Clinical trial NCT02111746
Conditions: Postoperative Pain
Keywords: Postoperative pain sternotomy laparotomy thoracotomy mini-thoracotomy truncal surgical incisions local anaesthetics bupivacaine
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2013-11-20; Completion date: 2017-06-30
Enrollment: 350 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy of the intraoperative injection of prolonged acting (liposomal) bupivacaine in postoperative pain control after truncal surgical incisions.

Detailed description:
Study Design:

This is a prospective, single-institution, parallel-group, single-blinded, randomized-controlled, two-arm, effectiveness study comparing bupivacaine liposomal injectable suspension (Exparel®) versus regular bupivacaine hydrochloride (HCl).

Procedure:

In patients aged 18 and over who require sternotomy, thoracotomy, mini-thoracotomy, or laparotomy incisions will be screened and consented for potential enrollment. Patients will be randomized following consenting to either Exparel® or regular bupivacaine hydrochloride group.

Course of Study:

The study will accrue patients over the course of 4 years.

Enrollment:

Enrollment will consist of all adult patients aged 18 and over undergoing surgical procedures requiring sternotomy, thoracotomy, mini-thoracotomy, or laparotomy incisions. Patients will be screened and consented preoperatively. If the patient is deemed eligible and consents to participate, randomization will occur and the patient will be considered enrolled.

Recruitment:

The target for enrollment will be 280 patients (the study target sample size per power analysis, but actual enrollment will be greater (330 patients) to account for exclusions for various reasons in order to achieve the target recruitment).

Risks:

There is a small increased risk to the patients by participating in the study in addition to a possible chance of breach in patient confidentiality as the study involves evaluation of an FDA-approved drug. As detailed in the informed consent, the subjects are at risk of developing adverse effects from Exparel®, described on the drug packet insert and from HCl Bupivacaine, also described on the drug packet insert. The investigators do not expect any additional physical risks other than an unintentional disclosure of sensitive patient health information.

Data Safety Monitoring:

As the Principal Investigator of this study, Dr. Charlton-Ouw from the Department of Cardiothoracic and Vascular Surgery at The University of Texas at Houston Medical School will conduct the data safety monitoring of this study. He will annually meet with all other co-investigators to review the patients enrolled in this study. As part of the data safety monitoring plan, all patients enrolled until that point in time would be unblinded in order to review the outcomes. Additionally, in view of the uncertainty attached to the treatment effects in this heterogeneous population, owing to limited currently available data, an independent Data Safety Monitoring Committee, will oversee the progress of the trial.

IND#:

The drugs that will be used are already approved by the FDA and do not have IND/IDE#

Proposed Funding Source:

The study is internally funded and is investigator-initiated.

Communication of Study Results:

The communication of study results will occur only between authorized individuals who are listed to take part in the study through our department. The individuals who will take part in the study will acknowledge and adhere to the importance of patient safety and the protection of their private information. The results of this study will be analyzed and published after the approval of the principal investigator, co-investigators, and biostatistician in a peer-reviewed scientific journal and/or presented at an international/national scientific conference or meeting regardless of outcome.

Arms: arm 1: Patients in this group will receive will receive the study drug \[bupivacaine liposomal injectable suspension (Exparel®)\] and Patient Controlled Analgesia (PCA). Exparel® is an FDA-approved bupivacaine liposome injectable suspension produced by Pacira Pharmaceuticals. arm 2: Patients in this group will receive will receive the standard regular bupivacaine hydrochloride (HCl) and PCA. Bupivacaine HCl is an FDA-approved injectable suspension. The standard non-liposomal bupivacaine will be from Hospira pharmaceuticals
Interventions: intervention 1: Exparel intervention 2: Bupivacaine hydrochloride intervention 3: Patient Controlled Analgesia (PCA)
Intervention descriptions: intervention 1: Participants will receive 266mg of liposomal bupivicaine (equivalent of one 1.3% 20ml vial of EXPAREL®) diluted in 60ml of preservative-free normal (0.9%) sterile saline for a total volume of 80mL. Drug will be administered at the end of the procedure just prior to wound closure. intervention 2: Participants will receive 125mg of bupivacaine hydrochloride (equivalent of one 0.25% 50ml or five 0.25% 10ml vials ) diluted in 30ml of preservative-free normal (0.9%) sterile saline for a total volume of 80mL. Drug will be administered at the end of the procedure just prior to wound closure. intervention 3: Patients will have access to the standard Patient Controlled Analgesia (PCA) offered at the Memorial Hermann Hospital - Texas Medical Center. The PCA drug will be Dilaudid (hydromorphone). Initial dosing will be per the standard hospital protocol of 0.2 mg demand dose, 10 minute lockout, 2 mg per hour max, 0.4 mg rescue dose. Adjustments to the PCA dosing will be made based on clinical needs. Patients will receive PCA until the third postoperative day

Protocol documents:
Prot_SAP_002.pdf: 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
 
 
 
 
 
 
 
A prospective randomized-controlled study on effectiveness of extended-release liposomal 
bupivacaine in postoperative pain control 
 
NCT02111746 
 
Version Date: 09/12/2016 
 


IRB APPROVAL DATE: 09/12/2016 
 
PAIN – Postoperative Analgesia INvestigation 
 
 
 
Study Protocol 
 
 
 
Table of Contents 
I. 
LIST OF ABBREVIATIONS .............................................................................................................. 3 
 
II. 
PRINCIPAL INVESTIGATOR & RESEARCH TEAM ........................................................... 3 
 
III. 
STUDY SITE............................................................................................................................................ 4 
 
IV. 
CONTACT INFORMATION .............................................................................................................. 4 
 
V. 
RESEARCH SYNOPSIS.................................................................................................................... 5 
 
A. 
Study Title .................................................................................................................................................................. 5 
 
B. 
Clinical Phase........................................................................................................................................................... 5 
 
C. 
Study Population..................................................................................................................................................... 5 
 
D. 
Study Design ............................................................................................................................................................ 5 
 
E. 
Sample Size .............................................................................................................................................................. 5 
 
F. 
Study Duration ......................................................................................................................................................... 5 
 
G. 
Study drug and Intervention Description .................................................................................................... 6 
 
H. 
Primary Objective ................................................................................................................................................... 6 
 
I. 
Secondary Objectives .......................................................................................................................................... 6 
 
VI. 
BACKGROUND AND SIGNIFICANCE ....................................................................................... 6 
 
VII. 
PRIMARY OBJECTIVES ................................................................................................................... 9 
 
H. 
SECONDARY OBJECTIVES........................................................................................................ 11 
 
IX. 
STUDY POPULATION..................................................................................................................... 11 
 
X. 
STUDY DRUGS .................................................................................................................................. 13 
 
XI. 
STUDY SCHEDULE ......................................................................................................................... 13 
 
XII. 
STUDY DESIGN/METHODOLOGY .......................................................................................... 14 
 
Study Conduct .................................................................................................................................................................. 17 
 
1. 
Screening ................................................................................................................................................................. 17 
 
2. 
Quality of life assessment - Brief Pain Inventory.................................................................................. 17 
 
3. 
Enrollment ................................................................................................................................................................ 18 
 
4. 
Randomization and Allocation Concealment.......................................................................................... 18 
 
5. 
Preoperative assessment................................................................................................................................. 19 
 
6. 
Follow-up .................................................................................................................................................................. 19 
 
 
1 | P a g e 
IRB NUMBER: HSC-MS-13-0620 


PAIN Protocol 
IRB NUMBER: HSC-M2S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
7. 
Termination of enrollment ................................................................................................................................ 20 
 
8. 
Termination of Study........................................................................................................................................... 20 
 
XIII. 
ADVERSE EVENT REPORTING ............................................................................................... 20 
 
XIV. 
STATISTICAL ANALYSIS PLAN ................................................................................................ 22 
 
A. 
Primary Outcomes ............................................................................................................................................... 22 
 
A. 
Secondary Outcomes......................................................................................................................................... 23 
 
B. 
Sample Size Determination............................................................................................................................. 23 
 
XV. 
ETHICS ................................................................................................................................................... 25 
 
B. 
Privacy and Confidentiality .............................................................................................................................. 26 
 
C. 
Risk/Benefit ............................................................................................................................................................. 26 
 
XVI. 
STUDY TIMELINE ............................................................................................................................. 27 
 
XVII. DATA SAFETY MONITORING .................................................................................................... 28 
 
XVIII.  CONFLICT OF INTEREST ............................................................................................................ 28 
 
XIX. 
FUTURE PUBLICATION AND PRESENTATION............................................................... 29 
 
XX. 
References ............................................................................................................................................ 29 


PAIN Protocol 
IRB NUMBER: HSC-M3S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
I. 
LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Effects 
 
BPI 
Brief Pain Inventory 
 
CNS 
Central Nervous System 
 
FDA 
Food and Drug Administration 
 
LOS 
Length of Stay 
 
NPS 
Numeric Pain Scale 
 
NSAID Nonsteroidal Anti-Inflammatory Drugs 
 
MG 
Milligrams 
 
PCA 
Patient Controlled Analgesia 
 
PI 
Principal Investigator 
 
 
 
 
 
II. 
PRINCIPAL INVESTIGATOR & RESEARCH TEAM 
 
 
Principal investigator: Kristofer Charlton-Ouw, MD (Vascular Surgeon) 
 
 
Co-Investigators: 
Hazim Safi, MD (Cardiothoracic Surgeon) 
 
 
Anthony Estrera, MD (Cardiothoracic Surgeon) 
Tom C Nguyen, MD (Cardiothoracic Surgeon) 
Philip A. Rascoe, MD (Cardiothoracic Surgeon) 
Ali Azizzadeh, MD (Vascular Surgeon) 
Kamal Khalil, MD (Cardiothoracic Surgeon) 
Charles C. Miller, PhD (Biostatistician) 
Research Team: 
Alexa Perlick, BS (Research Assistant) 


PAIN Protocol 
IRB NUMBER: HSC-M4S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
Harleen Sandhu, MD MPH (Research Coordinator) 
Samuel Leake, BS (Research Coordinator) 
Harith Mushtaq, MD (Research Coordinator) 
 
 
Jennifer Goodrick, RN (Research Nurse) 
 
 
III. 
STUDY SITE 
 
1.  Department of Cardiothoracic and Vascular Surgery 
 
University of Texas Medical School at Houston 
 
2.  Memorial Hermann Hospital – Texas Medical Center 
 
Houston, Texas 
 
 
 
 
IV. 
CONTACT INFORMATION 
 
 
1.  Kristofer Charlton-Ouw, MD 
 
Principal Investigator 
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2.  Harleen Sandhu 
 
Research Coordinator 
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3.  Alexa Perlick 
 
Research Assistant 
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4.  Samuel Leake 
 
Research Coordinator 


PAIN Protocol 
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V. 
RESEARCH SYNOPSIS 
 
 
 
A. Study Title 
 
Study Full Title 
 
A prospective randomized-controlled study on effectiveness of extended-release 
liposomal bupivacaine in postoperative pain control. 
Study Short Title 
 
PAIN – Postoperative Analgesia INvestigation 
 
B. Clinical Phase 
 
Phase IV 
 
C. Study Population 
 
The study will include patients aged 18 and over who require sternotomy, 
thoracotomy, mini- thoracotomy (including Video Assisted Thoracoscopic Surgery 
(VATS) procedures), or laparotomy incisions. 
D. Study Design 
 
Prospective single-blinded, controlled randomized clinical trial with 2-armed parallel- 
group sequential design 
E. Sample Size 
 
330 
 
F.  Study Duration 
 
4 years 


PAIN Protocol 
IRB NUMBER: HSC-M6S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
G. Study drug and Intervention Description 
 
Subjects will be randomized into two groups: group A will receive the study drug 
[bupivacaine liposomal injectable suspension (Exparel®)] and Patient Controlled 
Analgesia (PCA), and group B will receive regular bupivacaine hydrochloride (HCl) 
and PCA. 
H. Primary Objective 
 
To assess the efficacy of the intraoperative liposomal bupivacaine injection in 
postoperative pain control after truncal incisions.. 
I. Secondary Objectives 
 
  To compare opioid use between groups. 
 
  To evaluate and compare patient participation in physical therapy. 
 
  To evaluate and compare patient length of stay in hospital. 
 
  To evaluate cost-effectiveness of adding extended-release local anesthetic to a 
postoperative pain control regimen. 
J.  Clinical trials registration: 
 
This trial has been registered at and the ClinicalTrials.gov Identifier is NCT02111746 
 
 
 
 
 
VI. 
BACKGROUND AND SIGNIFICANCE 
 
 
 
In the United States, around 48 million inpatient surgical procedures were 
performed in 20091. Although pain is a predictable part of the postoperative experience 
(significant in up to 75% of patients 2, 3), inadequate management is still common. 
Adequate postoperative pain management has shown to improve healing period, 
contribute to faster patient mobilization, and reduce the hospital length of stay and 


PAIN Protocol 
IRB NUMBER: HSC-M7S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
healthcare cost.4-6 Some studies show that the economic load of chronic pain that 
develops from an acute episode of pain in a 30 year-old patient may be as much as $1 
million over a lifetime.7 Lack of postoperative pain control may also result in deep vein 
thrombosis, pulmonary embolism, coronary ischemia, myocardial infarction, pneumonia, 
poor wound healing, insomnia and demoralization.8,9  A number of drugs are available 
for postoperative pain control, such as opioids, nonsteroidal anti-inflammatory drugs 
(NSAIDS), local anesthetic agents infiltration (e.g., bupivacaine HCl), as well as 
combined regimens and protocols among them. Opioid use is the backbone of 
postoperative pain control but it does not come without risks. Severe opioid side-effects 
such as respiratory and central nervous system depression must be accounted for when 
assessing and managing pain. NSAIDs can affect integrity of gastric mucosa and 
overdose can cause renal impairment.  Acetaminophen (Tylenol®) is generally safe but 
high doses can cause hepatic toxicity. One of the limitations of many pain control 
regimens, including most local anesthetic infiltrations, is that the effect usually lasts for 
less than 8 hours only.10, 11 
Several drug delivery approaches and systems have been tested and are 
currently being used to prolong the duration and constancy of analgesic drug 
administration. The Patient Controlled Analgesia (PCA) method is one that is very 
commonly used in postoperative pain management protocols. This method was 
developed and introduced by Philip H. Sechzer in the late 1960s and described in 1971. 
It consists of allowing people to administer their own pain relief whenever they feel it is 
needed. On the surgical patient and while in hospital, the usual administration route is 
IV (intravenous), and the drugs usually used on a PCA system are from the opioid 


PAIN Protocol 
IRB NUMBER: HSC-M8S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
family. The infusion is programmed by the prescriber in terms of demand dose, lockout 
interval, maximum drug delivery per hour, and rescue dose. For example, a morphine 
PCA could be set to deliver 1 mg of morphine sulfate on demand after a lockout interval 
of 10 minutes, a maximum cumulative dose of 8 mg per hour, and a rescue dose of an 
extra 2 mg to be given if there is inadequate pain control.  If it is set and functioning as 
intended, the machine is unlikely to deliver an overdose of medication. 
It is known that local anesthetics such as bupivacaine can achieve a good pain control, 
but is effective for only up to 8 hours. Recently, an injectable liposomal formulation of 
bupivacaine for extended-release (Exparel®) has been approved by the FDA. Exparel® 
has demonstrated to be effective in delivering bupivacaine for up to 72 hours.12,13  Its 
liposome-based vehicle – DepoFoam®, ensures a slow yet continuous drug-release for 
a longer duration during the postoperative period as opposed to the shorter acting 
alternative of bupivacaine hydrochloride injection.12,13 
Exparel® has shown a 30% pain reduction when compared to placebo.12 The 
evidence comes from a few randomized controlled trials involving various types of 
surgeries, including hemorrhoidectomy, bunionectomy, mastectomy, orthopedic 
surgery, etc. At present, there is no study that analyzes its efficacy in truncal 
postoperative pain involving vascular, cardiac, laparotomy and/or thoracic surgical 
wounds. Such truncal wounds encompass sternotomy, thoracotomy, mini- thoracotomy 
(minimally invasive thoracic procedures, including, VATS), and laparotomy incisions. 
These fall under the regular practice of our group of surgeons. Postoperative pain 
management of these incisions can pose a difficult challenge. We propose a 
prospective, controlled and blinded randomized study to evaluate the effectiveness of 


PAIN Protocol 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
Exparel® for postoperative pain control. A prospective randomized study would allow an 
estimate on its efficacy and utilization as an option for the postoperative pain 
management for such operations. 
 
 
 
VII. PRIMARY OBJECTIVES 
 
The primary objective of the study is to compare the efficacy of standard local 
anesthetic  bupivacaine and liposomal bupivicaine in postoperative pain control both in 
magnitude and duration in patients undergoing sternotomy, thoracotomy, mini- 
thoracotomy, and laparotomy incisions. 
Specific assessment tools that will be used in our study: 
 
1)  Numeric Pain Scale (NPS): The NPS measures the intensity of pain. It consists 
 
of an 11-point scale from 0-10, where 0 means no pain and 10 means the most 
intense pain imaginable. Patients verbally select a value that correlates to the 
pain experienced by them. A written form can also be used. The NPS has good 
sensitivity and has a good capacity of producing data that can be statistically 
analyzed.17,18,19,20 
2)  Brief Pain Inventory (BPI): The Brief Pain Inventory is a medical 
 
questionnaire used to measure pain, developed by the Pain Research Group of 
the WHO Collaborating Centre for Symptom Evaluation in Cancer Care. Although 
the BPI is derived from the NPS it is more comprehensive and expanded. 
Besides assessing intensity of the pain, it provides a measure of effect of pain on 
the patient’s life. The BPI is a powerful tool and has been tested for reliability and 
validity across cultures and languages. It is being adopted in many countries for 
 
 
 
 
IRB NUMBER: HSC-M9S-13-0620 


PAIN Protocol 
IRB NUMBER: HSC-1M0S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
clinical pain assessment, epidemiological studies, and in studies evaluating the 
effectiveness of various pain treatments.21,22 
3)  Five-point satisfaction scale: This scale is used to assess the patient’s pain 
 
management experience during their postoperative care. It consists of patients 
rating their overall postoperative pain management experience using a 5-point 
rating system. The scale ranges from 1 to 5, with 1 being “extremely dissatisfied”, 
2 “somewhat dissatisfied”, 3 “Neutral/Neither satisfied nor dissatisfied”, 4 
“somewhat satisfied” and 5 “extremely satisfied” with their postoperative pain 
care. This rating has been used in other clinical trials where EXPAREL® 
analgesia was evaluated and it has proven to be a reproducible assessment 
tool.12 
Primary outcome measures 
 
Numeric Pain Scale (NPS) measurements will be assessed through 72 hours 
after the intraoperative injection. Each subject, using the numeric scale from 0 to 10 (11 
numbers, 0 being no pain, and 10 the highest pain) will self-assess pain level daily at 9 
a.m. (± 3 hours) beginning on post-operative day (POD) 1 through POD 3. The collected 
NPS measurements will be statistically transformed into rank scores which  will be used 
to analyze data between groups. 
Brief Pain Inventory (BPI) – Each subject will be asked to complete the BPI 
before the procedure and at 9 a.m. (± 3 hours) thereafter beginning on POD 1 through 
POD 3.. 
The 5-point satisfaction – Each subject, using a 5 number (1 to 5) scale will be 
assessed on post-surgical analgesia satisfaction (from 1 being “very dissatisfied” to 5 


PAIN Protocol 
IRB NUMBER: HSC-1M1S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
being “very satisfied”) at the same time as NPS and BPI are recorded (daily at 9 a.m. (± 
 
3 hours) beginning on POD 1 through POD 3.) 
 
 
 
 
H. SECONDARY OBJECTIVES 
 
 To compare opioid use between groups. 
 
 To evaluate and compare patient participation in physical therapy 
 
 To evaluate and compare patient length of stay in hospital. 
 
 To evaluate cost-effectiveness of adding extended-release local anesthesic to 
postoperative pain control regimen. 
 
Secondary outcome measures 
 
 
 
 The total amount in milligrams of opioid medication consumed through 12, 24, 
 
36, 48, 60 and 72 hours after surgery. 
 
 Patient participation during physical therapy rehabilitation duration to reach an 
optimal functional level 
 Length of hospital stay 
 
 Hospital cost for patient care during hospitalization will be estimated from 
hospital charges and financial records. 
 
 
 
IX. 
STUDY POPULATION 
 
 
 
The target population of our study will be comprised of patients that are 18 years-old 
and above that present to our group at The University of Texas Medical School at 


PAIN Protocol 
IRB NUMBER: HSC-1M2S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
Houston and will require at least one of the following: median sternotomy thoracotomy, 
mini-thoracotomy (minimally invasive thoracic procedures, including, VATS), or midline 
laparotomy. Our plan is to enroll 330 patients over a period of 4 years. 
 
Inclusion/Exclusion Criteria 
 
 
Patients will be eligible for the study if: 
 
 
 
 18 years-old or older, and 
 
 Sternotomy, thoracotomy, mini-thoracotomy, or laparotomy incision is planned 
 
 There is reasonable expectation that the patient will be extubated within 24 hours 
after surgery 
 
Patients will be excluded from the study if: 
 
 
 
 The patient has a known allergy to morphine or any opioid 
 
 The patient has a known chronic pain disorder or takes daily opioid medication > 1 
month prior to surgery 
 There is anticipated difficulty communicating pain status due to language or other 
barriers at the investigator discretion. 
 High postoperative morbidity index based on preoperative assessment, such as, low 
likelihood of extubation within 24 hours, extensive thoracoabdominal aortic 
aneurysm (Extent 2 TAAA), preoperative renal insufficiency/failure, etc. 
 
 
 
Protocol Deviation: 
 
 
 
 If during the first 72 hours after surgery, patients receive non opioid analgesics. 


PAIN Protocol 
IRB NUMBER: HSC-1M3S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
 If the patient was not given the scheduled drug intraoperatively due to unforeseen 
intraoperative situations, such as, prolonged operative time, delayed formal wound 
closure, etc. 
 
Withdrawal criteria: 
 
 
 
 Voluntary: patients who had consented and enrolled in the trial will maintain their 
right to withdraw at any point during the study as explained in the informed consent. 
 
 In case of unexpected/unpredicted events, the Principal Investigator and research 
staff will analyze if patient meets criteria for withdrawal. 
 
X. 
STUDY DRUGS 
 
 
 
Exparel® is an FDA-approved bupivacaine liposome injectable suspension 
produced by Pacira Pharmaceuticals. Bupivacaine HCl is an FDA-approved injectable 
suspension. The standard non-liposomal bupivacaine is from Hospira pharmaceuticals. 
 
XI. 
STUDY SCHEDULE 
 
 
 
Expected start date after protocol amendment 1: October 1st 2014 
 
 
 
Expected end date for enrollment: October 30th 2016 
 
 
 
Length of enrollment for each patient: 3 days 
 
 
 
Length of follow-up for each patient: 3 days after surgical procedure. A passive follow- 
up using review of electronic medical records for safety at 30 days. 


PAIN Protocol 
IRB NUMBER: HSC-1M4S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
XII. 
STUDY DESIGN/METHODOLOGY 
 
 
 
This will be a single institution, prospective, blinded, randomized, controlled 
effectiveness study with 2-armed parallel-group sequential design to assess the efficacy 
of liposomal bupivicaine in postoperative pain control when compared to regular 
bupivacaine HCl. Exparel® liposomal bupivicaine is an FDA-approved suspension 
consisting of a liposomal form of the local anesthetic bupivacaine; it is to be injected 
intraoperatively in the surgical wound just prior to closing the incision. 
 
Screened patients meeting the eligibility criteria will be randomized into one of 
 
the two study groups, i.e., liposomal bupivacaine and regular non-liposomal bupivacaine 
HCl injection into the surgical wound. Patients in both groups will receive the standard 
opioid PCA protocol during their postoperative period. Patients will receive a single dose 
of intravenous acetaminophen perioperatively as per the standard practice by our 
anesthesiologists. 
 
During the screening and consenting process prior to surgery in the preoperative 
holding area, the inpatient wards, or in the outpatient clinic, patients will be educated on 
PCA use and the NPS and BPI assessments. Their preoperative baseline pain level, 
using BPI will be recorded at this time. 
 
Patients from both groups will receive the same volume, 80ml, which will be 
given in four 20ml syringes using 22 gauge needles. The study drug group, will receive 
266mg of liposomal bupivicaine (equivalent of one 1.3% 20ml vial of EXPAREL®) 
 
diluted in 60ml of preservative-free normal (0.9%) sterile saline for a total volume of 
 
80ml. The non-liposomal bupivacaine HCl group, will receive 125mg of bupivacaine 


PAIN Protocol 
IRB NUMBER: HSC-1M5S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
hydrochloride (equivalent of one 0.25% 50ml or five 0.25% 10ml vials ) diluted in 30ml 
of preservative-free normal (0.9%) sterile saline for a total volume of 80ml. Study drug 
or Bupivacaine HCl infiltration will be performed at the end of the procedure, just prior to 
wound closure. The surgical wound length will be measured. 
 
Patients will receive an injection along their incision. Patients that require 
thoracotomies, mini-thoracotomies (minimally invasive thoracic procedures, including, 
VATS), and sternotomies will undergo serial intercostal nerve blocks. Intercostal nerve 
block will be done injecting 5cc (of the total 80cc) on each side of the incision on each 
intercostal space. The nerve blocks should be done on all intercostal spaces that 
compromise the incision. For patients undergoing VATS, the main thoracic surgical 
incision will be covered with a nerve block as previously explained for 
thoracotomies/mini-thoracotomies or sternotomies, while all additional incisions 
(typically 2-4 cm) will need drug infiltration if outside the region covered by nerve block. 
In addition, all patients (including all surgical incisions) will be injected in the fascia, 
subcutaneous tissues, periosteum (if applicable) and parietal pleura (if applicable). The 
total volume injected will be 80cc regardless of incision type. 
 
All patients will be blinded to the contents of the intraoperative injection. The 
surgical team will be blinded up until the time of injection following which the knowledge 
of drug is inevitable since Exparel® has a milky appearance as opposed to normal HCl 
bupivacaine, which is colorless. 
 
Patients will have access to the standard PCA (Patient Controlled Analgesia) 
 
offered at the Memorial Hermann Hospital – Texas Medical Center. The PCA drug will 


PAIN Protocol 
IRB NUMBER: HSC-1M6S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
be Dilaudid (hydromorphone).  Initial dosing will be per the standard hospital protocol of 
 
0.2 mg demand dose, 10 minute lockout, 2 mg per hour max, 0.4 mg rescue dose. 
Adjustments to the PCA dosing will be made based on clinical needs. Patients will 
receive PCA until the third postoperative day, and at that point, PCA will be switched to 
an oral analgesic, at the health-care team discretion. Modifications to the PCA regimen 
can be made by the health care team based on clinical need and will not be deemed a 
protocol deviation. 
 
Per the standards of care at our institution, pain assessment is performed 
periodically by the nursing staff in the post-operative period using the Numeric Pain 
Scale. Formal NPS will be recorded by the research personnel daily at 9 a.m. (± 3 
hours) beginning on post-operative day (POD) 1 through POD 3. NPS will also be 
recorded right before the first use of opioid rescue medication postoperatively (if 
applicable and if NPS had not been assessed within the last hour). 
 
Patients in the study should also complete the Brief Pain Inventory (BPI) before 
the procedure (at baseline during the screening process) and daily postoperatively at 9 
a.m. (± 3 hours) beginning on POD 1 through POD 3. Additionally, patients will be 
assessed on their satisfaction with the postsurgical analgesia. This will be done using 
the 5-point satisfaction scale with 1 being “very dissatisfied” to 5 being “very satisfied” 
daily postoperatively at 9 a.m. (± 3 hours) beginning on POD 1 through POD 3. After the 
 
3 days postoperative monitoring and BPI reporting, the patient terminates his/her 
enrollment. This enrollment termination does not mean severance of the physician- 
patient relationship. In addition, a passive follow-up for safety will be performed that will 
involve review of electronic medical records for complications or any readmissions. 


PAIN Protocol 
IRB NUMBER: HSC-1M7S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
Patients will be consented and their medical records pertinent to the study will be 
collected on a case report form and this information will be kept on a secured HIPPA- 
compliant web-accessed database. No protected health information (PHI) will be 
maintained on the web-accessible database. 
 
Study Conduct 
 
 
1.  Screening 
 
 
The research group will assess patients as possible candidates for enrollment 
based on the inclusion criteria and the planned surgical exposure: median sternotomy, 
thoracotomy, midline laparotomy, and/or mini- thoracotomy (including VATS) incision. 
Once the eligibility is met, an informed written consent will be collected. A member of 
the research team - the PI, Co-PI, research coordinator, or nurse will obtain the consent 
from the surgical candidates who met the preliminary inclusion criteria.  The consent 
process will take place either during the preoperative clinic visit, upon inpatient 
admission, or in the preoperative holding area. Patients will be consented before their 
surgical procedures and will be given the appropriate time to think and discuss with 
family about being part of the study. There will also be given enough time for the 
patients to ask questions about the protocol and research study. Should the patient 
decide to participate, patients will be educated on PCA use and the NPS and BPI 
assessments. Their preoperative baseline pain level, using BPI will be recorded at this 
time. A copy of the signed informed consent shall be provided to the patient, a copy will 
be placed in the patient’s hospital chart, and a copy will be kept by the research team. 
Medical/surgical history, vital signs measurements, drug/alcohol screening, and 


PAIN Protocol 
IRB NUMBER: HSC-1M8S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
standard preoperative testing will also be performed as per the usual surgical practice. 
 
 
 
2.  Quality of life assessment - Brief Pain Inventory 
 
 
The impact of pain on patient’s quality of life will be assessed through a brief pain 
inventory (BPI) that should be done before surgery and daily postoperatively at 9 a.m. 
(± 3 hours) beginning on POD 1 through POD 3. The BPI will be presented as an easy 
to comprehend questionnaire for the patients to quantify and communicate their pain 
experience and how it is affecting their life. It is designed such that patients with 6th- 
grade education should be able to complete the questionnaire on their own. Question 
and answers will be provided in a check-box format. The BPI that will be used on this 
study will be the short version. Patients with difficulty reading or who are physically 
unable to complete the questionnaire will be assisted by the research team based on 
their verbal responses to the BPI questions. 
 
3.  Enrollment 
 
 
After screening for eligibility, if all inclusion/exclusion criteria are met and the 
patient has consented; the patient will be enrolled in the trial. At this point, the study 
coordinator/research office will be notified so that the patient can be randomly allocated 
to one of the study groups. 
 
4.  Randomization and Allocation Concealment 
 
Randomization and allocation concealment will be performed via a web- 
based/computer generated block randomization sequence/list secured in a password- 
protected secure computer in the trial office accessible only to the research staff 


PAIN Protocol 
IRB NUMBER: HSC-1M9S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
independent of the trial administration process, who are not involved in the recruitment, 
data collection, analysis, assessment and/or follow-up. This office/research staff will be 
contacted by the blinded research assistant/investigator to provide certain specific 
details of the patient to be randomized that will be entered in the secure (password 
protected) computed-based entry system. The patient would then be allotted a trial or 
study number and allocated to a study arm group as per the randomized sequence list. 
Masking will include the operating surgeon who shall be blinded to the allocation 
process until the time of injection following which the knowledge regarding the drug to 
the administering surgeon is inevitable as the color of liposomal/extended release 
bupivacaine (study drug) is milky-white as opposed to the colorless bupivacaine 
hydrochloride (standard) formulations. 
 
The randomization will be designed to balance the groups at 94 and 188 total 
subjects to maximize statistical efficiency. We will use block randomization to achieve a 
patient allocation ratio of 1:1, using varying blocks of 4 as per a web-based/computer 
generated list. Patients will be randomly allocated based on this permuted sequence to 
either of the two study groups. 
 
5.  Preoperative assessment 
 
 
Pain assessment will be also done using the BPI form. 
 
 
 
6.  Follow-up 
 
 
After the surgical procedure is done, the follow-up will be: 
 
 
 
i. 
9 am (+ or - 3 hours) of the first post-op day the NPS, BPI, and 5-point 


PAIN Protocol 
IRB NUMBER: HSC-2M0S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
scale will be assessed 
 
 
 
ii. 
9 am (+ or - 3 hours) of the second post-op day the NPS, BPI, and 5-point 
scale will be assessed 
 
iii. 
9 am (+ or - 3 hours) of the third post-op day the NPS, BPI, and 5-point 
scale will be assessed 
 
7.  Termination of enrollment 
 
 
Patient will be considered to have his/her enrollment terminated: 
 
 
 
i. 
After the end of 3 days postoperatively 
 
 
 
ii. 
If any medical/surgical/environmental condition develops that would affect 
or impair primary or secondary outcomes measurements results 
 
iii. 
If the study is terminated 
iv. 
If the patient dies 
8.  Termination of Study 
 
 
i. 
End of study period 
 
 
 
ii. 
If a clinically/statistically significant difference is achieved early during an 
interim analysis. 
 
 
 
 
 
XIII. 
ADVERSE EVENT REPORTING 


PAIN Protocol 
IRB NUMBER: HSC-2M1S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
Patients enrolled in the trial will be informed to report any unwanted effect at any 
time during the study. Adverse effects of bupivacaine will be made plain to the patients 
during the screening/enrollment as well as in the informed consent process. Most 
adverse side effects are related to incorrect drug administration technique, resulting in 
systemic exposure to higher blood plasma levels. This incorrect drug administration is 
extremely rare amongst trained and board certified vascular surgeons. All the surgeons 
involved in our study have been extensively trained on the administration technique 
required for local anesthetic injections. Bupivacaine can be cardiotoxic and amongst its 
side effects it can cause hypotension, bradycardia, arrhythmias and/or cardiac arrest. 
Other adverse effects include symptoms of central nervous system excitation 
(nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, 
seizures) or depression (such as drowsiness, loss of consciousness, respiratory 
depression and apnea). 
 
Safety monitoring will include assessment of: 
 
 
i. 
Adverse Effects (AE) 
 
ii. 
Vital Signs 
 
iii. 
Wound healing status 
iv. 
Scarring 
v. 
Cardiac monitoring 
 
All aforementioned parameters will be closely monitored in a continuous manner, 
as part of our standard postoperative care. Any abnormalities found will be promptly 
assessed and described in the patient’s medical records. Once the patient is discharged 
it is very unlikely that any of the study drugs will cause any abnormalities. Several times 


PAIN Protocol 
IRB NUMBER: HSC-2M2S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
the half-life of both the study group and HCl bupivacaine will have passed before the 
patient is discharged. Despite this fact, patients will be asked to contact the hospital in 
case they feel anything unusual. Definitions and examples of the standard or known 
adverse events associated with Exparel® and HCl bupivacaine like restlessness, 
anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, hypotension, 
bradycardia, ventricular arrhythmias, etc., will be presented to the patient for reference. 
Patients will be also assessed on the above items on their postoperative clinic visits. In 
addition, emergency contact information of the office in order to speak to someone 
regarding documentation of these adverse events will be provided. If need be, an 
immediate unscheduled visit shall be arranged if the patient so desires. 
The PI will review AE as they occur, changes to the study design or drug use will 
be determined on an ongoing basis. AE will also be reported to the DSMB. 
 
 
 
 
XIV. 
STATISTICAL ANALYSIS PLAN 
 
 
A. Primary Outcomes 
 
 
NPS measurements will be collected for each subject over the initial 72 hours 
postoperatively and the primary endpoint will be measured by a statistical 
comparison using a Wilcoxon rank-sum test. NPS measurements are derived from a 
likert scale that does not follow a normal distribution.  Consequently, NPS 
measurements will be transformed to rank scores and analyzed by Wilcoxon rank- 
sum test between groups at each time point.  Summary measures will be by two-way 
non-parametric (Friedman) ANOVA to assess time-by-group interaction over the first 


PAIN Protocol 
IRB NUMBER: HSC-2M3S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
three postoperative days. Randomization is expected to balance the groups with 
respect to preoperative risk factors. 
 
A. Secondary Outcomes 
 
 
Cumulative dose of opioid medication will be assessed as the sum of morphine 
doses dispensed by PCA pump during the first 72 hours.  This will be compared by 
unpaired t test. 
 
Length of hospital stay will be transformed to log scale to normalize the distribution if 
necessary and will be compared between groups by an appropriate unpaired 
statistic. 
 
Attainment of physical therapy goal that justifies discharge from inpatient PT within 
 
72 hours will be assessed by an appropriate contingency table test. 
 
 
 
B. Sample Size Determination 
 
 
Our surgical service manages many different types of patients but utilizes four major 
incisions (sternotomy, thoracotomy, laparotomy and mini- thoracotomy (including 
VATS)) to achieve surgical exposure. While some variation in discomfort associated 
with each procedure is likely to exist, we propose to power the study for aggregate 
effect on the entire group rather than to quadruple (or more, depending on the 
analytical framework) the sample size to be able to look definitively at each 
individual incision type.  A complex incision-by-incision study would take years to 
accomplish and involve more than a thousand patients.  A reasonable answer that 
could improve patient care may be available sooner, with a far less detailed and 


PAIN Protocol 
IRB NUMBER: HSC-2M4S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
resource-intensive methodology.  The current dogma in the surgical community is 
that thoracotomies are the most painful and sternotomies the least painful of these 
incision types, but quantitative data sufficient to plan sample size on this basis are 
lacking.  Currently, the best available data on postoperative pain reduction with 
extended-release-Bupivacaine are from a randomized study after hemorrhoidectomy 
that reports cumulative pain scores as mean areas under the NRS curve of 141.8 
and 202.5 with a standard error of 10.7 in the Exparel® and HCl bupivacaine group, 
respectively.12 The Cohen’s delta effect size in this paper was 0.54, which is 
empirically determined to be a “medium sized” effect.15 
 
Because we expect that Bupivacaine-related effect sizes might be larger in 
thoracotomies (which are considered more painful) than sternotomies, we have 
reduced our aggregate effect size expectation to a Cohen delta of 0.35, which is at 
the low end of the “medium” range but still clinically meaningful as it corresponds to 
a treatment group non-overlap of about 20% (based on the statistical properties of 
the distributions involved).  As a hedge against the possibility that our assumptions 
are too conservative, we propose a group-sequential design 14 with three looks. This 
design confers the added benefit of ability to stop early for efficacy or harm (the 
alpha spending function is two-tailed) if an unexpectedly large signal is detected 
prior to full enrollment. 
 
 
 
A total sample size of 330 subjects (165 Exparel®, 165 HCl bupivacaine) at 
cumulative alpha = 0.05 yields a beta of 0.17.  The first interim look at 94 subjects 
requires a nominal alpha of 0.0002 to reject the null hypothesis.  The second look at 
188 patients puts the nominal critical value of alpha at 0.012.  The final alpha has to 


PAIN Protocol 
IRB NUMBER: HSC-2M5S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
reach 0.0462 to aggregate total alpha to 0.05 if the study goes all the way to the full 
 
330 cohort size. We think a conservative aggregate effect size estimate (Cohen 
 
0.35) with two interim looks provides the best balance of design efficiency and 
coverage of the unknown probability space of the multiple incision effect sizes. 
 
XV. 
ETHICS 
 
 
 
A. Informed Consent Process 
 
 
All eligible patients who meet the inclusion criteria will be consented, if willing, 
after an in-depth description of the study, the study drug and its adverse effects, the 
risks and benefits, follow-up routine, enrollment and termination terms. The importance 
of follow-up will be emphasized; however, the patient will retain the right to voluntarily 
withdraw from the study at any point. It will also be stressed that patient confidentiality 
will be kept at all times during study through de-identification of data. 
 
Information will be stated clearly in a written consent form that will be designed at 
a 6th grade level of understanding. Information will also be presented verbally. A 
member of the research team, either the PI, Co-PI, or co-investigators will obtain the 
consent of the patient or other the legally authorized representative of the patient.  The 
consent process will take place either during the preoperative clinic visit, upon inpatient 
admission, or in the preoperative holding area.  The member of the team who is 
obtaining the written consent will describe the research project in its entirety and answer 
the questions of the patient and/or family members should they ask any. Sufficient time 
will be provided to the patient party to review the study before making an informed 
decision to participate or decline. We will make sure the patient have time to deliberate 


PAIN Protocol 
IRB NUMBER: HSC-2M6S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
on the risk/benefits of joining the study. If they require, patients will be given at least one 
hour for deliberation and discussion with the research staff, friends and/or family 
members about enrolling or not the study Should they decide to participate, three 
copies of the consent form would be attested by the patient or legally authorized 
individual for the patient’s medical record, the study record, and one copy will be 
provided to the patient. 
 
B. Privacy and Confidentiality 
 
 
The study will be conducted in compliance with all HIPAA guidelines to protect 
patient confidentiality. All sensitive information or patient identifiers will be stored in form 
of a patient linkage file that will link the patient study/trial number to their clinical records 
and secured on the Zone 100 drive on specific networked computers of our department. 
We have a password protected electronic database that, along with the case report 
forms, will be de-identified and contain only study relevant data points and the patient’s 
trial number. Access to any data pertaining to the study will be restricted to approved 
research team members, the FDA, institutional review boards of the University of Texas 
and Memorial Hermann Hospital. 
 
C. Risk/Benefit 
 
 
Risks to participants 
 
 
 
There is a small increased risk to the patients by participating in the study in addition to 
a possible chance of breach in patient confidentiality as the study involves evaluation of 
an FDA-approved drug. As detailed in the informed consent, the subjects are at risk of 


PAIN Protocol 
IRB NUMBER: HSC-2M7S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
developing adverse effects from Exparel®, described on the drug packet insert and from 
HCl Bupivacaine, also described on the drug packet insert. Patients will be offered 
standard optimal medical therapy options, even if that will culminate in withdrawal from 
the study. In addition, there is risk of an unintentional disclosure of personal health 
information. 
 
Benefits to participants 
 
 
 
The patients stand to receive no direct benefit from the study. However, in the event our 
results endorse the published reports of reduction in postoperative pain by Exparel®, the 
group of patients receiving it might be indirectly benefitted through participation. 
 
 
 
 
XVI. 
STUDY TIMELINE 
 
 
Considering our group’s monthly average for the given procedures and the 
enrollment rates, drop-outs and withdrawal, and interim analyses we estimate 
recruitment of our sample size will take 3 years. Once the follow-up of all enrolled 
participants is finished, data will be analyzed and published. The following is a 
chronological estimate of the stages: 
 
Stage 1: Patient screening and enrollment 
0 - 3 years 
 
Stage 2: Follow-up 
(0 – 3 years) No long-term follow-up relevant 
 
Stage 3: Data collection and analysis 
1 year 
 
Stage 4: Presentation and publication period (at the end of data analysis) 


PAIN Protocol 
IRB NUMBER: HSC-2M8S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
XVII.  DATA SAFETY MONITORING 
 
 
In view of the uncertainty attached to the treatment effects in this heterogeneous 
population, owing to limited currently available data, an independent Data Safety 
Monitoring Committee, will oversee the progress and: 
 
i. 
Monitor avoidable risks associated with patient data and confidentiality. 
 
 
 
ii. 
Monitor achievement of trial recruitment targets, appropriateness of 
trial size, 
 
iii. 
Evaluate interim analysis and advise remedial actions in case of 
superiority/futility situations 
 
Two interim analyses will be conducted after the enrollment of the 94th and 188th patient, 
respectively using a group-sequential design. During these interim assessments the 
DSMC will decide on need for continuation based on the evidence that a reliable 
conclusion can be drawn based on available data (superiority) or unlikely to observe a 
statistical difference (futility). As for instance, if one between-group difference is 
demonstrably inferior to the other using a three-stage group-sequential overall nominal 
value of 0.05 14 (alpha spending of 0.0002, 0.012 and .0462 at 94, 188 and 330 
participants accrued, respectively ) the study will be stopped early and the results will be 
reported to the IRB and published. 
 
 
 
 
XVIII. CONFLICT OF INTEREST 
 
 
There is no relationship between the PI or any other research staff member and Pacira 


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IRB NUMBER: HSC-2M9S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
pharmaceuticals. 
 
 
 
 
 
 
 
XIX. 
FUTURE PUBLICATION AND PRESENTATION 
 
 
The results of this study will be analyzed and published after the approval of 
 
the principal investigator and biostatistician in a peer-reviewed scientific journal and/or 
presented at an international/national scientific conference or meeting regardless of 
outcome. The publication will acknowledge members of the study research group for 
their contributions and will maintain patient data protection. 
 
 
 
 
 
XX. 
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IRB NUMBER: HSC-3M0S-13-0620 
IRB APPROVAL DATE: 09/12/2016 
 
 
 
 
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