Clinical trial NCT02662036
Conditions: Mammaplasty
Sponsor: Washington University School of Medicine
Start date: 2016-02-29; Completion date: 2018-03-08
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy of analgesia provided by liposomal bupivacaine (Exparel) when compared to bupivacaine HCL as a transverse abdominis plane (TAP) block in terms of discharge milestones, opioid use, costs, and patient-reported satisfaction at 12, 24, and 72 hours. The investigators propose that Exparel will lower opioid use, length of stay, and overall cost of abdominally-based autologous breast reconstruction, and will lead to greater patient satisfaction.

Detailed description:

Arms: arm 1: -TAP block of 30 cc of 0.25% bupivicaine arm 2: -TAP block of 266 mg/30 cc liposomal bupivacaine
Interventions: intervention 1: Bupivicaine HCL intervention 2: Liposomal bupivacaine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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A PROSPECTIVE TRIAL TO ASSESS ANALGESIC EFFICACY OF LIPOSOMAL 
BUPIVACAINE VS BUPIVACAINE HCL AS A TAP BLOCK AFTER ABDOMINALLY 
BASED AUTOLOGOUS BREAST RECONSTRUCTION 
 
 
Washington University School of Medicine 
Department of Surgery 
660 S. Euclid Ave., Campus Box 8109 
St. Louis, MO 63110 
 
HRPO #: 201601064 
Version date: 11/01/2018 
Version 3 
 
 
 
 
 
Principal Investigator:  
Terence M. Myckatyn, MD 
 
Phone:   
 
 
(314) 996-8800 
Email:   
 
 
myckatynt@wudosis.wustl.edu 
 
 
Sub-Investigators: 
 
Ryan Guffey, MD 
 
 
 
 
Elizabeth B. Odom, MD 
 
 
 
 
Yu Tao, PhD 
Rajiv Parikh, MD 
 
 


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SCHEMATIC DESIGN 
 
 
 
 


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Table of Contents 
SCHEMATIC DESIGN ...................................................................................................................................... 2 
1. 
BACKGROUND AND RATIONALE ........................................................................................................... 4 
1.1. 
Background ................................................................................................................................... 4 
1.2. 
Rationale ....................................................................................................................................... 5 
2. 
OBJECTIVES ........................................................................................................................................... 5 
2.1. 
Primary Objective.......................................................................................................................... 5 
2.2. 
Secondary Objective ..................................................................................................................... 5 
3. 
PATIENT SELECTION .............................................................................................................................. 5 
3.1. 
Inclusion Criteria ........................................................................................................................... 5 
3.2. 
Exclusion Criteria ........................................................................................................................... 6 
3.3. 
Inclusion of Women and Minorities .............................................................................................. 6 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 7 
4.1. 
Confirmation of Patient Eligibility ................................................................................................. 7 
4.2. 
Patient Registration in the Siteman Cancer Center OnCore Database ......................................... 7 
4.3. 
Assignment of UPN ....................................................................................................................... 7 
4.4. 
Randomization .............................................................................................................................. 7 
5. 
PATIENT VISITS ...................................................................................................................................... 7 
5.1. 
Preoperative Evaluation ................................................................................................................ 7 
5.2. 
Surgery, Administration of Study Intervention, and Postoperative Care ..................................... 8 
5.3. 
Postoperative Follow-Up Visit....................................................................................................... 8 
5.4. 
Adverse Event Monitoring ............................................................................................................ 9 
6. 
PHARMACEUTICAL INFORMATION ....................................................................................................... 9 
6.1. 
Bupivacaine HCl ............................................................................................................................ 9 
6.2. 
Liposomal Bupivacaine (Exparel) ................................................................................................ 11 
7. 
REGULATORY AND REPORTING REQUIREMENTS ............................................................................... 12 
7.1. 
Definitions ................................................................................................................................... 12 
7.2. 
Reporting to the Human Research Protection Office (HRPO) at Washington University ........... 14 
7.3. 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at Washington 
University ................................................................................................................................................ 14 
7.4. 
Timeframe for Reporting Required Events ................................................................................. 14 
8. 
DATA SUBMISSION SCHEDULE ............................................................................................................ 15 
9. 
DATA AND SAFETY MONITORING ....................................................................................................... 15 
10. STATISTICAL CONSIDERATIONS ........................................................................................................... 16 
10.1. 
Outcome Measures ................................................................................................................. 16 
10.2. 
Study Design ............................................................................................................................ 16 
10.3. 
Sample Size ............................................................................................................................. 16 
10.4. 
Data Analysis ........................................................................................................................... 16 
11. References .......................................................................................................................................... 18 
Appendix 1: QoR-15 .................................................................................................................................... 20 
Appendix 2: Standard Post-Operative Medications ................................................................................... 21 
Appendix 3: Patient Milestones .................................................................................................................. 23 
 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Background 
 
Abdominally-based tissue transfer for breast reconstruction after mastectomy was introduced in 
the early 1980s and is the primary donor site for autologous breast reconstruction1,2.  There were 
over 8,000 cases of autologous breast reconstruction performed at Barnes Jewish Hospital 
between 2005 and 20123.  Both the mastectomy and laparotomy sites are sources of 
postoperative pain; however, groups have found that the abdomen is the main source of this 
discomfort4,5.  Relieving this pain is a persistent challenge to both surgeons and anesthesiologists.  
The potential benefits of optimal postoperative pain control include improved cardiac, 
respiratory, and gastrointestinal functions, as well as fewer thromboembolic complications, fewer 
septic complications, and lower incidence of the development of chronic pain states6,7.  Opioids 
have been the primary form of pain control in the postoperative period, but they have been 
associated with nausea, vomiting, central nervous system and respiratory depression, 
constipation, urinary retention, itching, and the development of hyperalgesia.  These 
consequences can significantly lengthen a patient’s hospital stay and decrease their satisfaction 
with their procedure8,9. 
 
Several studies have shown decreased postoperative opioid use and a shorter hospital stay with 
the use of bupivacaine HCl in the donor site after abdominally-based autologous breast 
reconstruction using a transverse rectus abdominis (TRAM) and deep inferior epigastric 
perforator (DIEP) flap10-13.  Most of these studies have also found improved patient satisfaction.  
However, they have either looked at a single dose of bupivacaine injected into the transverse 
abdominis tissue plane (TAP) (which provides only 6-8 hours of pain relief postoperatively) or the 
use of an indwelling catheter, which places further burden on the patient in the recovery period 
and requires multiple further bupivacaine instillations by the healthcare team at set time points.  
Current standard of care for the PI of this study is for patients to receive bupivacaine as a TAP 
block at the conclusion of the case.  Standard post-operative medications may be found in 
Appendix 2 to this protocol. 
 
Liposomal bupivacaine (Exparel) was approved for use by the FDA in 2011, and provides up to 72 
hours of analgesia after surgery due to encapsulation of the drug into multivesicular liposomes 
allowing for controlled diffusion14,15.  Dasta et al reviewed 9 studies in which Exparel was used in 
orthopedic or plastic surgery settings and concluded that there was a statistically significant lower 
cumulative pain score at 72 hours, delayed and decreased consumption of opioids, and fewer 
opioid-related complications when compared to patients receiving bupivacaine HCl16.   
Additionally, patients undergoing abdominal surgeries such as hysterectomy and colon resection 
have been shown to have a lower opioid requirement and faster recovery when given a TAP block 
with liposomal bupivacaine when compared with those patients who have not17,18. 
 
1.1.1. Quality of Recovery – 15 
 
The Quality of Recovery – 15 (QOR15) score was generated as a short questionnaire used 
to evaluate the recovery process from a patient perspective on a scale of 0-150.  The 
questionnaire originated as a 40-question survey (QOR40), which is a global recovery 
survey, but was condensed and validated against both this longer version and the VAS 


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pain scoring system.  It may be completed in less than 3 minutes, which increases the 
feasibility of using it in the postoperative setting. 
 
1.2. 
Rationale 
 
This study will evaluate the efficacy of analgesia provided by Exparel when compared to 
bupivacaine HCl as a TAP block in terms of discharge milestones, opioid use, costs, and patient-
reported satisfaction at 12, 24, and 72 hours.  We propose that Exparel will lower opioid use, 
length of stay, and overall cost of abdominally-based autologous breast reconstruction, and will 
lead to greater patient satisfaction. 
 
 
2. 
OBJECTIVES 
 
2.1. 
Primary Objective 
 
To evaluate the analgesic effectiveness of liposomal bupivacaine (Exparel) versus bupivacaine HCl 
as a TAP block in women who have received abdominal-based autologous breast reconstruction 
measured by total opioid use during the hospital stay.  
 
2.2. 
Secondary Objective 
 
To evaluate the analgesic effectiveness of liposomal bupivacaine (Exparel) as a TAP block versus 
bupivacaine HCl as a TAP block in women who have received abdominal-based autologous breast 
reconstruction as measured by: 
1. total antiemetic use during the hospital stay 
2. length of hospital stay 
3. time until ambulation 
4. time until urinary catheter removal 
5. pain scores 
6. patient satisfaction with recovery 
 
To evaluate the cost of liposomal bupivacaine (Exparel) versus bupivacaine HCl when accounting 
for length of hospital stay and use of other analgesics. 
 
 
3. 
PATIENT SELECTION 
 
3.1. 
Inclusion Criteria 
 
1. Scheduled for abdominal-based autologous breast reconstruction (DIEP, MS-TRAM, or 
TRAM). 
2. At least 18 years of age. 
3. Female. 
4. Able to understand and willing to sign a written informed consent document. 
 
 


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3.2. 
Exclusion Criteria 
 
1. Cognitive impairment. 
2. History of abdominal surgery precluding free flap donor site. 
3. Allergy or intolerance to bupivacaine or “amide” anesthetics. 
4. Significant preoperative chronic pain (requiring daily narcotics) or neuropathic pain (requiring 
daily use of pregabalin or gabapentin) within the previous 3 months. 
5. Pregnant or breastfeeding. 
 
3.3. 
Inclusion of Women and Minorities 
 
Only women will be enrolled due to the anatomical specificity of breast cancer.  Members of all 
races and ethnic groups are eligible for this trial. 
 
3.4 
Retrospective Controls 
 
All patients who received an abdominal-based autologous breast reconstruction after 
4/1/2010 but before study enrollment begins will be reviewed to evaluate the impact of other 
recent changes in perioperative care on the secondary objective outcome measures.  Prior to 
this study’s conception standard of care practice changed to include additional perioperative 
pain medications.  Diet and mobility orders were also changed to adopt enhanced recovery 
after surgery (ERAS) standards.  Quantification of the effect of these changes will add context 
to the effects of the liposomal bupivacaine.  
 
The data points for this retrospective medical record review will include: 
 
• 
Weight 
• 
ASA Class (Anesthesia record) 
• 
Anesthesia Case Duration (In OR to Exit OR time) 
• 
Height 
• 
2 hour Pain Scores (PACU) 
• 
Takeback reason if return to OR 
• 
Postoperative Emesis  
• 
Smoking history (CPAP assessment) 
• 
Preoperative opioid usage  
• 
PONV history (CPAP assessment) 
• 
Medical comorbidities (DM, vascular disease, heart disease/CAD, CHF, respiratory 
disease, kidney disease, stroke, use CPAP or surgeon H and P) 
• 
Chemo (pre surgery) 
• 
Radiation (pre surgery) 
• 
Breast CA Stage 
• 
Breast CA Side 
• 
Pectoralis muscle repair? (yes/no/unknown) 
• 
Fap loss right? (yes/no/NA …. If there was no flap its NA) 
• 
Flap loss left? (yes/no/NA) 
• 
TTON (Time to oral only narcotics from end surgery time) 


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4. 
 REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman Cancer 
Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1. 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2. 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3. 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
4.4. 
Randomization 
 
All consenting and eligible patients (those in the prospective cohort) will be randomized at the 
time of their operation to receive either 0.25% bupivacaine HCl with epinephrine or Exparel as a 
TAP block in a 1:1 ratio.  Patients will be blinded to their assignment.  The randomization table 
will be uploaded to REDCap, and randomization will occur via an online form with entry of the 
patient ID number and confirmation of eligibility status.  Once all information is entered, 
randomization is carried out via a submit button through REDCap.  The randomization scheme will 
be generated using the SAS program PROC PLAN. 
 
 
5. 
PATIENT VISITS 
 
5.1. 
Preoperative Evaluation 
 


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The plastic surgeon will discuss treatment options given each patient’s expected or acquired 
deformity.  This decision will be based on medical/surgical history, age, patient expectations, and 
anatomy.  If a patient is deemed a candidate for autologous breast reconstruction using 
abdominal tissue and she meets the eligibility criteria specified in Section 3.1, she will be 
approached about her ability and willingness to participate in this trial.   
 
The Quality of Life – 15 questionnaire (Appendix 1), will be given to all patients who are potential 
candidates for a DIEP flap as standard of care.  This module was developed to evaluate recovery 
after surgery.  Baseline values are best assessed at a preoperative visit days to weeks prior to the 
surgery date.  The module takes approximately 2 minutes to complete. 
 
If a patient chooses to enroll in the study, after the consent and enrollment process this 
questionnaire will be entered in to the prospective study database. 
 
5.2. 
Surgery, Administration of Study Intervention, and Postoperative Care 
 
On the day of surgery, patients will receive standardized preoperative care.  Uniform operative 
techniques will be used in both treatment groups, performed by an experienced reconstructive 
breast surgeon. Prior to closure of the abdominal donor site, a transversus abdominis muscle 
plane nerve block will be performed under direct vision.   To do so, a 2cm incision will be made in 
the Triangle of Petit, the anatomic landmark to perform this block.  The transversus abdominis 
muscle will be visualized deep to the external and internal oblique muscle planes and 15cc of 
0.25% bupivacaine HCl with epinephrine or 15cc of Exparel will be administered on each side, or 
in unilateral cases, the entire amount will be given to the respective hemi-abdomen.  There is no 
preparation of the medication required by the pharmacy; it is in 266 mg vials and is drawn into a 
syringe by the OR staff. The fascial incisions will be closed with standard suture.  The abdominal 
wound will then be closed in the usual fashion. 
 
Postoperative care will follow a standardized recovery pathway.  Patients will be given standard 
postoperative medications and will be allowed to progress through recovery (ambulation, Foley 
catheter removal, and diet progression) at a rate dictated by their comfort level.  Milestones 
including activity, foley catheter removal, diet progression, and discharge time will be recorded 
(Appendix 3). 
 
Pain scores (on a scale of 1 to 10) are collected clinically every 4 hours or when pain medication 
is administered.  These scores will be documented at 12, 24, 48, and 72 hours postoperatively in 
the case report forms for this study. Pain scores recorded at the closest time to each of these time 
points within a 4 hour window on either side, otherwise the score will be left as N/A.   On 
postoperative Day 2 the Quality of Recovery – 15 survey will be administered.  This survey will 
again be administered prior to discharge. 
 
5.3. 
Postoperative Follow-Up Visit 
 
Patients will return to clinic for a visit with the surgeon approximately two weeks postoperatively 
(+7/-9 days).  Timing will vary depending on discharge date, nurse visits, and recovery.  Up to 6 
weeks postop is accepted before the visit will be considered out of window.  The Quality of 
Recovery – 15 survey will again be administered.  A member of the study team may contact 
patients over the phone or by email to assess postoperative adverse events and to complete 


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questionnaires. 
 
5.4. 
Adverse Event Monitoring 
Exparel itself can cause adverse events related to Bupivicaine toxicity. These are predominantly 
cardiac arrhythmias. We have previously examined the pharmacokinetics of Exparel and how 
this interacts with an antecedent paravertebral block. We use standard dosing of Exparel and 
based on our experience thus far, and planning for this study with anesthesia and pharmacology 
preoperatively, have had no issues with our protocol. Notably, patients who have DIEP 
reconstruction that uses the IMA vessels as a donor, as we do, have some tachycardia in the 
absence of any TAP block, bupivicaine or Exparel. We have published on this ourselves 
“Sachanandani, N. S., Kale, S. S., Skolnick, G. B., Barbour, J. R., Myckatyn, T. M. Tachycardia in 
breast reconstructive microsurgery: Affirmation of the IMA tachycardia syndrome. J Plast 
Reconstr Aesthet Surg 2015”. So, we are looking for arrhythimas beyond tachycardia when 
evaluating these patients for an adverse event.  
The TAP (transversus abdominis plane) block, regardless of which drug is used (Exparel, 
Bupivicaine, or other) carries with it the risk of visceral injury by injecting the drug deep to the 
transversalis fascia. As such, we do the injection under direct visualization since we are already 
operating on the abdominal wall during this procedure, and we use a blunt-tipped cannula for 
injection to optimize safety. We have had no issues with this either.  
 
Only adverse events deemed to be serious, unexpected, severe, and related to the study drug will 
be recorded. Specifically, bleeding requiring blood transfusion, infection requiring readmission or 
surgery, life-threatening arrhythmias, wound healing problems requiring surgical intervention, 
and reconstructive failures due to flap loss will be recorded and evaluated for relatedness.  
Adverse event monitoring will begin when the study drug is administered. Adverse events that do 
not require clinical intervention will not be recorded. 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1. 
Bupivacaine HCl 
 
6.1.1. Bupivacaine HCl Description 
 
Bupivacaine hydrochloride is 2-piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, 
monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 
95% ethanol, soluble in water, and slightly soluble in chloroform or acetone.  It has the 
following structural formula: 
 
 
 
 
Epinephrine is (-)-3,4-dihydroxy-α-[(methylamino)methyl] benzyl alcohol.  It has the 


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following structural formula: 
 
 
 
 
Bupivacaine HCl is indicated for the production of local or regional anesthesia or analgesia 
for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, 
and for obstetrical procedures. 
 
6.1.2. Clinical Pharmacology 
 
Local anesthetics block the generation and the conduction of nerve impulses, presumably 
by increasing the threshold for electrica excitation in the nerve, by slowing the 
propagation of the nerve impulse, and by reducing the rate of rise of the action potential. 
 
6.1.3. Pharmacokinetics and Drug Metabolism 
 
The rate of systemic absorption of local anesthetics is dependent upon the total dose and 
concentration of drug administered, the route of administration, the vascularity of the 
administration site, and the presence or absence of epinephrine in the anesthetic 
solution.  A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces 
the rate of absorption and peak plasma concentration of bupivacaine HCl, permitting the 
use of moderately larger total doses and sometimes prolonging the duration of action. 
 
The onset of action with bupivacaine HCl is rapid and anesthesia is long lasting.  It has also 
been noted that there is a period of analgesia that persists after the return of sensation, 
during which time the need for strong analgesics is reduced. 
 
PK studies on the plasma profile of bupivacaine HCl after direct IV injection suggest a 
three-compartment open model.  The first compartment is represented by the rapid 
intravascular distribution of the drug.  The second compartment represents the 
equilibration of the drug throughout the highly perfused organs such as the brain, 
myocardium, lungs, kidneys, and liver.  The third compartment represents an 
equilibration of the drug with poorly perfused tissues, such as muscle and fat.  The 
elimination of drug from tissue distribution depends largely upon the ability of binding 
sites in the circulation to carry it to the liver where it is metabolized. 
 
After injection of bupivacaine HCl for caudal, epidural, or peripheral nerve block in main, 
peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a 
decline to insignificant levels during the next three to six hours. 
 
6.1.4. Supplier 
 
Bupivacaine HCl is commercially available. 


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6.1.5. Storage and Stability 
 
Store at 20 to 25°C (68 to 77°F). 
 
6.1.6. Administration 
 
As described in Section 5.2. 
 
6.1.7. Special Handling Instructions 
 
None. 
 
6.2. 
Liposomal Bupivacaine (Exparel) 
 
6.2.1. Liposomal Bupivacaine Description 
 
Exparel is a liposome injection of bupivacaine, an amide local anesthetic, indicated for 
single-dose infiltration into the surgical site to produce postsurgical analgesia.  Please 
refer to Section 6.1.1 for a description of bupivacaine HCl. 
 
Liposomal encapsulation or incorporation in a lipid complex can substantially affect a 
drug’s functional properties relative to those of the unencapsulated or nonlipid-
associated drug.  The median diameter of the liposome particles ranges from 24 to 31 µm.  
The liposomes are suspended in a 0.9% sodium chloride solution. 
 
6.2.2. Clinical Pharmacology 
 
Local anesthetics block the generation and the conduction of nerve impulses, presumably 
by increasing the threshold for electrica excitation in the nerve, by slowing the 
propagation of the nerve impulse, and by reducing the rate of rise of the action potential. 
 
6.2.3. Pharmacokinetics and Drug Metabolism 
 
Local infiltration of Exparel results in significant systemic plasma levels of bupivacaine 
which can persist for 96 hours.  Systemic plasma levels of bupivacaine following 
administration of Exparel are not correlated with local efficacy. 
 
The rate of systemic absorption of bupivacaine is dependent upon the total dose of drug 
administered, the route of administration, and the vascularity of the administration site. 
 
After bupivacaine has been released from Exparel and is absorbed systemically, 
bupivacaine distribution and excretion is expected to be the same as for any bupivacaine 
HCl solution formulation. 
 
Amide-type local anesthetics, such as bupivacaine, are metabolized primarily in the liver 
via conjugation with glucuronic acid. 
 


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6.2.4. Supplier 
 
Exparel is commercially available.  It will be paid for by the study. 
 
6.2.5. Storage and Stability 
 
Exparel vials should be stored refrigerated between 2°C and 8°C (36°F to 46°F).  Exparel 
may be held at a controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 30 
days in sealed, intact (unopened) vials.  Vials should not be re-refrigerated.  Exparel 
should not be frozen or exposed to high temperatures for an extended period. 
 
6.2.6. Administration 
 
As described in Section 5.2. 
 
6.2.7. Special Handling Instructions 
 
None. 
 
7. 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as outline 
below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events meeting 
the definition of unanticipated problem or serious noncompliance be reported as outlined in Section 7.2. 
For the purposes of this study, AEs related to the patient’s surgical intervention are not reportable.   
 
7.1. 
Definitions 
 
7.1.1.  Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity 
reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can be 
found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
For the purposes of this study, AEs related to the patient’s surgical intervention are not 
reportable.   
 


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7.1.2. Serious Adverse Events (SAEs) 
 
Definition:  any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgement, may 
jeopardize the subject and may require medical or surgical intervention to 
prevent on of the outcomes listed above 
 
7.1.3. Unexpected Adverse Experience 
 
Definition:   any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
7.1.4. Life-Threatening Adverse Experience 
 
Definition:  any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in more severe form, might have caused death. 
 
7.1.5. Unanticipated Problems 
 
Definition: 
 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
7.1.6. Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human subject’s research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 


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7.1.7. Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, which result in substantial 
harm to subjects or others, or that materially, compromises the rights or welfare of 
participants. 
 
7.1.8. Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
IRB pre-approval of all protocol exceptions must be obtained prior to the event.   
 
7.2. 
Reporting to the Human Research Protection Office (HRPO) at Washington University 
 
The PI is required to promptly notify the IRB of the following events: 
• 
Any unanticipated problems involving risks to participants or others which occur at WU, 
any BJH or SLCH institution, or that impacts participants or the conduct of the study. 
• 
Noncompliance with federal regulations or the requirements or determinations of the 
IRB. 
• 
Receipt of new information that may impact the willingness of participants to participate 
or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the event 
or notification to the PI of the event.  The death of a research participant that qualified as a 
reportable event should be reported within 1 working day of the occurrence of the event or 
notification to the PI of the event. 
 
7.3. 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or any BJH 
or SLCH institution that has been reported to and acknowledged by HRPO as reportable.  
(Unanticipated problems reported to HRPO and withdrawn during the review process need not 
be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to a QASMC 
auditor. 
 
7.4. 
Timeframe for Reporting Required Events  
 
Adverse events and unanticipated events will be tracked for 30 days following the day of surgery.  
For the purposes of this study, AEs related to the patient’s surgical intervention are not 
reportable.  Adverse events will be graded according to the CTCAE version 4.0 form, as reflected 
in the CRF in the REDCap database. 
 
 


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8. 
DATA SUBMISSION SCHEDULE 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Eligibility Checklist 
Medical/Surgical History Form  
Prior to starting treatment 
Quality of Recovery – 15  
Baseline 
Postoperative Day 2 
Prior to discharge 
~2 weeks postoperatively 
Hospital Stay Outcomes 
At the time of discharge 
Follow-Up Form 
~2 weeks postoperatively 
Unanticipated Event Reporting Form 
At the time of any unanticipated event 
 
 
9. 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the Principal 
Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington University Quality 
Assurance and Safety Monitoring Committee (QASMC) semi-annually beginning six months after accrual 
has opened (if at least five patients have been enrolled) or one year after accrual has opened (if fewer 
than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least monthly and provide a semi-annual report 
to the Quality Assurance and Safety Monitoring (QASM) Committee.  This report will include: 
 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of HRPO 
expiration, date of most recent QA audit, study status, and phase of study 
• 
History of study including summary of substantive amendments; summary of accrual suspensions 
including start/stop dates and reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 
• 
Average rate of accrual observed in year 1, year 2, and subsequent years 
• 
Expected accrual end date and accrual by cohort 
• 
Objectives of protocol with supporting data and list the number of participants who have met 
each objective 
• 
Measures of efficacy 
• 
Early stopping rules with supporting data and list the number of participants who have met the 
early stopping rules 
• 
Summary of toxicities separated by cohorts with the number of dose-limiting toxicities indicated 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for unexpected events on 


Version 11/01/2018 
 
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an ongoing basis. Once the principal investigator or Research Patient Coordinator becomes aware of a 
research related and unanticipated adverse event, it will be reported to the HRPO according to 
institutional guidelines.  
 
 
10. 
STATISTICAL CONSIDERATIONS 
 
10.1. 
Outcome Measures 
 
• 
Primary outcome 
o Total opioid use during the hospital stay 
• 
Secondary outcomes  
o Length of hospital stay 
o Total antiemetic use during the hospital stay 
o Pain scores (Wong-Baker scale) 
o Recovery satisfaction (Quality of Recovery – 15) 
o Length of time until urinary catheter removal 
o Length of time until ambulation 
o Cost of patient care 
 
 
10.2. 
Study Design 
 
All patients who are candidates for autologous breast reconstruction will be screened for 
eligibility for participation in this study.  They will then be randomized to receive bupivacaine HCl 
or liposomal bupivacaine at the time of their operation.   Patients will be blinded to the group to 
which they have been randomized.  The recovery period will follow a standardized pathway to 
avoid heterogeneity in postoperative care and medication use. 
 
10.3. 
Sample Size 
 
A sample size of 52 in each group will be needed to achieve 80% power to detect 20.0mg 
difference in total opioid use at a 0.05 significance level (alpha) using a two-sided two-sample 
unequal-variance t-test19-22, assuming standard deviations of 29.0 for group 1 and 41.7 for group 
2.  Studies on narcotic use were from general surgery literature looking at narcotic use after TAP 
blocks for colectomy/ileostomy takedown, as well as use of bupivacaine after similar breast 
reconstruction cases in plastic surgery.  This literature describes at least a 30 mg difference in 
narcotic use over the hospital stay between patients receiving Exparel vs. no local anesthetic after 
ileostomy reversal, and a 55 mg difference after open colectomy.  Plastic surgery literature shows 
a 16 mg decrease in narcotic use over the hospital stay using implantable local anesthetic 
catheters after autologous breast reconstruction.  The standard deviation for these studies was 
large at 41 mg.  The 20.0 mg difference was selected based on these findings10,23,24. 
 
10.4. 
Data Analysis 
 
This is a prospective single-blinded randomized control trial to evaluate the efficacy of 
bupivacaine HCl versus liposomal bupivacaine when given as a TAP block after autologous breast 
reconstruction with an abdominal donor site.  For each patient, we will collect data on baseline 
pain and recovery variables (length of hospital stay, total opioid use, total antiemetic use, pain 


Version 11/01/2018 
 
page 17 of 23 
score, date and time of urinary catheter removal, date and time of ambulation).  Demographic 
and clinical characteristics will be summarized using descriptive statistics.  We hypothesize that 
patients who receive liposomal bupivacaine will have a lower total opioid and antiemetic use, 
shorter hospital stay, shorter time to ambulation and urinary catheter removal, lower pain scores, 
and improved satisfaction. Independent t-test or Wilcoxon Rank Sum test will be used to 
estimate the difference in the length of hospital stay, total opioid use, total antiemetic use, 
pain score, date and time of urinary catheter removal, date and time of ambulation between 
patients given bupivacaine HCl and liposomal bupivacaine. Fisher exact or Chi-Squared tests 
will be applied to detect significant associations between categorical variables.  All analysis 
will be done in SAS (Cary, USA) 
 


Version 11/01/2018 
 
page 18 of 23 
11. 
References 
1. 
Lipa JE. Breast reconstruction with free flaps from the abdominal donor site: TRAM, DIEAP, and 
SIEA flaps. Clin Plast Surg. 2007;34(1):105-121; abstract vii. 
2. 
Tachi M, Yamada A. Choice of flaps for breast reconstruction. Int J Clin Oncol. 2005;10(5):289-
297. 
3. 
Kwok AC, Goodwin IA, Ying J, Agarwal JP. National trends and complication rates after bilateral 
mastectomy and immediate breast reconstruction from 2005 to 2012. Am J Surg. 
2015;210(3):512-516. 
4. 
Dahmani S, Dupont H, Mantz J, Desmonts JM, Keita H. Predictive factors of early morphine 
requirements in the post-anaesthesia care unit (PACU). Br J Anaesth. 2001;87(3):385-389. 
5. 
Hivelin M, Wyniecki A, Plaud B, Marty J, Lantieri L. Ultrasound-guided bilateral transversus 
abdominis plane block for postoperative analgesia after breast reconstruction by DIEP flap. Plast 
Reconstr Surg. 2011;128(1):44-55. 
6. 
Loeser JD, Melzack R. Pain: an overview. The Lancet. 1999;353(9164):1607-1609. 
7. 
Miljanich G, Rauck R, Saulino M. Spinal Mechanisms of Pain and Analgesia. Pain Practice. 
2013;13(2):114-130. 
8. 
Kessler ER, Shah M, Gruschkus SK, Raju A. Cost and quality implications of opioid-based 
postsurgical pain control using administrative claims data from a large health system: opioid-
related adverse events and their impact on clinical and economic outcomes. Pharmacotherapy. 
2013;33(4):383-391. 
9. 
Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical 
hospitalizations: impact on costs and length of stay. Ann Pharmacother. 2007;41(3):400-406. 
10. 
Boehmler JHt, Venturi ML, Nahabedian MY. Decreased narcotic use with an implantable local 
anesthetic catheter after deep inferior epigastric perforator flap breast reconstruction. Ann 
Plast Surg. 2009;62(6):618-620. 
11. 
Zhong T, Wong KW, Cheng H, et al. Transversus abdominis plane (TAP) catheters inserted under 
direct vision in the donor site following free DIEP and MS-TRAM breast reconstruction: a 
prospective cohort study of 45 patients. J Plast Reconstr Aesthet Surg. 2013;66(3):329-336. 
12. 
Zhong T, Ojha M, Bagher S, et al. Transversus abdominis plane block reduces morphine 
consumption in the early postoperative period following microsurgical abdominal tissue breast 
reconstruction: a double-blind, placebo-controlled, randomized trial. Plast Reconstr Surg. 
2014;134(5):870-878. 
13. 
Wheble GA, Tan EK, Turner M, Durrant CA, Heppell S. Surgeon-administered, intra-operative 
transversus abdominis plane block in autologous breast reconstruction: a UK hospital 
experience. J Plast Reconstr Aesthet Surg. 2013;66(12):1665-1670. 
14. 
Chahar P, Cummings KC, 3rd. Liposomal bupivacaine: a review of a new bupivacaine 
formulation. J Pain Res. 2012;5:257-264. 
15. 
Uskova A, O'Connor JE. Liposomal bupivacaine for regional anesthesia. Curr Opin Anaesthesiol. 
2015;28(5):593-597. 
16. 
Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine liposome injectable suspension 
compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting. 
Curr Med Res Opin. 2012;28(10):1609-1615. 
17. 
Hutchins J, Delaney D, Vogel RI, et al. Ultrasound guided subcostal transversus abdominis plane 
(TAP) infiltration with liposomal bupivacaine for patients undergoing robotic assisted 
hysterectomy: A prospective randomized controlled study. Gynecol Oncol. 2015;138(3):609-613. 
18. 
Keller DS, Tahilramani RN, Flores-Gonzalez JR, Ibarra S, Haas EM. Pilot study of a novel pain 
management strategy: evaluating the impact on patient outcomes. Surg Endosc. 2015. 


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19. 
Chow SC SJ, Wang H. Sample Size Calculations in Clinical Research (2nd Edition). Boca Raton, FL: 
Chapman & Hall/CRC; 2008. 
20. 
Julius S. Sample Sizes for Clinical Trials. Boca Raton, FL: Chapman & Hall/CRC; 2010. 
21. 
Zar J. Biostatstical Analysis (2nd Edition). Englewood Cliffs, NJ: Prentice-Hall; 1994. 
22. 
Machin D CM, Fayers P, Pinol A. Sample Size Tables for Clinical Studies (2nd Edition). Malden, 
MA: Blackwell Science; 1997. 
23. 
Vogel JD. Liposome bupivacaine (EXPAREL(R)) for extended pain relief in patients undergoing 
ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase 
IV health economics trial. J Pain Res. 2013;6:605-610. 
24. 
Marcet JE, Nfonsam VN, Larach S. An extended paIn relief trial utilizing the infiltration of a long-
acting Multivesicular liPosome foRmulation Of bupiVacaine, EXPAREL (IMPROVE): a Phase IV 
health economic trial in adult patients undergoing ileostomy reversal. J Pain Res. 2013;6:549-
555. 
 
 
 


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Appendix 1: QoR-15 
 
  
  
Abstract  
Perth, Western Australia 
  


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Appendix 2: Standard Post-Operative Medications 
Order 
Dose 
Route 
Frequency 
Start Date 
Indication 
Comments 
Analgesics (choose all) 
 
 
 
 
 
 
☒Celecoxib 
200mg 
PO 
BID 
 
Pain 
 
☒Acetaminophen 
1000mg 
PO 
Q6h 
 
pain 
 
☒Gabapentin 
300mg 
PO 
qhs 
 
Pain 
 
☒Hydromorphone 
0.5mg 
IVP 
Q1h prn 
 
pain 
Use while NPO. Once tolerating 
liquids, administer for severe pain 
(≥7) 
☒Oxycodone IR 
5-10mg 
PO 
Q3h prn 
POD#1 
pain 
Once tolerating liquids, use for mild 
to moderate pain (<7) 
☒Oxycodone SR 
10mg 
PO 
BID 
 
pain 
 
Antiemetics 
 
 
 
 
 
 
☒Ondansetron 
4mg 
IVP 
Q6h prn 
 
Nausea/vomiting  
☐Scopolamine patch 
 
Transdermal 
Q72h 
 
Placed 
preoperatively 
 
Constipation 
 
 
 
 
 
 
☒Docusate Sodium 
100mg 
PO 
BID 
 
constipation 
 
Order 
Dose 
Route 
Frequency 
Start Date 
Indication 
Comments 


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Analgesic 
 
 
 
 
 
 
☐Ibuprofen 
400mg 
PO 
Q6h 
 
Pain 
If intolerance to celecoxib 
☐Morphine 
3mg 
IVP 
Q1h prn 
 
pain 
If intolerance to Hydromorphone.  
Use while NPO. Once tolerating 
liquids, administer for severe pain 
(≥7) 
☐Morphine IR 
7.5-
15mg 
PO 
Q3h 
POD#1 
 
If intolerance to oxycodone.  Once 
tolerating liquids, use for mild to 
moderate pain (<7) 
☐Morphine Sulfate 
Extended Release 
15mg 
PO 
BID 
 
Pain 
If intolerance to oxycodone CR 
Antiemetics 
 
 
 
 
 
 
☐Prochlorperazine 
10mg 
PO 
Q6h prn 
 
Nausea/vomiting  


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Appendix 3: Patient Milestones 
Resident/nursing team: Please mark progress in charts daily.  At discharge, please leave this document with the unit secretary for collection by 
the research team. 
 
 
 
 
 
Post-Operative Day 
Diet 
 
Clear liquids Date    ________   @            am/pm 
Regular Date    ________   @            am/pm 
Activity 
 
To chair Date    ________   @            am/pm 
Independent Ambulation Date    ________   @            am/pm 
Other 
 
Foley removal Date    ________   @            am/pm 
Discharge 
Date    ________   @            am/pm 
 
* If patients are using > 30mg of oxycodone per day pre-operatively, call acute pain service for assistance with management 
 
Patient Sticker