time frame: 1 Week
description: The secondary outcome will be defined as the Quality of Recovery (QoR-15) score at 1 week after surgery. There are 15 questions assessed on a scale of 0-10, 10 being the better outcome.
measure: Pain scores
time frame: 72 hours
description: Patient reported pain scores on a scale of 0(no pain)-10(extreme pain),
measure: Opioid Use
time frame: 72 hours
description: Patient reported opioid use for 72 hours.
measure: PACU LOS
time frame: 1 Day
description: PACU length of stay
measure: PACU Medications
time frame: 1 Day
description: Measurement of opioid given to patient at PACU in morphine equivalents.
arm group label: GROUP 1 Liposomal Bupivacaine
arm group type: Other
description: Will receive a 20 ml mixture of 10 ml of Liposomal Bupivacaine 1.3% and 10 ml of Bupivacaine HCl 0.5%.
arm group label: GROUP 2 Bupivacaine with dexamethasone
arm group type: Other
description: Will receive 20 ml of Bupivacaine HCl 0.5% with 4 mg of preservative-free dexamethasone.
intervention type: Drug
intervention name: Liposomal bupivacaine
description: 20 ml mixture of 10 ml of Liposomal Bupivacaine 1.3% and 10 ml of Bupivacaine HCl 0.5%.
arm group label: GROUP 1 Liposomal Bupivacaine
other name: Exparel
intervention type: Drug
intervention name: Bupivacaine with Dexamethasone Solution
description: 20 ml of Bupivacaine HCl 0.5% with 4 mg of preservative-free dexamethasone.
arm group label: GROUP 2 Bupivacaine with dexamethasone
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nabil M Elkassabany, MD
role: Principal Investigator
affiliation: University of Pennsylvania
last name: Nabil M Elkassabany, MD
phone: 2156623761
email: Nabil.Elkassabany@pennmedicine.upenn.edu
facility: 
status: Recruiting
investigator: 
investigator: 
country: United States
citation: Warrender WJ, Syed UAM, Hammoud S, Emper W, Ciccotti MG, Abboud JA, Freedman KB. Pain Management After Outpatient Shoulder Arthroscopy: A Systematic Review of Randomized Controlled Trials. Am J Sports Med. 2017 Jun;45(7):1676-1686. doi: 10.1177/0363546516667906. Epub 2016 Oct 13.
PMID: 27729319
citation: Uquillas CA, Capogna BM, Rossy WH, Mahure SA, Rokito AS. Postoperative pain control after arthroscopic rotator cuff repair. J Shoulder Elbow Surg. 2016 Jul;25(7):1204-13. doi: 10.1016/j.jse.2016.01.026. Epub 2016 Apr 11.
PMID: 27079219
citation: Hughes MS, Matava MJ, Wright RW, Brophy RH, Smith MV. Interscalene brachial plexus block for arthroscopic shoulder surgery: a systematic review. J Bone Joint Surg Am. 2013 Jul 17;95(14):1318-24. doi: 10.2106/JBJS.L.01116. No abstract available.
PMID: 23864181
citation: Pehora C, Pearson AM, Kaushal A, Crawford MW, Johnston B. Dexamethasone as an adjuvant to peripheral nerve block. Cochrane Database Syst Rev. 2017 Nov 9;11(11):CD011770. doi: 10.1002/14651858.CD011770.pub2.
PMID: 29121400
citation: Kahn RL, Cheng J, Gadulov Y, Fields KG, YaDeau JT, Gulotta LV. Perineural Low-Dose Dexamethasone Prolongs Interscalene Block Analgesia With Bupivacaine Compared With Systemic Dexamethasone: A Randomized Trial. Reg Anesth Pain Med. 2018 Aug;43(6):572-579. doi: 10.1097/AAP.0000000000000817.
PMID: 29889698
citation: Holland D, Amadeo RJJ, Wolfe S, Girling L, Funk F, Collister M, Czaplinski E, Ferguson C, Leiter J, Old J, MacDonald P, Dufault B, Mutter TC. Effect of dexamethasone dose and route on the duration of interscalene brachial plexus block for outpatient arthroscopic shoulder surgery: a randomized controlled trial. Can J Anaesth. 2018 Jan;65(1):34-45. doi: 10.1007/s12630-017-0989-7. Epub 2017 Nov 10.
PMID: 29127558
citation: Tandoc MN, Fan L, Kolesnikov S, Kruglov A, Nader ND. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth. 2011 Oct;25(5):704-9. doi: 10.1007/s00540-011-1180-x. Epub 2011 Jun 17.
PMID: 21681533
citation: Balocco AL, Van Zundert PGE, Gan SS, Gan TJ, Hadzic A. Extended release bupivacaine formulations for postoperative analgesia: an update. Curr Opin Anaesthesiol. 2018 Oct;31(5):636-642. doi: 10.1097/ACO.0000000000000648.
PMID: 30074492
citation: Viscusi ER. Liposomal drug delivery for postoperative pain management. Reg Anesth Pain Med. 2005 Sep-Oct;30(5):491-6. doi: 10.1016/j.rapm.2005.05.001. No abstract available.
PMID: 16135355
citation: Bowyer A, Jakobsson J, Ljungqvist O, Royse C. A review of the scope and measurement of postoperative quality of recovery. Anaesthesia. 2014 Nov;69(11):1266-78. doi: 10.1111/anae.12730. Epub 2014 Jun 2.
PMID: 24888412
citation: Myles PS. Measuring quality of recovery in perioperative clinical trials. Curr Opin Anaesthesiol. 2018 Aug;31(4):396-401. doi: 10.1097/ACO.0000000000000612.
PMID: 29846193
citation: Chazapis M, Walker EM, Rooms MA, Kamming D, Moonesinghe SR. Measuring quality of recovery-15 after day case surgery. Br J Anaesth. 2016 Feb;116(2):241-8. doi: 10.1093/bja/aev413.
PMID: 26787793
citation: Myles PS, Hunt JO, Nightingale CE, Fletcher H, Beh T, Tanil D, Nagy A, Rubinstein A, Ponsford JL. Development and psychometric testing of a quality of recovery score after general anesthesia and surgery in adults. Anesth Analg. 1999 Jan;88(1):83-90. doi: 10.1097/00000539-199901000-00016.
PMID: 9895071
citation: Stark PA, Myles PS, Burke JA. Development and psychometric evaluation of a postoperative quality of recovery score: the QoR-15. Anesthesiology. 2013 Jun;118(6):1332-40. doi: 10.1097/ALN.0b013e318289b84b.
PMID: 23411725
citation: Myles PS, Reeves MD, Anderson H, Weeks AM. Measurement of quality of recovery in 5672 patients after anaesthesia and surgery. Anaesth Intensive Care. 2000 Jun;28(3):276-80. doi: 10.1177/0310057X0002800304.
PMID: 10853209
citation: Myles PS, Myles DB, Galagher W, Chew C, MacDonald N, Dennis A. Minimal Clinically Important Difference for Three Quality of Recovery Scales. Anesthesiology. 2016 Jul;125(1):39-45. doi: 10.1097/ALN.0000000000001158.
PMID: 27159009
responsible party type: Principal Investigator
investigator affiliation: University of Pennsylvania
investigator full name: Nabil Elkassabany
investigator title: Physician
mesh term: Rotator Cuff Injuries
mesh term: Dexamethasone
mesh term: Bupivacaine
sharing ipd: No