<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/NCT03043027</url>
  </required_header>
  <id_info>
    <org_study_id>IRB# 16-748</org_study_id>
    <nct_id>NCT03043027</nct_id>
  </id_info>
  <brief_title>Efficacy of Liposomal Bupivacaine for Pain Control After Percutaneous Nephrostolithotomy</brief_title>
  <official_title>Efficacy of Liposomal Bupivacaine for Pain Control After Percutaneous Nephrostolithotomy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwell Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwell Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Percutaneous nephrostolithotomy (PCNL) is a common endoscopic procedure performed for upper&#xD;
      urinary tract calculus disease. Despite being minimally invasive, it is associated with&#xD;
      significant postoperative pain, often necessitating inpatient hospitalization and narcotic&#xD;
      pain medications. Additionally, one of a number of catheters is often left protruding from&#xD;
      the access tract for a period of time following the procedure, adding to patient discomfort.&#xD;
      Attempts have been made to study peri-tubular or access tract analgesic installation, which&#xD;
      have shown promise.1-2 However, no studies, to our knowledge, have examined the use of&#xD;
      liposomal bupivacaine preparations in this regard. In this study we hope to prospectively&#xD;
      analyze the use of liposomal bupivacaine injected to the access tract site at the time of&#xD;
      PCNL and determine its effects on postoperative narcotic requirement and pain scores.&#xD;
&#xD;
      Patients presenting for PCNL will be randomized to either the liposomal bupivacaine or usual&#xD;
      care, which involves no injection of local anesthesia. Patients will then be followed during&#xD;
      their inpatient stay. Total narcotic requirement (in milligrams) and pain scores (using&#xD;
      Wong-Baker FACES rating scale) will be compared.3 Typical postoperative care and discharge&#xD;
      criteria will not change during the course of this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Subjects will be randomly assigned by a 1:1:1 ratio to one of the following groups:&#xD;
&#xD;
        1. Saline (control arm)&#xD;
&#xD;
        2. Liposomal bupivicaine (long-acting local anesthetic)&#xD;
&#xD;
        3. Bupivacaine (local anesthetic)&#xD;
&#xD;
           The Biostatistics Unit will develop a randomization procedure using a permuted block&#xD;
           design. Randomization will be stratified by site (LIJ or NSUH). The randomization&#xD;
           process will occur in REDCap using the Randomization Module. Details of the procedure,&#xD;
           including required record keeping, will be further developed upon approval of this&#xD;
           protocol.&#xD;
&#xD;
           Patients undergoing PCNL will need no alterations of procedure in regards to&#xD;
           positioning, obtaining access, or removal of calculi. Efforts will be made to remove the&#xD;
           calculus with use of one access tract only; however, if the surgeon performing the&#xD;
           procedures deems that additional access tracts are needed they can be obtained.&#xD;
           Similarly, efforts will be taken to include a single nephrostomy tube without the need&#xD;
           for a ureteral stent. However, if the attending surgeon deems either of these factors&#xD;
           need to be altered, he may do so at his discretion. The use of multiple access tracts,&#xD;
           multiple nephrostomy tubes, or a ureteral stent will then disqualify the patient from&#xD;
           the trial and they shall then be withdrawn from the study. Because of the nature of the&#xD;
           procedure, it is difficult to predict with certainty if patients will need any of these&#xD;
           alterations and thus these decisions may need to be made intraoperatively.&#xD;
&#xD;
           If the patient still meets inclusion criteria, 20 mL of agent will be infiltrated&#xD;
           subcutaneously depending on what arm the patient was randomized to. 10 mL will be place&#xD;
           at the lateral edge of the tract while 10 mL will be placed at the medial edge. The&#xD;
           patient will be awakened without any other changes to standard PCNL protocol. All PCNL&#xD;
           procedures will be performed in the aforementioned manner by one of three fellowship&#xD;
           trained endourologists with high-volume stone practices (David Hoenig, Zeph Okeke, and&#xD;
           Arthur Smith).&#xD;
&#xD;
           The primary outcome being assessed is the patient's pain rating at 24 hours after the&#xD;
           procedure. All patient scores will be recorded using a specific VAS, the Wong-Baker&#xD;
           FACES Pain Rating Scale. These values will be converted to a numerical scale from 0-10&#xD;
           accordingly. Patients will be assigned a pain rating handout which will be present in&#xD;
           their hospital room for 48 hours or until they are discharged, whichever comes first.&#xD;
           Nursing staff or a urology inpatient team member will prompt the patient at the 24 hour&#xD;
           period to describe their pain using the FACES scale and they will record this on their&#xD;
           handout. Nursing or a urology inpatient team member will collect handouts at time of&#xD;
           discharge or after 48 hours, whichever comes first.&#xD;
&#xD;
           Primary Objective:&#xD;
&#xD;
           To determine the effects of liposomal bupivacaine injections at the access site during&#xD;
           PCNL on postoperative pain and narcotic requirement.&#xD;
&#xD;
           Primary Outcome:&#xD;
&#xD;
           • Visual analog scale (VAS) at 24 hours (Liposomal bupivicaine vs. bupivicaine only)&#xD;
&#xD;
           Secondary Outcomes:&#xD;
&#xD;
             -  Total dose of narcotics (mg) over the course of hospital stay&#xD;
&#xD;
             -  VAS pain scores (across time)&#xD;
&#xD;
             -  Length of Stay (LOS)&#xD;
&#xD;
             -  Time-to-first rescue pain medication after surgery&#xD;
&#xD;
           Randomization:&#xD;
&#xD;
           Subjects will be randomly assigned by a 1:1:1 ratio to one of the following groups:&#xD;
&#xD;
        4. Saline (control arm)&#xD;
&#xD;
        5. Liposomal bupivicaine (long-acting)&#xD;
&#xD;
        6. Bupivacaine (local anesthetic)&#xD;
&#xD;
      The Biostatistics Unit will develop a randomization procedure using a permuted block design.&#xD;
      Randomization will be stratified by site (LIJ or NSUH). The randomization process will occur&#xD;
      in REDCap using the Randomization Module. Details of the procedure, including required record&#xD;
      keeping, will be further developed upon approval of this protocol.&#xD;
&#xD;
      Statistical Methods:&#xD;
&#xD;
      Descriptive statistics (means ± standard deviations or medians and interquartile range [25th&#xD;
      percentile, 75th percentile] for continuous data; frequencies and percentages for categorical&#xD;
      data) will be calculated by group.&#xD;
&#xD;
      Comparability of the three groups at baseline will be analyzed using the chi-square test or&#xD;
      Fisher's exact test, as deemed appropriate, for categorical variables. Continuous variables&#xD;
      such as age and narcotic usage will be compared using Analysis of Variance (ANOVA) or the&#xD;
      Kruskal-Wallis test as indicated.&#xD;
&#xD;
      For the primary outcome, the 24 hour VAS score will be compared between the liposomal&#xD;
      bupivacaine vs. bupivacaine groups using the two-sample t-test or Mann-Whitney test as deemed&#xD;
      appropriate.&#xD;
&#xD;
      A repeated measures analysis of variance (RMANOVA) with a mixed models approach will be used&#xD;
      to determine if the groups' trajectories for VAS differ across time, measured at 6, 12, 24,&#xD;
      and 48 hours post-operatively (i.e., the group x time interaction). The standard assumptions&#xD;
      of Gaussian residuals and equality of variance will be tested. If the normality assumption is&#xD;
      not met, a transformation will be used for the analysis of VAS. The repeated within subjects&#xD;
      factor will be time and the within subjects factor will be group (Saline, Liposomal&#xD;
      bupivicaine, or Bupivacaine).&#xD;
&#xD;
      &quot;Time-to-first rescue pain medication after surgery&quot; will be analyzed by applying standard&#xD;
      methods of survival analysis, i.e., computing the Kaplan-Meier product limit curves, where&#xD;
      group will be the stratification variable. In cases where the endpoint event, &quot;first rescue&#xD;
      pain medication after surgery&quot;, did not occur, the number of hours until last follow-up will&#xD;
      be used and considered 'censored'. The groups will be compared using the log-rank test. The&#xD;
      median &quot;time to first rescue pain medication after surgery&quot; and corresponding 95% confidence&#xD;
      intervals for each group will be obtained from the Kaplan-Meier/Product-Limit Estimates.&#xD;
&#xD;
      LOS will also be analyzed using the standard methods of survival described above, however,&#xD;
      without any censored data.&#xD;
&#xD;
      A result will be considered statistically significant at the p&lt;0.05 level of significance.&#xD;
      Upon finding a significant difference among the three groups in any of the above analyses,&#xD;
      Bonferroni adjusted multiple pairwise comparisons will be carried out in order to determine&#xD;
      specifically which groups differed from one another. A pairwise comparison will be considered&#xD;
      statistically significant if p&lt;0.0167 (=0.05/3).&#xD;
&#xD;
      All analyses will be performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).&#xD;
&#xD;
      Intention-to-Treat (ITT):&#xD;
&#xD;
      Statistical analysis will be performed using the modified intention-to-treat population&#xD;
      (mITT), defined as all randomized subjects who receive treatment and who have completed at&#xD;
      least one pain score after baseline assessment.&#xD;
&#xD;
      Interim Analysis and Early Stopping:&#xD;
&#xD;
      There are no plans for interim analysis for efficacy.&#xD;
&#xD;
      Sample Size Considerations:&#xD;
&#xD;
      The proposed sample size for this prospective, single-blinded randomized trial is 99 subjects&#xD;
      (n=33 per group). The sample size is based on the primary analysis of VAS at 24 weeks between&#xD;
      the Liposomal bupivicaine vs. bupivicaine groups. Although other analyses will be performed&#xD;
      on all 3 groups, the sample size calculation has been simplified to the analysis of Liposomal&#xD;
      bupivicaine vs. bupivicaine at a single time point.&#xD;
&#xD;
      Based on data published by Kirac et al. (2013), the mean 24-hour VAS score for the&#xD;
      bupivicaine group was 2.8 ± 0.9. We assume that the VAS score at 24-hours for the Liposomal&#xD;
      bupivicaine group will be 25% greater (VAS=3.5). A sample size of 33 in each group will have&#xD;
      80% power to detect such a difference in means of -0.7 assuming that the common standard&#xD;
      deviation is 1.0 using a two group t-test with a 0.05 two-sided significance level. Expanding&#xD;
      this to 3 groups will yield a total sample size of 99 subjects.&#xD;
&#xD;
      Outcomes The primary outcome being assessed is the patient's pain rating at 24 hours after&#xD;
      the procedure. All patient scores will be recorded using a specific VAS, the Wong-Baker FACES&#xD;
      Pain Rating Scale. These values will be converted to a numerical scale from 0-10 accordingly.&#xD;
      Patients will be assigned a pain rating handout which will be present in their hospital room&#xD;
      for 48 hours or until they are discharged, whichever comes first. Nursing staff or a urology&#xD;
      inpatient team member will prompt the patient at the 24 hour period to describe their pain&#xD;
      using the FACES scale and they will record this on their handout. Nursing or a urology&#xD;
      inpatient team member will collect handouts at time of discharge or after 48 hours, whichever&#xD;
      comes first.&#xD;
&#xD;
      The following data will also be recorded and serve as the secondary outcomes:&#xD;
&#xD;
        1. Patient's pain rating at 6, 12, and 48 hours in all arms&#xD;
&#xD;
        2. Patient's pain rating at 24 hours in the saline arm&#xD;
&#xD;
        3. Patient length of stay (LOS)&#xD;
&#xD;
        4. Time-to-first rescue pain medication after surgery&#xD;
&#xD;
        5. Total narcotic use&#xD;
&#xD;
        6. Weight adjusted total narcotics use&#xD;
&#xD;
        7. Narcotic density (mg of morphine equivalent/hours) used at 0-6 hours, 6-12 hours, 12-24&#xD;
           hours, 24-48 hours&#xD;
&#xD;
      Additionally, patient demographics and clinical characteristics such as age, gender, BMI, and&#xD;
      previous medical and surgical history will be collected. Procedural characteristics such as&#xD;
      location of tracts (supracostal vs infracostal), size of nephrostomy tract, and type of&#xD;
      nephrostomy tube will be recorded.&#xD;
&#xD;
      A secondary outcome that deserves further mention will be the total dose of narcotics from&#xD;
      over the inpatient hospital course. This will be measured from 1 hour after the patient&#xD;
      reaches the post-anesthesia care unit (PACU) until the discharge order is placed. All opiate&#xD;
      medication will be converted morphine equivalents and the values will be reported as total&#xD;
      number of milligrams of morphine. In order to help reduce variability due to variations in&#xD;
      prescriber patterns, patients will be started on a pain regimen as followed.&#xD;
&#xD;
      Mild pain: 1 tablet PO Oxycodone 5mg/Acetaminophen 325mg q4 hours Moderate pain: 2 tablets PO&#xD;
      Oxycodone 5mg/Acetaminophen 325mg q4 hours Severe pain: 1 mg IV hydromorphone q4 hours&#xD;
      Breakthrough pain: 0.5 mg IV hydromorphone q4 hours The analgesic regimen can be altered by&#xD;
      the physician or physician assistant treating the patient at their discretion but efforts&#xD;
      will be maintained to follow this analgesic regimen. Amount of narcotics used will be gleaned&#xD;
      from the electronic medical record upon discharge of the patient. Time to start recording&#xD;
      analgesics will begin one hour after patient is sent to the PACU. This will help decrease&#xD;
      variability in anesthesiologist and peri-anesthesia prescribing patterns immediately at the&#xD;
      conclusion of the procedure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    cost of medicine too expensive to continue without funding&#xD;
  </why_stopped>
  <start_date type="Actual">August 8, 2017</start_date>
  <completion_date type="Actual">August 8, 2017</completion_date>
  <primary_completion_date type="Actual">August 8, 2017</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Scores from the Visual Analog Scale for pain 24 hours post-procedurally in the liposomal bupivacaine group and the bupivacaine group</measure>
    <time_frame>24 hours</time_frame>
    <description>Scores from the Visual Analog Scale for pain 24 hours post-procedurally in the liposomal bupivacaine group and the bupivacaine group</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>narcotic usage</measure>
    <time_frame>pain scores at 6, 12, 24, and 48 hours</time_frame>
    <description>quantify mg of morphine equivalent used post operative</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Renal Calculi</condition>
  <condition>Postoperative Pain</condition>
  <arm_group>
    <arm_group_label>Liposomal bupivicaine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>bupivicaine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>liposomal bupivicaine</intervention_name>
    <description>local anesthetic</description>
    <arm_group_label>Liposomal bupivicaine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupivacaine</intervention_name>
    <description>local anesthetic</description>
    <arm_group_label>bupivicaine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Saline Solution</intervention_name>
    <description>saline injection</description>
    <arm_group_label>saline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients &gt;18 years old&#xD;
&#xD;
          2. Patients with calculus disease that can be treated with PCNL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients &lt;18 years old.&#xD;
&#xD;
          2. Patients who are not able to give consent for study&#xD;
&#xD;
          3. Patients with active urinary tract infection&#xD;
&#xD;
          4. Pregnant women&#xD;
&#xD;
          5. Patients with hepatic insufficiency&#xD;
&#xD;
          6. Patients with more than 2 access tracts created&#xD;
&#xD;
          7. Allergies to bupivacaine or liposomal bupivacaine&#xD;
&#xD;
          8. Patients with chronic pain syndromes as determined by using &gt;30mg oral morphine&#xD;
             equivalents per day&#xD;
&#xD;
          9. Patients who are neurologically impaired and may have altered pain sensation due to&#xD;
             previous diseases (e.g. paraplegics, quadriplegics, systemic neurological condition,&#xD;
             etc.)&#xD;
&#xD;
         10. Patients who are undergoing staged procedures during that same hospital stay&#xD;
&#xD;
         11. Patients who are placed on patient controlled analgesia or patient controlled epidural&#xD;
             analgesia&#xD;
&#xD;
         12. Patients who remain intubated after surgery&#xD;
&#xD;
         13. Patients who will have ureteral stents&#xD;
&#xD;
         14. Patients who do not require care in the intensive care unit&#xD;
&#xD;
         15. Patients who are mentally impaired.&#xD;
&#xD;
         16. Patients who are criminal prisoners.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David M Hoenig, md</last_name>
    <role>Principal Investigator</role>
    <affiliation>Urologist</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>North Shore University Hospital</name>
      <address>
        <city>Manhasset</city>
        <state>New York</state>
        <zip>11030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Jonnavithula N, Pisapati MV, Durga P, Krishnamurthy V, Chilumu R, Reddy B. Efficacy of peritubal local anesthetic infiltration in alleviating postoperative pain in percutaneous nephrolithotomy. J Endourol. 2009 May;23(5):857-60. doi: 10.1089/end.2008.0634.</citation>
    <PMID>19397429</PMID>
  </reference>
  <reference>
    <citation>Lojanapiwat B, Chureemas T, Kittirattarakarn P. The efficacy of peritubal analgesic infiltration in postoperative pain following percutaneous nephrolithotomy - A prospective randomized controlled study. Int Braz J Urol. 2015 Sep-Oct;41(5):945-52. doi: 10.1590/S1677-5538.IBJU.2014.0471.</citation>
    <PMID>26689520</PMID>
  </reference>
  <reference>
    <citation>Cherian JJ, Barrington J, Elmallah RK, Chughtai M, Mistry JB, Mont MA. Liposomal Bupivacaine Suspension, Can Reduce Length of Stay and Improve Discharge Status of Patients Undergoing Total Hip Arthroplasty. Surg Technol Int. 2015 Nov;27:235-9.</citation>
    <PMID>26680403</PMID>
  </reference>
  <reference>
    <citation>Marcet JE, Nfonsam VN, Larach S. An extended paIn relief trial utilizing the infiltration of a long-acting Multivesicular liPosome foRmulation Of bupiVacaine, EXPAREL (IMPROVE): a Phase IV health economic trial in adult patients undergoing ileostomy reversal. J Pain Res. 2013 Jul 18;6:549-55. doi: 10.2147/JPR.S46467. Print 2013.</citation>
    <PMID>23901290</PMID>
  </reference>
  <reference>
    <citation>Vogel JD. Liposome bupivacaine (EXPAREL(R)) for extended pain relief in patients undergoing ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase IV health economics trial. J Pain Res. 2013 Jul 29;6:605-10. doi: 10.2147/JPR.S46950. Print 2013.</citation>
    <PMID>23935387</PMID>
  </reference>
  <reference>
    <citation>Hu D, Onel E, Singla N, Kramer WG, Hadzic A. Pharmacokinetic profile of liposome bupivacaine injection following a single administration at the surgical site. Clin Drug Investig. 2013 Feb;33(2):109-15. doi: 10.1007/s40261-012-0043-z.</citation>
    <PMID>23229686</PMID>
  </reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>January 20, 2017</study_first_submitted>
  <study_first_submitted_qc>February 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 3, 2017</study_first_posted>
  <last_update_submitted>August 24, 2017</last_update_submitted>
  <last_update_submitted_qc>August 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 28, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwell Health</investigator_affiliation>
    <investigator_full_name>David Hoenig</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Calculi</mesh_term>
    <mesh_term>Nephrolithiasis</mesh_term>
    <mesh_term>Calculi</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>
  <!-- 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/NCT03043027
org study id: IRB# 16-748
nct id: NCT03043027
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Percutaneous nephrostolithotomy (PCNL) is a common endoscopic procedure performed for upper
      urinary tract calculus disease. Despite being minimally invasive, it is associated with
      significant postoperative pain, often necessitating inpatient hospitalization and narcotic
      pain medications. Additionally, one of a number of catheters is often left protruding from
      the access tract for a period of time following the procedure, adding to patient discomfort.
      Attempts have been made to study peri-tubular or access tract analgesic installation, which
      have shown promise.1-2 However, no studies, to our knowledge, have examined the use of
      liposomal bupivacaine preparations in this regard. In this study we hope to prospectively
      analyze the use of liposomal bupivacaine injected to the access tract site at the time of
      PCNL and determine its effects on postoperative narcotic requirement and pain scores.

      Patients presenting for PCNL will be randomized to either the liposomal bupivacaine or usual
      care, which involves no injection of local anesthesia. Patients will then be followed during
      their inpatient stay. Total narcotic requirement (in milligrams) and pain scores (using
      Wong-Baker FACES rating scale) will be compared.3 Typical postoperative care and discharge
      criteria will not change during the course of this study.
Subjects will be randomly assigned by a 1:1:1 ratio to one of the following groups:

        1. Saline (control arm)

        2. Liposomal bupivicaine (long-acting local anesthetic)

        3. Bupivacaine (local anesthetic)

           The Biostatistics Unit will develop a randomization procedure using a permuted block
           design. Randomization will be stratified by site (LIJ or NSUH). The randomization
           process will occur in REDCap using the Randomization Module. Details of the procedure,
           including required record keeping, will be further developed upon approval of this
           protocol.

           Patients undergoing PCNL will need no alterations of procedure in regards to
           positioning, obtaining access, or removal of calculi. Efforts will be made to remove the
           calculus with use of one access tract only; however, if the surgeon performing the
           procedures deems that additional access tracts are needed they can be obtained.
           Similarly, efforts will be taken to include a single nephrostomy tube without the need
           for a ureteral stent. However, if the attending surgeon deems either of these factors
           need to be altered, he may do so at his discretion. The use of multiple access tracts,
           multiple nephrostomy tubes, or a ureteral stent will then disqualify the patient from
           the trial and they shall then be withdrawn from the study. Because of the nature of the
           procedure, it is difficult to predict with certainty if patients will need any of these
           alterations and thus these decisions may need to be made intraoperatively.

           If the patient still meets inclusion criteria, 20 mL of agent will be infiltrated
           subcutaneously depending on what arm the patient was randomized to. 10 mL will be place
           at the lateral edge of the tract while 10 mL will be placed at the medial edge. The
           patient will be awakened without any other changes to standard PCNL protocol. All PCNL
           procedures will be performed in the aforementioned manner by one of three fellowship
           trained endourologists with high-volume stone practices (David Hoenig, Zeph Okeke, and
           Arthur Smith).

           The primary outcome being assessed is the patient's pain rating at 24 hours after the
           procedure. All patient scores will be recorded using a specific VAS, the Wong-Baker
           FACES Pain Rating Scale. These values will be converted to a numerical scale from 0-10
           accordingly. Patients will be assigned a pain rating handout which will be present in
           their hospital room for 48 hours or until they are discharged, whichever comes first.
           Nursing staff or a urology inpatient team member will prompt the patient at the 24 hour
           period to describe their pain using the FACES scale and they will record this on their
           handout. Nursing or a urology inpatient team member will collect handouts at time of
           discharge or after 48 hours, whichever comes first.

           Primary Objective:

           To determine the effects of liposomal bupivacaine injections at the access site during
           PCNL on postoperative pain and narcotic requirement.

           Primary Outcome:

           • Visual analog scale (VAS) at 24 hours (Liposomal bupivicaine vs. bupivicaine only)

           Secondary Outcomes:

             -  Total dose of narcotics (mg) over the course of hospital stay

             -  VAS pain scores (across time)

             -  Length of Stay (LOS)

             -  Time-to-first rescue pain medication after surgery

           Randomization:

           Subjects will be randomly assigned by a 1:1:1 ratio to one of the following groups:

        4. Saline (control arm)

        5. Liposomal bupivicaine (long-acting)

        6. Bupivacaine (local anesthetic)

      The Biostatistics Unit will develop a randomization procedure using a permuted block design.
      Randomization will be stratified by site (LIJ or NSUH). The randomization process will occur
      in REDCap using the Randomization Module. Details of the procedure, including required record
      keeping, will be further developed upon approval of this protocol.

      Statistical Methods:

      Descriptive statistics (means ± standard deviations or medians and interquartile range [25th
      percentile, 75th percentile] for continuous data; frequencies and percentages for categorical
      data) will be calculated by group.

      Comparability of the three groups at baseline will be analyzed using the chi-square test or
      Fisher's exact test, as deemed appropriate, for categorical variables. Continuous variables
      such as age and narcotic usage will be compared using Analysis of Variance (ANOVA) or the
      Kruskal-Wallis test as indicated.

      For the primary outcome, the 24 hour VAS score will be compared between the liposomal
      bupivacaine vs. bupivacaine groups using the two-sample t-test or Mann-Whitney test as deemed
      appropriate.

      A repeated measures analysis of variance (RMANOVA) with a mixed models approach will be used
      to determine if the groups' trajectories for VAS differ across time, measured at 6, 12, 24,
      and 48 hours post-operatively (i.e., the group x time interaction). The standard assumptions
      of Gaussian residuals and equality of variance will be tested. If the normality assumption is
      not met, a transformation will be used for the analysis of VAS. The repeated within subjects
      factor will be time and the within subjects factor will be group (Saline, Liposomal
      bupivicaine, or Bupivacaine).

      "Time-to-first rescue pain medication after surgery" will be analyzed by applying standard
      methods of survival analysis, i.e., computing the Kaplan-Meier product limit curves, where
      group will be the stratification variable. In cases where the endpoint event, "first rescue
      pain medication after surgery", did not occur, the number of hours until last follow-up will
      be used and considered 'censored'. The groups will be compared using the log-rank test. The
      median "time to first rescue pain medication after surgery" and corresponding 95% confidence
      intervals for each group will be obtained from the Kaplan-Meier/Product-Limit Estimates.

      LOS will also be analyzed using the standard methods of survival described above, however,
      without any censored data.

      A result will be considered statistically significant at the p<0.05 level of significance.
      Upon finding a significant difference among the three groups in any of the above analyses,
      Bonferroni adjusted multiple pairwise comparisons will be carried out in order to determine
      specifically which groups differed from one another. A pairwise comparison will be considered
      statistically significant if p<0.0167 (=0.05/3).

      All analyses will be performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

      Intention-to-Treat (ITT):

      Statistical analysis will be performed using the modified intention-to-treat population
      (mITT), defined as all randomized subjects who receive treatment and who have completed at
      least one pain score after baseline assessment.

      Interim Analysis and Early Stopping:

      There are no plans for interim analysis for efficacy.

      Sample Size Considerations:

      The proposed sample size for this prospective, single-blinded randomized trial is 99 subjects
      (n=33 per group). The sample size is based on the primary analysis of VAS at 24 weeks between
      the Liposomal bupivicaine vs. bupivicaine groups. Although other analyses will be performed
      on all 3 groups, the sample size calculation has been simplified to the analysis of Liposomal
      bupivicaine vs. bupivicaine at a single time point.

      Based on data published by Kirac et al. (2013), the mean 24-hour VAS score for the
      bupivicaine group was 2.8 ± 0.9. We assume that the VAS score at 24-hours for the Liposomal
      bupivicaine group will be 25% greater (VAS=3.5). A sample size of 33 in each group will have
      80% power to detect such a difference in means of -0.7 assuming that the common standard
      deviation is 1.0 using a two group t-test with a 0.05 two-sided significance level. Expanding
      this to 3 groups will yield a total sample size of 99 subjects.

      Outcomes The primary outcome being assessed is the patient's pain rating at 24 hours after
      the procedure. All patient scores will be recorded using a specific VAS, the Wong-Baker FACES
      Pain Rating Scale. These values will be converted to a numerical scale from 0-10 accordingly.
      Patients will be assigned a pain rating handout which will be present in their hospital room
      for 48 hours or until they are discharged, whichever comes first. Nursing staff or a urology
      inpatient team member will prompt the patient at the 24 hour period to describe their pain
      using the FACES scale and they will record this on their handout. Nursing or a urology
      inpatient team member will collect handouts at time of discharge or after 48 hours, whichever
      comes first.

      The following data will also be recorded and serve as the secondary outcomes:

        1. Patient's pain rating at 6, 12, and 48 hours in all arms

        2. Patient's pain rating at 24 hours in the saline arm

        3. Patient length of stay (LOS)

        4. Time-to-first rescue pain medication after surgery

        5. Total narcotic use

        6. Weight adjusted total narcotics use

        7. Narcotic density (mg of morphine equivalent/hours) used at 0-6 hours, 6-12 hours, 12-24
           hours, 24-48 hours

      Additionally, patient demographics and clinical characteristics such as age, gender, BMI, and
      previous medical and surgical history will be collected. Procedural characteristics such as
      location of tracts (supracostal vs infracostal), size of nephrostomy tract, and type of
      nephrostomy tube will be recorded.

      A secondary outcome that deserves further mention will be the total dose of narcotics from
      over the inpatient hospital course. This will be measured from 1 hour after the patient
      reaches the post-anesthesia care unit (PACU) until the discharge order is placed. All opiate
      medication will be converted morphine equivalents and the values will be reported as total
      number of milligrams of morphine. In order to help reduce variability due to variations in
      prescriber patterns, patients will be started on a pain regimen as followed.

      Mild pain: 1 tablet PO Oxycodone 5mg/Acetaminophen 325mg q4 hours Moderate pain: 2 tablets PO
      Oxycodone 5mg/Acetaminophen 325mg q4 hours Severe pain: 1 mg IV hydromorphone q4 hours
      Breakthrough pain: 0.5 mg IV hydromorphone q4 hours The analgesic regimen can be altered by
      the physician or physician assistant treating the patient at their discretion but efforts
      will be maintained to follow this analgesic regimen. Amount of narcotics used will be gleaned
      from the electronic medical record upon discharge of the patient. Time to start recording
      analgesics will begin one hour after patient is sent to the PACU. This will help decrease
      variability in anesthesiologist and peri-anesthesia prescribing patterns immediately at the
      conclusion of the procedure.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Scores from the Visual Analog Scale for pain 24 hours post-procedurally in the liposomal bupivacaine group and the bupivacaine group
time frame: 24 hours
description: Scores from the Visual Analog Scale for pain 24 hours post-procedurally in the liposomal bupivacaine group and the bupivacaine group
measure: narcotic usage
time frame: pain scores at 6, 12, 24, and 48 hours
description: quantify mg of morphine equivalent used post operative
arm group label: Liposomal bupivicaine
arm group type: Experimental
arm group label: bupivicaine
arm group type: Active Comparator
arm group label: saline
arm group type: Placebo Comparator
intervention type: Drug
intervention name: liposomal bupivicaine
description: local anesthetic
arm group label: Liposomal bupivicaine
intervention type: Drug
intervention name: Bupivacaine
description: local anesthetic
arm group label: bupivicaine
intervention type: Drug
intervention name: Saline Solution
description: saline injection
arm group label: saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: Accepts Healthy Volunteers
last name: David M Hoenig, md
role: Principal Investigator
affiliation: Urologist
facility: 
country: United States
citation: Jonnavithula N, Pisapati MV, Durga P, Krishnamurthy V, Chilumu R, Reddy B. Efficacy of peritubal local anesthetic infiltration in alleviating postoperative pain in percutaneous nephrolithotomy. J Endourol. 2009 May;23(5):857-60. doi: 10.1089/end.2008.0634.
PMID: 19397429
citation: Lojanapiwat B, Chureemas T, Kittirattarakarn P. The efficacy of peritubal analgesic infiltration in postoperative pain following percutaneous nephrolithotomy - A prospective randomized controlled study. Int Braz J Urol. 2015 Sep-Oct;41(5):945-52. doi: 10.1590/S1677-5538.IBJU.2014.0471.
PMID: 26689520
citation: Cherian JJ, Barrington J, Elmallah RK, Chughtai M, Mistry JB, Mont MA. Liposomal Bupivacaine Suspension, Can Reduce Length of Stay and Improve Discharge Status of Patients Undergoing Total Hip Arthroplasty. Surg Technol Int. 2015 Nov;27:235-9.
PMID: 26680403
citation: Marcet JE, Nfonsam VN, Larach S. An extended paIn relief trial utilizing the infiltration of a long-acting Multivesicular liPosome foRmulation Of bupiVacaine, EXPAREL (IMPROVE): a Phase IV health economic trial in adult patients undergoing ileostomy reversal. J Pain Res. 2013 Jul 18;6:549-55. doi: 10.2147/JPR.S46467. Print 2013.
PMID: 23901290
citation: Vogel JD. Liposome bupivacaine (EXPAREL(R)) for extended pain relief in patients undergoing ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase IV health economics trial. J Pain Res. 2013 Jul 29;6:605-10. doi: 10.2147/JPR.S46950. Print 2013.
PMID: 23935387
citation: Hu D, Onel E, Singla N, Kramer WG, Hadzic A. Pharmacokinetic profile of liposome bupivacaine injection following a single administration at the surgical site. Clin Drug Investig. 2013 Feb;33(2):109-15. doi: 10.1007/s40261-012-0043-z.
PMID: 23229686
responsible party type: Principal Investigator
investigator affiliation: Northwell Health
investigator full name: David Hoenig
investigator title: Principal Investigator
mesh term: Kidney Calculi
mesh term: Nephrolithiasis
mesh term: Calculi
mesh term: Bupivacaine
sharing ipd: No