Randomized Controlled Trial Investigating Use of Liposomal Bupivacaine in Bariatric Surgery
Phase: PHASE2
Conditions: Bariatric Surgery Analgesia
Sponsor: Montefiore Medical Center

IRB NUMBER: 2017-7706
IRB APPROVAL DATE: 12/29/2017
Protocol No. 2017-7706
Template version: January 24 , 2017
Title:
Randomized Controlled Trial Investigating Use of Liposomal Bupivacaine 
in Bariatric Surgery. 
Study Key Name
Liposomal Bupivacaine in Bariatric Surgery
Protocol No:
2017-7706
Protocol Date:
1/24/2017
Diego Camacho, MD
Montefiore Medical Center
Department of Surgery
3400 Bainbridge Ave                          
Bronx, NY, 10467
Phone (718) 920-4800
email: DICAMACH@montefiore.org

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TABLE OF CONTENTS
Table of Contents.................................................................................................................................ii
Abbreviations and Definitions of Terms...........................................................................................iii
Abstract.................................................................................................................................................v
1.1
INTRODUCTION .........................................................................................................................................1
1.2
COMPLIANCE STATEMENT........................................................................................................................1
1.3
RELEVANT LITERATURE AND DATA .........................................................................................................1
2.1
PRIMARY OBJECTIVE ................................................................................................................................2
2.2
SECONDARY OBJECTIVES .........................................................................................................................2
3.1
GENERAL SCHEMA OF STUDY DESIGN......................................................................................................2
3.2
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES.......................................................................2
3.2.1
Date Range of Study .........................................................................................................................2
3.2.2
Total Number of Study Sites/Total Number of Subjects Projected...................................................2
3.3
STUDY POPULATION .................................................................................................................................3
3.3.1
Inclusion Criteria .............................................................................................................................3
3.3.2
Exclusion Criteria.............................................................................................................................3
4.1
DATA VARIABLES AND SOURCES .............................................................................................................4
4.1.1
Subject Recruitment..........................................................................................................................4
4.1.2
Data sources.....................................................................................................................................4
4.2
MEASURES TO AVOID BIAS.......................................................................................................................4
5.1
PRIMARY AND SECONDARY OUTCOMES ...................................................................................................4
5.2
SAMPLE SIZE AND POWER ........................................................................................................................5
5.3
DATA ANALYSIS PLAN ..............................................................................................................................5
5.4
RANDOMIZATION......................................................................................................................................5
6.1
DATA COLLECTION AND MANAGEMENT ..................................................................................................5
6.2
CONFIDENTIALITY ....................................................................................................................................6
6.3
REGULATORY AND ETHICAL CONSIDERATIONS........................................................................................6
6.3.1
Risk Assessment ................................................................................................................................6
6.3.2
Potential Benefits of Study Participation .........................................................................................6
6.3.3
Data Safety Monitoring Plan............................................................................................................6
6.4
INFORMED CONSENT.................................................................................................................................6
9.1.1
STUDY-MASTER LIST.....................................................................................................................8
9.1.2
DATA COLLECTION SHEET..........................................................................................................9

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ABBREVIATIONS AND DEFINITIONS OF TERMS
MMC
Montefiore Medical Center
LP
LSG
LRYGB
PCA
TAP
LB
RB
Liposomal Bupivacaine
Laparoscopic Sleeve Gastrectomy
Laparoscopic Roux en y Gastric Bypass
Patient Controlled Analgesia
Transversus Abdominis Plane
Liposomal Bupivacaine
Regular Bupivacaine

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ABSTRACT
Context: 
There has been increasing effort to reduce the use of opiates in the general population.  The obese 
population, and in particular those undergoing bariatric surgery, represent an especially high-risk 
group for the adverse effects associated with opiate use.  
The aim of this study is to perform a randomized controlled trial for patients undergoing bariatric 
surgery, comparing the need for opiates with and without administration of a transversus abdominis 
plane (TAP) block using the long acting local anesthetic, liposomal bupivacaine (Exparel®).  From 
this study, we will investigate whether use of long acting local anesthetic can reduce the need for 
opiates in the bariatric population.  
Objectives: 

To determine the effect of using long acting local anesthetic for a transversus abdominis plane 
block on opiate use in the bariatric population
Study Design: 

A prospective randomized controlled trial investigating the use of long acting local anesthetic for 
transversus abdominis block in patients undergoing bariatric surgery at Montefiore Medical 
Center.
Setting/Participants:

This is a single center study of patients undergoing bariatric surgery in the Department of 
Surgery at Montefiore Medical Center.  
Study Interventions and Measures: 

Main study outcome measures will include but not limited to: opiate use (adjusted for opioid 
equivalence).  

Secondary study outcome measures will include: 24-hour composite paint scores, length of stay, 
respiratory complications (pneumonia, atelectasis), venous thromboembolic event, myocardial 
infarction, nausea, vomiting, time to adequate oral intake (3 ounces each hour), and time to 
ambulation.  

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1
BACKGROUND INFORMATION AND RATIONALE
1.1
Introduction
More than one third of the population in the United States is obese.  Over 190,000 people have 
undergone bariatric surgery each year for the last 2 years.  The most common procedures performed 
are the laparoscopic sleeve gastrectomy (LSG) and laparoscopic roux en y gastric bypass (LRYGB).  
Pain management is essential for prevention of post operative respiratory complications.  Obtaining 
adequate analgesia, particularly judicious administration of opiates, can be a double-edged sword.  
While opiates provide a large part of the post operative pain regimen that is essential to achieve 
early ambulation and accommodate adequate ventilation and chest excursion, it also acts as a 
respiratory depressant and holds strong addictive potential.  The aim of this study is to perform a 
prospective randomized controlled trial of patients undergoing bariatric surgery examining opiate 
use and pain control in those who undergo intraoperative TAP block with liposomal bupivacaine 
(LB) or regular bupivacaine (RB) compared to those who receive standard postoperative pain 
regimens.   
1.2
Compliance Statement
This study will be conducted in full accordance of all applicable Montefiore Medical Center 
Research Policies and Procedures and all applicable Federal and state laws and regulations 
including 45 CFR 46, and the HIPAA Privacy Rule. Any episode of noncompliance will be 
documented.
The investigators will perform the study in accordance with this protocol, will obtain consent and 
assent (unless a waiver is granted), and will report unexpected problems in accordance with The 
Montefiore Medical Center IRB Policies and Procedures and all federal requirements. Collection, 
recording, and reporting of data will be accurate and will ensure the privacy, health, and welfare of 
research subjects during and after the study. 
1.3
Relevant Literature and Data
Increased opiate use is associated with increased rates of delirium, ileus, urinary retention, and 
respiratory depression.  Transversus abdominis plane (TAP) block is a safe and effective approach 
to achieve optimum pain control and reduce the use of opiates in patients undergoing major 
abdominal surgery.  A randomized controlled trial comparing TAP block with bupivacaine and a 
standard post-operative analgesia regimen demonstrated a reduction in visual analog pain scales 
throughout the initial 24 hour post-operative period, as well as a 4-fold reduction in the amount of 
morphine required by patients.  All of the patients included in this study were undergoing 
exploratory laparotomy and bowel resection (McDonnell et al).
Numerous studies have compared the use of liposomal bupivacaine and non-liposomal anesthetic 
for the use of TAP block with data indicating a benefit with the use of liposomal bupivacaine.  
Fayezizadeh et al. compared TAP block in patients undergoing abdominal wall reconstruction with 
historical cohorts.  This study demonstrated improved pain scores and decreased narcotic 
consumption with the TAP block.  Keller et al. performed a prospective pilot study comparing pain 
scores and narcotic use with and without TAP block in patients undergoing colorectal surgery.  
They found that the group who underwent TAP block had decreased pain scores, decreased narcotic 
use and shorter length of stay compared with the control group.  Hutchins et al. compared the use of 
liposomal bupivacaine with nonliposomal local anesthetic in patients undergoing hysterectomy.  
This trial was a prospective randomized controlled observer blinded study.  It demonstrated 
decreased total opioid use in the first 72 hours after surgery as well as decreased pain scores.  

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Morbidly obese patients due to high incidence of obstructive sleep apnea (OSA) are predisposed to 
opioid induced airway obstruction and thus frontline high ceiling analgesics (opioids) have concerns 
based on safety in their liberal use (Alvarez et al). Multiple studies have demonstrated a decrease in 
post-operative pain and thus diminished opioid consumption post-intervention. The morbidly obese 
bariatric population, who are at a particularly higher-risk for opioid induced complications such as 
apneic events and possible cardiac death, would benefit from a post-surgical analgesia regimen that 
would decrease or eliminate said risks.
2
STUDY OBJECTIVES

The aim of this study is to perform a prospective randomized controlled trial to investigate the 
effect of performing a TAP block using long acting local anesthetic on opiate use and pain 
control in the bariatric population.   From this data we propose to determine if we can 
adequately and safely forego implementation of PCA and reduce the overall use of opiates, 
while providing sufficient analgesia.  
2.1
Primary Objective 

To determine if the use of long acting or regular acting local anesthetic for TAP block will have 
an effect on the use of opiates in patients undergoing bariatric surgery at MMC.
2.2
Secondary Objectives 

To identify associations between demographic factors, such as age, race, types, pathology 
findings with outcomes.

To identify any difference in 24 and 48-hour composite pain scores, the length of stay, 
incidence of cardiac or respiratory complications, or incidence of venous thromboembolic 
events between the three groups.  
3
INVESTIGATIONAL PLAN
3.1
General Schema of Study Design

Prospective randomized controlled trial of patients undergoing bariatric surgery at 
Montefiore Medical Center.  

This will only include inpatient data
3.2
Study Duration, Enrollment and Number of Sites
3.2.1
Date Range of Study

Cases included will take place at MMC between 01/01/2018 and 12/31/2018 over a 1 year 
period.  
3.2.2
Total Number of Study Sites/Total Number of Subjects Projected

This prospective study will enroll patients at a single study site of MMC (Moses Division).  

We plan to enroll 219 patients/subjects (73 patients for each arm)

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3.3
Study Population
3.3.1
Inclusion Criteria
1)
Obese patients undergoing bariatric surgery (LSG or LRYGB)
2)
Patients 18 years of age and older
3)
Surgical treatment between 01/01/2018 and 12/31/2018 over a 1 year period
3.3.2
Exclusion Criteria
1)
Patients under the age of 18 years old
2)
Patients taking any opiates within 30 days of enrollment in the trial
3)
Patients with a history of chronic pain.
4)
Patients taking pregabalin or gabapentin.  
5)
ASA IV
6)
Prior laparotomy
7)
Body Mass Index ≥ 60 kg/m2
8)
History of cardiac arrhythmia
9)
History of Seizure
10) Psychiatric Diagnosis currently on antipsychotic medication
11) Pregnancy
12) Patients who are breastfeeding.
4
STUDY PROCEDURES
Patients will be randomized to either receive an intraoperative TAP block with LB, an 
intraoperative TAP block with RB, or no TAP block.  All patients will receive standard post-
operative analgesia regimen.  This includes fentanyl PCA at 10mcg every 10 minutes for the first 24 
hours.  Acetaminophen with codeine elixir (360mg/36mg) by mouth every 4 hours, ketorolac 30mg 
intravenously every 6  hours and dilaudid 0.4mg intravenously every 3 hours are for breakthrough 
pain are ordered post- postoperatively and continued until discharge.  
The solution used to perform the TAP block with LB will comprise of 20mL of liposomal 
bupivacaine solution, 30mL of 0.25% bupivacaine, and 100mL of normal saline.  The solution used 
to perform the TAP block with RB will comprise of 50mL of 0.25% bupivacaine and 100mL of 
normal saline.  The TAP block is performed under laparoscopic visualization.  An initial 5mm 
optical trocar is placed.  The peritoneum and then TAP are then infiltrated with the local anesthetic 
under direct visualization.  Skin incisions are infiltrated and trocar sites are anesthetized prior to 
placement of ports.  Analog pain scale will be used to determine the pains score of the subjects as 
they emerge from general anesthesia (Time 0 hours).  Pain scores will be recorded every 4-6 hours 

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by the nursing staff as reported by the patients.  Patients will be monitored for secondary post-
operative complications up to the 2-week mark following intervention.
4.1
Data Variables and Sources
4.1.1
Subject Recruitment
All subjects will have undergone the standard rigorous preoperative evaluation by our 
multidisciplinary team.  Risks and benefits will be explained to subjects in our clinic and consent 
will be obtained by our research coordinator during the preoperative visit.  
4.1.2
Data sources
The subject will be the primary source of demographic data and past medical history.  The 
electronic medical record will also be reviewed prior to offering enrollment to ensure that patients 
meet all of the inclusion criteria and do not meet any of the exclusion criteria.  Pain scores and 
quantity of opiates used will be documented by nursing staff.   
4.2
Measures to Avoid Bias
All patients enrolled in the study will be blinded.  The TAP block is performed 
intraoperatively, and there is no outward sign of injection that would allow the patient or person 
examining the patient to tell whether the patient had received the TAP block.  The surgeon will not 
be blinded.  The liposomal bupivacaine has a distinct cloudy appearance that would be difficult to 
replicate otherwise.  In addition, as part of the TAP block, the transversus abdominus plane is 
hydrodissected by the local anesthetic.  Injection/hydrodissection using a placebo (no local 
anesthetic) may increase pain and therefore has been excluded from the control arm of the study.  
Anesthesia will be blinded.  The anesthesiologist will leave the room and be replaced by another 
anesthesiologist for the duration of the block.  Once an appropriate amount of time has lapsed, the 
attending anesthesiologist will return to the room.  This is done so as to avoid bias in administration 
of opiates intraoperatively by anesthesia depending on which arm of the study the patient is on.  In 
addition, the nursing staff will be blinded, which is important as they will be recording the pain 
scores as per nursing protocol.  The research staff collecting data will not be blinded.  Pharmacy 
will document in the orders “Study Drug – TAP Block.”  This will allow researchers to look 
through the record and know the patient was enrolled in the study, but it will not allow them to 
know which arm of the study the patient was in.  
All relevant chart information and collection will be standardized to avoid bias.  Before 
commencing chart reviews, all relevant terminology will be determined and standardized.  The 
specific sources of relevant information will be identified, as will their location within the 
documents.  During the review process, regular meetings between the Principal Investigator and 
chart reviewer will be held to discuss any modifications to the standard that may be needed.  Five 
percent of charts will be selected at random and reviewed by a third party who is trained in the 
standardized terminology and sources of information in order to validate the original review for 
accuracy.
5
STATISTICAL CONSIDERATIONS 
5.1
Primary and Secondary Outcomes
The primary outcome will be quantity of opiates used in terms of morphine equivalents.  
Secondary outcomes will include 24-hour composite pain scores, length of stay, respiratory 

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complications (pneumonia, atelectasis), venous thromboembolic event, myocardial infarction, 
nausea, vomiting, time to adequate oral intake (3 ounces each hour), and time to ambulation.  Pain 
scores will be recorded by nursing staff using the universal pain assessment tool.  
5.2
Sample Size and Power
The hypothesis for this study is that the 48 hour opioid consumption is different in one of the 
three groups. The study is powered to show a minimum clinically significant reduction of 30% in 
opioid usage compared to the control group (placebo group) 20% between the regular bupivacaine 
groups.  According to our clinical audit, the mean (standard deviation) of amount of opioids used by 
patients undergoing these surgeries is 23.3±14 mg morphine equivalents.  Based on a two-sided 
alpha of 0.05 and 20% Type II error, 200 subjects need to be studied to disprove the null 
hypothesis. Additionally, to accommodate for attrition and missing data we plan to increase our 
sample size by 10%, a total of 219 subjects will be randomized. 
5.3
Data analysis plan
         Demographic and clinical characteristics such as (age, gender, type of surgery, medications, 
ASA status, co- morbidities, etc.) between the three study groups will be compared using one-way 
ANOVA or a non-parametric Kruskal Wallis test. Chi-square or Fisher’s exact tests for categorical 
variables to ensure that randomization is appropriately implemented. The primary outcome of the 
study the opioid consumption at 48 hours will be analyzed using one-way ANOVA or a non-
parametric Kruskal Wallis test. Mixed model analysis will be used to examine the effect of 
treatment on change in pain scores between the groups at 24 hours and 48 hours. All categorical 
variables such as, post-operative nausea and vomiting and any other clinically important medical 
conditions will be compared using chi-square or Fisher’s exact tests.  
 
5.4
Randomization 
The research data collector will be responsible for the randomization. Subjects will be randomized 
in a1:1:1 ratio to receive LB as a TAP block infiltration or RB as a TAP block infiltration or no 
TAP block infiltration.   
6
STUDY ADMINISTRATION
6.1
Data Collection and Management
Nursing staff will document pain every 4-6 hours using the patient reported composite 
measure pain score, with a total range of 0 to 10, with 0 being the absence of pain, 1 being the least 
amount of pain and 10 being the highest amount of pain. Data will be obtained from patients and 
the electronic medical records.  Privacy and security will be maintained by minimizing the amount 
of identifiable data as much as possible.  All information will be compiled in Excel spreadsheets 
that are password protected.  
All necessary identifiers will be used only to identify the relevant source documents (as 
described above).  Following this, surrogate numbers will be given to identify the patients for data 
analysis.  All identifiers will be deleted from the file.  This information will remain in a separate 
password protected file that served as the initial list of cohort patients to be searched until after 
completion of the study period and analysis, at which point it will be deleted. 

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6.2
Confidentiality
All data and records generated during the process of this study will remain confidential in 
accordance with all Institutional and HIPAA policies on subject privacy.  All documents will be 
used by the Investigator and other personnel solely for the purposes of this study.  All safeguards to 
maintain subject confidentiality are described above (“6.1 Data Collection and Management”).  No 
information will leave Montefiore in the event that an investigator leaves during the duration of the 
study.  
6.3
Regulatory and Ethical Considerations
6.3.1
Risk Assessment
The risks of the proposed study include any of the risks with bariatric surgery in general.  
The following are risks of the proposed intervention: hematoma at site of injection, anaphylaxis, 
arrhythmia, vascular/visceral/nerve injuries, block failure, seizures.  There is also an anticipated 
risks of breech of privacy and confidentiality.  As explained in Data Collection and Management, 
extreme care will be taken to maintain the patient’s privacy, security, and confidentiality.  
6.3.2
Potential Benefits of Study Participation
The main benefit of this study would be to reduce the amount of narcotics utilized by the 
bariatric population.  As explained previously, this population is at particularly high risk of 
respiratory complications associated with excessive opiate use.
6.3.3
Data Safety Monitoring Plan
The investigators will closely monitor the data safety as described in Einstein’s IRB Data 
Safety Monitoring Policy. We have also established a data safety monitoring committee (DSMC) to 
review the protocol on an ongoing basis for adverse events that will report to the IRB immediately 
should any serious adverse event occur. All serious unanticipated adverse events will be reported to 
the IRB and DSMB in a timely manner. In the event of unanticipated serious adverse event, 
including death, continuation of the study will be at the discretion of DSMB and IRB. The DSMB 
meeting will only be held in the event of serious adverse events. The DSMC will be comprised of 
an anesthesiologist (Dr. Mike Ruffino), a surgeon (Dr. Scott Melvin), an internist (Dr. Regina Lee), 
and a statistician (Dr. Patricia Friedman) who are independent of the study. These individuals are 
completely independent from this project and have no conflict of interest.  
6.4
Informed Consent
This study represents a prospective randomized controlled trial of patients undergoing 
bariatric surgery at MMC.  All patients will be explained the risks and benefits of surgery and will 
have the option to opt out of the study with no effect on delivery of their care.  Demographic 
information will be obtained, such as name, medical record number, age and gender, but beyond 
this no more specific identifying information is necessary and will be left out.  Once possible, all 
identifiers will be removed from our databases. Study results will not include any identifying 
information, and privacy will be protected as previously described.  
7
PUBLICATION
Once the study is complete and conclusions are made, a manuscript will be submitted to a 
relevant journal for publication.  

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REFERENCES
Alvarez, A., Singh, PM., & Sinha, AC. (2014) Postoperative Analgesia in Morbid Obesity. 
Obesity Surgery. (2014) Apr;24(4):652-9. 
Fayezizadeh et al. Efficacy of transversus abdominis plane block with liposomal 
bupivacaine during open abdominal wall reconstruction.  American J of Surg (2016) 212: 
399-405.
Hah, R., Bateman, B., Ratcliff, J., Curtin, C., & Sun, E. Chronic opioid use after surgery: 
Implications for perioperative management in the face of the opioid epidemic. Anesthesia 
& Analgesia. (2017) 125(5):1733-1740.
Hutchins et al. Ultrasound guided subcostal transversus abdominis plane (TAP) infiltration 
with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: A 
prospective randomized controlled study. Gynecol Oncol (2015) 3:609-613.
Keller et al. Pilot study of a novel pain management strategy: evaluating the impact on 
patient outcomes. Surg Endosc (2016) 30: 2192-2198. 
Mc Donnell et al. The Analgesic Efficacy of Transversus Abdominis Plane Block After 
Abdominal Surgery: A Prospective Randomized Controlled Trial.  Anesth Analg (2007) 
104: 193-197.

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APPENDIX
9.1.1
STUDY-MASTER LIST
Study 
number
Patient’s 
name
Patient’s 
medical 
record 
number
Operative 
Procedure
24-Hour 
Composite 
Pain Score
Overall Opioid Use 
in morphine 
equivalents
1
2
3
4
5

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9.1.2
DATA COLLECTION SHEET
Patient study number    ______
Patient gender:     male / female
Race: Caucasian____, African American____, Asian____, Hispanic (white)____ Other_____
Patient’s age ____ 
Patient’s weight /BMI____
Procedure ____
Comorbidities ____
Pathology ____
Outcomes:
Overall narcotic use ____
24-Hour composite pain score ____