Clinical trial NCT02356198
Conditions: Conditions Requiring Colorectal Surgery
Sponsor: Mayo Clinic
Start date: 2015-03-01; Completion date: 2017-10-01
Enrollment: 209 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is prospective, randomized trial in which EXPAREL TAP block is compared to standard IT opioid administration, in relieving postoperative pain, decreasing length of stay, and use of narcotic medication.

Detailed description:
Primary Objective To assess efficacy of EXPAREL TAP blocks in improving pain scores for 48 hours postoperatively, and in reducing total oral morphine equivalents (OME) use, compared to standard Intrathecal opioid administration (IT).

Secondary Objective Assess the length of stay (LOS), postoperative ileus (POI) incidence, and the use of intravenous patient controlled analgesia (PCA) in patients that had EXPAREL TAP blocs compared to IT.

Arms: arm 1: After induction of anesthesia, the patients will receive a single injection with 133 mg of EXPAREL in the transversus abdominis plane (TAP), on each side, suspended in 20 milliliters (mL) of injectable saline. arm 2: single injection intrathecal hydromorphone analgesia given preoperatively
Interventions: intervention 1: EXPAREL intervention 2: Intrathecal hydromorphone
Intervention descriptions: intervention 1: transversus abdominis plane injection intervention 2: Intrathecal opioid administration

Protocol documents:
Prot_SAP_000.pdf: 
 
 
EXPAREL TRANSVERSUS 
ABDOMINIS PLANE BLOCK VS. 
INTRATHECAL ANALGESIA IN 
COLORECTAL SURGERY: A 
PROSPECTIVE RANDOMIZED 
TRIAL 
 
NCT# 02356198  
 
May 2, 2017 


EXPAREL vs. Intrathecal 
May 2, 2017 
EXPAREL TRANSVERSUS ABDOMINIS PLANE BLOCK VS. 
INTRATHECAL ANALGESIA IN COLORECTAL SURGERY: A 
PROSPECTIVE RANDOMIZED TRIAL. 
Regulatory Sponsors: 
David Larson,           
Dorin Colibaseanu 
Div. of Colorectal Surgery               Dept. of General Surgery 
Mayo Clinic, MN            
 Mayo Clinic, FL 
Study Product: 
Injectable liposomal bupivacaine (EXPAREL) 
Protocol Number: (IRBe) 
14-003143


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
Table of Contents 
 
STUDY SUMMARY ........................................................................................................ 5 
1 INTRODUCTION ...................................................................................................... 6 
1.1 BACKGROUND ........................................................................................................ 6 
1.2 INVESTIGATIONAL AGENT ........................................................................................ 6 
1.3 CLINICAL DATA TO DATE ........................................................................................ 6 
1.4 DOSE RATIONALE AND RISK/BENEFITS ...................................................................... 7 
2 STUDY OBJECTIVES ............................................................................................... 7 
3 STUDY DESIGN ........................................................................................................ 7 
3.1 GENERAL DESIGN ................................................................................................... 7 
3.2 PRIMARY STUDY ENDPOINTS .................................................................................... 9 
3.3 SECONDARY STUDY ENDPOINTS ............................................................................... 9 
3.4 PRIMARY SAFETY ENDPOINTS................................................................................... 9 
4 SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL .............................. 9 
4.1 INCLUSION CRITERIA ............................................................................................... 9 
4.2 EXCLUSION CRITERIA .............................................................................................. 9 
4.3 SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ............................................ 10 
4.4 SUBJECTS ............................................................................................................. 10 
4.4.1 When and How to Withdraw Subjects ............................................................... 10 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ..................................... 10 
5 STUDY DRUG ......................................................................................................... 10 
5.1 DESCRIPTION ........................................................................................................ 10 
5.2 TREATMENT REGIMEN ........................................................................................... 10 
5.3 METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ..................................... 10 
5.4 PREPARATION AND ADMINISTRATION OF STUDY DRUG .............................................. 10 
5.5 SUBJECT COMPLIANCE MONITORING ....................................................................... 11 
5.6 PRIOR AND CONCOMITANT THERAPY ....................................................................... 11 
5.7 PACKAGING ......................................................................................................... 11 
5.8 MASKING/BLINDING OF STUDY ............................................................................... 11 
5.9 RECEIVING, STORAGE, DISPENSING AND RETURN ...................................................... 11 
5.9.1 Receipt of Drug Supplies ................................................................................ 11 
5.9.2 Storage ......................................................................................................... 11 
5.9.3 Dispensing of Study Drug ............................................................................... 11 
5.9.4 Return or Destruction of Study Drug ................................................................ 11 
6 STUDY PROCEDURES ........................................................................................... 11 
7 STATISTICAL PLAN .............................................................................................. 12 
7.1 RANDOMIZATION .................................................................................................. 12 
8 SAFETY AND ADVERSE EVENTS ......................................................................... 14 
8.1 DEFINITIONS ........................................................................................................ 14 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
8.2 RECORDING OF ADVERSE EVENTS ........................................................................... 16 
8.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................ 16 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB .................................... 16 
8.4 UNMASKING/UNBLINDING PROCEDURES .................................................................. 16 
8.5 ADVERSE EVENT STOPPING RULE ........................................................................... 16 
8.6 MEDICAL MONITORING ......................................................................................... 17 
8.6.1 Internal Data and Safety Monitoring Board ...................................................... 17 
9 DATA HANDLING AND RECORD KEEPING ........................................................ 17 
9.1 CONFIDENTIALITY ................................................................................................. 17 
9.2 SOURCE DOCUMENTS ............................................................................................ 17 
9.3 RECORDS RETENTION ............................................................................................ 18 
10 STUDY MONITORING, AUDITING, AND INSPECTING ..................................... 19 
10.1 STUDY MONITORING PLAN ................................................................................... 19 
10.2 AUDITING AND INSPECTING .................................................................................. 19 
11 ETHICAL CONSIDERATIONS ............................................................................. 19 
12 STUDY FINANCES ................................................................................................ 20 
12.1 FUNDING SOURCE ............................................................................................... 20 
12.2 CONFLICT OF INTEREST ........................................................................................ 20 
13 PUBLICATION PLAN ........................................................................................... 20 
14 REFERENCES ....................................................................................................... 20 
 
 
 
 
 
 
 
 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
 
List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
 
 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
 
 
 
 
 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
Study Summary 
Title 
EXPAREL transversus abdominis plane block vs. intrathecal analgesia 
in colorectal surgery: a prospective randomized trial. 
Running Title 
EXPAREL injection vs. intrathecal analgesia 
Protocol Number 
14-003143 
Phase 
Phase IV 
Methodology 
Prospective, randomized trial 
Overall Study 
Duration 
12 months 
Subject Participation 
Duration 
2-5 days 
Single or Multi-Site  
Single institution, multicenter 
Objectives 
Compare postoperative pain control between intrathecal analgesia and 
EXPAREL transversus abdominis plane injection.  Length of stay, and 
complications will also be recorded.  
Number of Subjects 
226 total for both sites   
Diagnosis and Main 
Inclusion Criteria 
Consentable, nonpregnant adults undergoing elective colorectal surgery 
and enrolment in enhanced recovery program 
Study Product, Dose, 
Route, Regimen 
Liposomal injectable bupivacaine, injected once in the transversus 
abdominis plane bilaterally, 133mg per side. 
Duration of 
Administration 
Once 
Reference therapy 
Intrathecal hydromorphone 
Statistical 
Methodology 
Patients will be randomized in a 1:1 fashion. There will be two 
stratification factors: MIS vs. open surgery, and site (Jacksonville vs 
Rochester). Randomization will be performed with an online system and 
will use a permuted block design with varying block sizes 
 
 
 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
1 Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
1.1 
Background 
Multimodal analgesia has played a key role in decreasing postoperative pain in patients 
undergoing colorectal operations.  Recently, its role in decreasing oral morphine equivalents 
(OME) has been shown to decrease length of stay (LOS) and decrease the risk of postoperative 
ileus (POI) at Mayo 1.  Multimodal analgesia and limiting systemic opiate use are critical 
components in enhanced recovery pathways.  Numerous studies have assessed the best agent and 
mode of neuraxial blockade.  Its role in decreasing narcotic use and improving POI and LOS has 
been well-studied 2-4. Currently at our institution, single injection intrathecal hydromorphone 
analgesia is routinely used in addition to systemic, non-opiate analgesia (e.g., gabapentin, 
acetaminophen, non-steroidal anti-inflammatory medications).  
Transversus abdominis plane (TAP) block is an alternative to neuraxial analgesia, and it 
has had promising results for analgesia after colorectal surgery 4-6.   A limitation of bupivacaine 
TAP blockade is the relatively short duration of effect, ranging on average from 6-12 hours 7. 
Liposomal bupivacaine (EXPAREL) is a relatively new product currently FDA-approved for 
wound infiltration with an analgesic effect for 72 hours.  EXPAREL has been shown to safe and 
effective. 
1.2 
Investigational Agent 
EXPAREL has been approved by FDA in 2011, and has been used for wound infiltration 
and nerve blocks.  Its analgesic effects can last up to 72 hours. It is encapsulated in vesicular 
liposomes, which dissolve slowly, and release bupivacaine over time, providing a longer 
analgesic effect than ordinary bupivacaine 8,9.  EXPAREL is supplied in one vial, containing 
266mg of bupivacaine suspended in multivesicular liposomes in normal saline. (DepoFoam) 10. 
1.3 
Clinical Data to Date 
FDA approval was based on two double blind, Phase III trials on soft tissue and orthopedic 
surgical models.  Subsequent to that, the medication was used in another Phase III trial with 
patients having bunionectomies11.  It found that EXPAREL use in 97 patients was associated 
with better postoperative pain, and no adverse side effects were found. Subsequently, another 
randomized, double blind, prospective Phase III trial was done, in patients undergoing 
hemorrhoidectomy 12. The EXPAREL group (n=94) had less pain, and used less opioid 
medication. No adverse events were observed.  
The safety profile of EXPAREL has been evaluated and in a meta-analysis, and its side effect 
profile has been found to be similar to bupivacaine.  The most common side effects in the 800 
patients in the EXPAREL group were nausea (3.3%) and constipation (2.0%).  Cardiac 
complications were tachycardia (4%), and bradycardia (2%), which did not require treatment, 
and were similar to bupivacaine group.  One death was reported in the 800 patients that received 
EXPAREL, and one in the bupivacaine group; both drugs were deemed as not the causative 
agents 13 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
EXPAREL has been used in TAP infiltrations and has been used in two small studies totaling 
37 patients.  No side effects were reported, and the patients had low pain scores, with minimal 
narcotic use 14,15.  
At our institution, EXPAREL has been used for over one year with hundreds of patients both 
in the Rochester and Jacksonville campuses without any side effects attributed to EXPAREL 
injection. 
1.4 
Dose Rationale and Risk/Benefits 
After induction of anesthesia, the patients will receive a single injection with 133 mg of 
EXPAREL suspended in 20mL of injectable saline, in each side, in the transversus abdominis 
plane (TAP).  The injection will be ultrasound guided, and performed by our interventional 
anesthesiologists.  The risks are the same as any non-EXPAREL TAP block, which include 
bleeding, infection, and pain. Systemic absorption of EXPAREL is possible, but as above 
(section 1.3), the side effects have not been found to be any different than the use of ordinary 
bupivacaine. 
The risks will be included in the consent form, which include arrhythmias, bleeding 
infection, pain, and are no different than the use of TAP Bupivacaine, which is a standard of 
practice in our institution.  
The alternate treatment group (the control group) will receive 100 mcg hydromorphone in a 
single intrathecal injection, administered by our interventional anesthesiologists immediately 
preoperatively.  This is currently used routinely in the colorectal practice, as well as other 
practices across the enterprise. 
2 Study Objectives 
Primary Objective 
To assess efficacy of EXPAREL TAP blocks in improving pain scores for 48 hours 
postoperatively, and in reducing total oral morphine equivalents (OME) use, compared to 
standard Intrathecal opioid administration (IT). 
 
Secondary Objective 
Assess the length of stay (LOS), postoperative ileus (POI) incidence, and the use of 
intravenous patient controlled analgesia (PCA) in patients that had EXPAREL TAP blocs 
compared to IT. 
 
3 Study Design 
3.1 
General Design 
 
This study is prospective, randomized trial in which EXPAREL TAP block is compared to 
standard IT opioid administration, in relieving postoperative pain, decreasing length of stay, and 
use of narcotic medication. Subjects will be screened at outpatient clinic visit appointments and 
interested qualified subjects will be consented and offered participation in this trial.  All enrolled 
patients will be entered by the surgeon through written informed consent.  All data will be 
entered in a prospective automated institutional database. 
 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
 
 
All patients undergoing 
elective CRS surgery, and 
meeting inclusion criteria.- 
200 patients 
 
Randomize 1:1 EXPAREL 
TAP vs. IT 
EXPAREL TAP 
113 patients 
IT 
113 patients 
OPERATION  
ERP postoperative 
recovery 
30-Day Follow-up 
Capture:  
-
Vitals 
-
Pain scores 
-
Opioid consumption 
-
PCA use 
-
Return to bowel 
function 
-
Complications 
 
Capture:  
-
Vitals 
-
Pain scores 
-
Complications 
 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
 
3.2 
Primary Study Endpoints 
Primary end points include mean pain scores for 48 hours and OME use associated with IT 
and EXPAREL TAP. 
3.3 
Secondary Study Endpoints 
Secondary endpoints include LOS, the incidence of POI, and use of PCA 
 
3.4 
Primary Safety Endpoints 
Patients will be monitored both intraoperatively and postoperatively for any adverse events 
(as defined below and in section 8).  Patients will be connected to a cardiac monitor 
intraoperatively, and until the morning of postoperative day 1 (POD1).  Patient will also be 
connected to a continuous pulse oximeter until the morning of postoperative day 1 (POD 1).  
These are standard practice for the recovery units. The surgical team will assess the patient 
routinely twice daily, more often if necessary.  Vital signs (heart rate, oxygen saturation, and 
blood pressure) will be captured at least four times per day, more frequently if the clinical 
situation dictates.  In addition, patients will all have a complete blood count, and creatinine 
checked on POD1 routinely. None of the patients enrolled in the trial will receive any amide-type 
anesthetics within 72 hours after EXPAREL use. 
 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
• All patients undergoing elective minimally invasive or open small bowel or colorectal 
resections who are eligible for IT, and able to be enrolled in ERP. 
• Age >18 years 
• BMI <40 
• Ability to understand and read English 
 
4.2 
Exclusion Criteria 
• Not able or unwilling to sign consent. 
• Currently pregnant or lactating.  
• Patients with chronic pain, requiring daily opiate use at time of surgery. 
• Patients intolerant or allergic to opiates, NSAIDS, acetaminophen or amide-type local 
anesthetics. 
• Patients requiring emergent surgery. 
• Abdominoperineal resections. 
• Any contraindications to neuraxial analgesia (coagulopathy, localized infection at 
the potential site of injection, pre-existing spinal canal pathology, previous spine 
surgery or peripheral neuropathy) 
• Patients with a diagnosis of inflammatory bowel disease.  


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
• Patients have had or planned to have hepatic resection 
• AST and/or ALT abnormal 
• Renal insufficiency (creatinine clearance less than 30) 
• Any patient currently receiving any anticoagulation medication other than aspirin, and/or 
with an INR > 1.4, as per ASRA guidelines 16. 
4.3 
Subject Recruitment, Enrollment and Screening 
After institutional review board approval, all adult patients undergoing elective laparoscopic 
and open colorectal resections are considered for admittance into the trial.  All enrolled patients 
will be entered by the surgeon through written informed consent. All patients enrolled will need 
to meet the inclusion idea (see section 4.1). 
4.4 
Subjects 
4.4.1 When and How to Withdraw Subjects 
Patients may withdraw from the study at any point before induction of anesthesia for their 
elective operation. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Patients that withdraw from the study will not have received the treatment; therefore, no data 
will need to be collected, other than that they were considered for enrolment.  
5 Study Drug  
5.1 
Description 
The EXPAREL solution will be housed in a transparent vial, which will appear milky-
white because the solution itself is milky white.  
 
5.2 
Treatment Regimen 
After induction of anesthesia, the patients will receive a single injection with 133 mg of 
EXPAREL in the transversus abdominis plane (TAP), on each side, suspended in 20mL of 
injectable saline.  
5.3 
Method for Assigning Subjects to Treatment Groups 
All enrolled patients will be entered by the surgeon through written informed consent. 
Patients will be randomized 1:1 to either receive:  
  
Group A: IT  
Or 
Group B: EXPAREL TAP.   
 
There will be two stratification factors: type of surgery (MIS versus open), and site 
(Jacksonville versus Rochester). 
5.4 
Preparation and Administration of Study Drug 
EXPAREL is suspended in 20 ml of injectable saline from the manufacturer (containing 
266 mg of liposomal bupivacaine). An additional 20 mL of injectable saline will be used to 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
further dilute the drug to a total volume of 40ml.  Under ultrasound guidance, 20 ml (133 mg) of 
the solution will be injected once in the transversus abdominis plane on each side. Thus, each 
side will receive 133 mg of EXPAREL suspended in 20 mL of saline. 
5.5 
Subject Compliance Monitoring 
Patients receiving treatment will be enrolled in a prospective database.  No other treatment 
is necessary, except the single injection before their scheduled procedure. 
5.6 
Prior and Concomitant Therapy 
Patients may receive therapy for any conceivable condition, while enrolled in this trial, as 
long as the meet the inclusion criteria (section 4.1). 
 
5.7 
Packaging 
Exparel solution will be packaged from the manufacturer, and will appear as a vial 
containing 20 ml of milky white suspension.  
5.8 
Masking/Blinding of Study  
The study will not be blinded. 
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
EXPAREL is already being used throughout the enterprise, and its storage, handling, 
transport and disposal will not change. 
5.9.2 Storage 
EXPAREL is already being used throughout the enterprise, and its storage, handling, 
transport and disposal will not change. 
5.9.3 Dispensing of Study Drug 
EXPAREL is already being used throughout the enterprise, and its storage, handling, 
transport and disposal will not change. 
 
5.9.4 Return or Destruction of Study Drug 
 
EXPAREL is already being used throughout the enterprise, and its storage, handling, 
transport and disposal will not change. 
 
 
6 Study Procedures 
EXPAREL is administered only once as described in section 5.4. 
 


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May 2, 2017 
Safety data will be collected on the patient for 30 days, +/- 10 days after administration of study 
treatment. The collection of data will be through the patient’s medical record from their normal 
post-operative care visits to the clinic.   If the patient does not return to the clinic, they patient 
will be contacted by phone to assess the patient for any adverse events.  All adverse events are 
reported to the study PI. 
 
 
 
 
 
 
7 Statistical Plan 
7.1 
Randomization 
 
Patients will be randomized in a 1:1 fashion. There will be two stratification factors: type 
of surgery (MIS vs. open surgery) and site (Jacksonville versus Rochester). Randomization will 
be performed with an online system and will use dynamic allocation.. 
 
7.2 Sample size 
The two primary endpoints of interest are pain scores over 48 hours post-surgery and the 
amount of narcotic medication used, standardized to OME, over 48 hours post-surgery. The pain 
score endpoint will be summarized as area under the curve (AUC), normalized for the total time 
of observation. A sample size of 100 patients per arm provides 80% power to detect an effect 
size of 0.40 using a two group t-test with a 0.05 two-sided significance level. The effect size is 
the expected difference in the mean AUCs divided by the within group standard deviation. A 
difference of 0.5 standard deviations in pain scores has been demonstrated to be clinically 
meaningful in the QOL literature. This study is adequately powered to detect this; a sample size 
of 100 patients in each group has 94% power to detect a difference in the mean AUC pain scores 
between the two groups of 0.50 standard deviations. The narcotic medication use (standardized 
OME) will be the cumulative use over the 48 hour period. It is also felt that a difference of 0.4 
standard deviations in the mean narcotic use (standardized to OME) between the groups is 
clinically meaningful. 
 
7.3 Analysis plans 
 
Patient Population(s) for Analysis 
The patient for the primary analysis will be all randomized patients who did not withdraw 
prior to the initiation of anesthesia. The numbers of patients that withdraw prior to undergoing 
surgery will be monitored for imbalances between the arms. 
 
Primary analysis plan 
The primary analysis will be a modified intent-to-treat analysis. This means it will be an 
analysis of all randomized patients who did not withdraw prior to surgery according to the arm to 
which they were randomized.  


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
 
The mean pain scores over 48 hours will be summarized as the area under the curve (AUC) of 
the observed pain score (y-axis) plotted by the time it was measured (x-axis). The difference in 
mean AUCs of the two groups will be evaluated using a two-sample t-test. In addition, the 
cumulative narcotic use over the 48 hour period will be determined for each patient (standardized 
OME). The difference in mean standardized OME will be compared with a two-sample test. If 
the data are skewed, a two-sample t-test will be performed on the logged values of OME or a 
Wilcoxon rank sum test will be used on the untransformed data.A two-sided p-value will be 
declared statistically significant for each primary endpoint. This will mean that the overall two-
sided level of significance for the trial will be 0.10. 
 
In addition to looking at the summary of the pain scores and OME scores, we will also plot these 
values over time and determine whether there are differences at individual time points. 
 
Secondary analysis plan 
The mean length of stay will be compared between the two groups with a two-sample 
test. If there are no outliers, a two-sample t-test will be used. If there are outliers, a Wilcoxon 
rank sum test will be used. A chi-square test (or Fisher’s exact test) will be used to compare the 
rates of POI, need for a PCI and post-operative hypotension. 
 
Comparisons will be made between the randomized groups of the baseline variables 
(patient, disease, and surgical) to determine if there were any randomization imbalances. If 
imbalances are found, a secondary analysis will be done using linear regression and adding the 
variables that were not balanced between the groups. 
 
Descriptive Statistics 
Univariable descriptive statistics will be calculated for all variables; categorical variables 
will be summarized as counts (relative frequencies) and continuous variables will be summarized 
as mean± standard (SD) and median (min value, max value) .     
 
Handling of Missing Data 
Missing data will prompt individual review of the patient’s electronic record to obtain 
missing variables.  Analyses will be done using all patients who have the necessary data for the 
analysis. If the amount of missing data within an analysis is greater than 10%, imputation 
methods will be used and the data re-analyzed as a sensitivity analysis. 
 
 
7.5 Data Collection 
Data will be captured in an electronic fashion via institutional database that is already in 
use for the Rochester site. A REDCap database will be used to capture the information at the 
Jacksonville site and to capture adverse event (complication) data from both sites. The same 
definition of variables will be used at both sites. 
  
 
 
 


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May 2, 2017 
8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization, readmission, or 
prolonged hospital stay; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling change) 
that in the opinion of the local investigator may adversely affect the rights, safety, or 
welfare of the subjects or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
 
Adverse Event 
An untoward or undesirable experience associated with the use of the medications used in 
this trial, as bellow: 
• Any arrhythmia/ tachycardia/bradycardia necessitating intervention (medicine or 
cardioversion)  
• Vertigo, tinnitus, seizure 
• Any myocardial infarction 
• Any site infection / hemorrhage / persistent injection site pain, neuropathy or nerve injury 
• Postoperative headaches  
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• Death 
• Life threatening adverse experience 
• Hospitalization 
• Inpatient, new, or prolonged; disability/incapacity 
• Persistent or significant birth defect/anomaly 
 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
and/or as per protocol there may be problems/events that in the opinion of the sponsor-
investigator may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromised the research data. 
 
Other important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance.  They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization or intensive treatment 
of bronchospasm in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period is defined as 30 days following the 
last administration of study treatment.  
 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the character of 
the condition worsens during the study period. 
 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  
At the last scheduled visit, the sponsor-investigator should instruct each subject to report, to the 
sponsor-investigator, any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.  
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 


EXPAREL vs. Intrathecal 
 
 
 
 
May 2, 2017 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances:  
 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event worksheet.  All clearly related signs, symptoms, and abnormal diagnostic, laboratory or 
procedure results should recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course 
of each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs after the study period and is considered to 
be at least possibly related to the study treatment or study participation should be recorded and 
reported immediately. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified (as previously identified), the study team will 
take appropriated action necessary to protect the study participant and then complete the Study 
Adverse Event Worksheet and log.  The sponsor-investigator will evaluate the event and 
determine the necessary follow-up and reporting required. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-
UPIRTSOs according to the Mayo IRB Policy and Procedures. 
 
 
8.4 
Unmasking/Unblinding Procedures 
This study is not blinded. 
 
8.5 
Adverse Event Stopping Rule  
Adverse events will be continuously monitored by the study team for patient safety.  
Each month, a report of the adverse events and SAEs will be generated. This report will 


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include the enumeration and tallies of the adverse events (and SAEs) by arm. A chi-
square test (or Fisher’s exact test, whichever is appropriate) will be used to compare the 
AE and SAE rates between the arms.  If there is a statistically significant difference in 
SAE rates between the two arms, accrual to the trial will be temporarily suspended 
while the study team does a thorough evaluation of the SAEs observed. Upon a 
thorough review of the observed SAEs, the study team and DSMB will made a 
determination whether to reopen the trial with no amendments, to amend the trial and 
reopen, or to permanently close the trial. 
 
The monthly SAE rate report will be sent to the DSMB Chair. This will determine 
whether or not a non-scheduled DSMB meeting needs to be convened prior to the 6 
month DSMB review. 
 
 
8.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data and 
safety-monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
8.6.1 Internal Data and Safety Monitoring Board 
The sponsor-investigator and participating surgeons, as well as the study coordinator will 
meet once monthly to review any adverse events. 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 


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May 2, 2017 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
 
Data Management 
Data will be captured in an electronic fashion via institutional database that is already 
developed 
 
Data Processing 
 
Each campus will record the same data separately; all data will be combined quarterly 
and interim analysis will be performed. 
 
Data Security and Confidentiality 
Access to the data will be provided to only necessary persons, those that collect the data, 
or need to analyze the data.  Data will be stored in a password-protected folder behind the Mayo 
firewall. All data collection and analysis will be done behind the firewall. 
 
Data Quality Assurance 
All data will be entered by appropriately trained personnel, and 1 in 50 records will be 
“biopsied” for correct data collection.  
 
Data Clarification Process 
Incomplete, or erroneous data will be corrected by analyzing the original patient electronic 
record. 
9.3 
Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717   
Whichever is longer 
 


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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance reviewer 
is given access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
As a service to the sponsor-investigator, this study may be monitored during the conduct of 
the trial by staff from the Mayo Clinic Office of Research Regulatory Support.  Clinical trial 
monitoring may include review of the study documents and data generated throughout the 
duration of the study to help ensure the validity and integrity of the data along with the 
protection of human research subjects.  This will assist sponsor-investigators in complying with 
Food and Drug Administration regulations. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study.  The decision of the IRB concerning the conduct of the study will be made 
in writing to the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review and 
approval by the IRB for the study.  The formal consent of a subject, using the Approved IRB 
consent form, must be obtained before that subject undergoes any study procedure.  The consent 
form must be signed by the subject or the subject’s legally authorized representative, and the 
individual obtaining the informed consent. 
 


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12 Study Finances 
12.1 Funding Source 
This study has been approved to have study coordinator, and statistics support from the 
Department of Surgery for the Jacksonville campus.  The Rochester campus will receive 
coordinator and statistics support from the Department of Surgery Rochester campus. 
 
The medication (EXPAREL) is not a new medicine and is already being used in the 
colorectal surgery practice, and thus, will be billed to the patient as part of the operation. 
12.2 Conflict of Interest 
None. 
13 Publication Plan 
Subsequent to trial closure, data will be analyzed, and a manuscript will be submitted to the 
appropriate journal, after consensus among all the investigators. 
 
 
14 References 
 
 
 
1. 
Larson DW, Lovely JK, Cima RR, et al: Outcomes after implementation of a multimodal 
standard care pathway for laparoscopic colorectal surgery. Br J Surg 101:1023-30, 2014 
 
2. 
Meylan N, Elia N, Lysakowski C, et al: Benefit and risk of intrathecal morphine without 
local anaesthetic in patients undergoing major surgery: meta-analysis of randomized trials. Br J Anaesth 
102:156-67, 2009 
 
3. 
Hubner M, Lovely JK, Huebner M, et al: Intrathecal analgesia and restrictive perioperative 
fluid management within enhanced recovery pathway: hemodynamic implications. J Am Coll Surg 
216:1124-34, 2013 
 
4. 
Favuzza J, Brady K, Delaney CP: Transversus abdominis plane blocks and enhanced 
recovery pathways: making the 23-h hospital stay a realistic goal after laparoscopic colorectal surgery. 
Surg Endosc 27:2481-6, 2013 
 
5. 
Favuzza J, Delaney CP: Outcomes of discharge after elective laparoscopic colorectal 
surgery with transversus abdominis plane blocks and enhanced recovery pathway. J Am Coll Surg 
217:503-6, 2013 
 
6. 
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 6:605-10, 2013 
 
7. 
Taylor R, Jr., Pergolizzi JV, Sinclair A, et al: Transversus abdominis block: clinical uses, 
side effects, and future perspectives. Pain Pract 13:332-44, 2013 
 
8. 
EXPAREL (bupivacaine liposome injectable suspension) [product monograph]. 
Parsippany, NJ: Pacira Pharmaceuticals, inc; 2012.  
 
9. 
Hu D, Onel E, Singla N, et al: Pharmacokinetic profile of liposome bupivacaine injection 
following a single administration at the surgical site. Clin Drug Investig 33:109-15, 2013 
 
10. 
EXPAREL (bupivacaine liposome injectable suspension) [prescribing information]. San 
Diego, CA: Pacira Pharmaceuticals, Inc; 2012.  
 
11. 
Golf M, Daniels SE, Onel E: A phase 3, randomized, placebo-controlled trial of 
DepoFoam(R) bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther 
28:776-88, 2011 


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12. 
Gorfine SR, Onel E, Patou G, et al: Bupivacaine extended-release liposome injection for 
prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, 
double-blind, placebo-controlled trial. Dis Colon Rectum 54:1552-9, 2011 
 
13. 
Viscusi ER, Sinatra R, Onel E, et al: The safety of liposome bupivacaine, a novel local 
analgesic formulation. Clin J Pain 30:102-10, 2014 
 
14. 
Reierman DE KM, Gupta PM: Evaluation of Exparel use via infiltration into the 
transversus abdominis plane for prolonged postoperative analgesia in subjects undergoing open 
abdominal hernia repair. Poster Presented at: International Anasthesia Research Society, Annual 
Meeting; May 4-7, 2013; San Diego, CA, 2013 
 
15. 
Sternlicht A SM, Robelen G, et al. Initial findins using EXPAREL via infiltration into the 
transversus abdominis plane for postsurgical analgesia in robotic prostatectomy.  : Poster presented at: 
Pain Medicine Annual Meeting: November 15-18; Miami, FL  
 
16. 
Horlocker TT, Wedel DJ, Rowlingson JC, et al: Executive summary: regional anesthesia 
in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia 
and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 35:102-5, 2010