Clinical trial NCT02601027
Conditions: Breast - Female
Sponsor: Stanford University
Start date: 2015-11-01; Completion date: 2021-06-01
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to determine if pre-operative transversus abdominis plane (TAP) nerve blocks by continued infusion of local anesthetic post-operatively affects post-operative narcotic usage, as compared to a placebo TAP block, after breast reconstruction surgery.

Detailed description:
Primary Objective: The primary objective is to determine if pre-operative transversus abdominis plane (TAP) blocks with continued infusion of local anesthetic post-operatively affect post-operative narcotic usage as compared to a placebo TAP block.

Secondary Objectives:

* Determine if pre-operative TAP blocks with continued infusion of local anesthetic post-operatively affect post-operative pain scores as compared to a placebo TAP block.
* Determine if pre-operative TAP blocks with continued infusion of local anesthetic post-operatively affect anti-emetic usage as compared to a placebo TAP block.
* Determine if pre-operative TAP blocks with continued infusion of local anesthetic post-operatively affect time to ambulation post-operatively as compared to a placebo TAP block.
* Determine if pre-operative TAP blocks with continued infusion of local anesthetic post-operatively affect time to first bowel movement as compared to a placebo TAP block.
* Determine if pre-operative TAP blocks with continued infusion of local anesthetic post-operatively affect patient-reported quality of life as compared to a placebo TAP block.

Arms: arm 1: 0.125% bupivacaine infusion via transversus abdominis plane (TAP) catheter arm 2: Saline infusion (sham) via transversus abdominis plane (TAP) catheter.
Interventions: intervention 1: Transversus Abdominis Plane (TAP) block intervention 2: Nimbus Infusion Pump IV Administration intervention 3: Bupivacaine infusion intervention 4: Acetominophen intervention 5: Hydromorphone intervention 6: Oxycodone intervention 7: Ondansetron
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None

Protocol documents:
Prot_SAP_000.pdf: 
NCT02601027




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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS .............................................................................................................. 5 
SCHEMA ........................................................................................................................................ 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (EXAMPLE) ....................... 6 
1. OBJECTIVES ......................................................................................................................... 7 
1.1. 
PRIMARY OBJECTIVE ........................................................................................................ 7 
1.2. 
SECONDARY OBJECTIVES ................................................................................................. 7 
2. BACKGROUND ..................................................................................................................... 7 
2.1 
STUDY DISEASE ................................................................................................................ 7 
2.2 
STUDY AGENT/DEVICE/PROCEDURE ................................................................................ 7 
2.3 
RATIONALE ....................................................................................................................... 8 
2.4 
STUDY DESIGN ................................................................................................................. 8 
2.5 
CORRELATIVE STUDIES BACKGROUND ........................................................................... 10 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ........................ 10 
3.1 
INCLUSION CRITERIA ...................................................................................................... 10 
3.2 
EXCLUSION CRITERIA ..................................................................................................... 10 
3.3 
INFORMED CONSENT PROCESS ........................................................................................ 10 
3.4        RANDOMIZATION PROCEDURES ...................................................................................... 10 
3.5 
STUDY TIMELINE ............................................................................................................ 11 
4. TREATMENT PLAN .......................................................................................................... 12 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ................ 13 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 13 
4.3 
ALTERNATIVES ............................................................................................................... 13 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ................. 13 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE ............................................................ 13 
5.2 
AVAILABILITY ................................................................................................................ 16 
5.3 
AGENT ORDERING .......................................................................................................... 16 
5.4 
AGENT ACCOUNTABILITY ............................................................................................... 16 
6. DOSE MODIFICATIONS ................................................................................................... 16 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................. 17 
7.1 
POTENTIAL ADVERSE EVENTS ........................................................................................ 17 
7.2 
ADVERSE EVENT REPORTING ......................................................................................... 17 
8. CORRELATIVE/SPECIAL STUDIES .............................................................................. 17 
8.1 
LABORATORY CORRELATIVE STUDIES ...................... ERROR! BOOKMARK NOT DEFINED. 
9. STUDY CALENDAR ........................................................................................................... 18 
10. MEASUREMENT .............................................................................................................. 19 
10.1  PRIMARY AND SECONDARY OUTCOME MEASURES ......................................................... 19 
10.2  SECONDARY OUTCOME .................................................................................................. 19 
11. REGULATORY CONSIDERATIONS ............................................................................ 20 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL .......................................................................... 20 


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11.2 
DATA AND SAFETY MONITORING PLAN .......................................................................... 21 
11.3 
DATA MANAGEMENT PLAN ............................................................................................ 21 
12. STATISTICAL CONSIDERATIONS .............................................................................. 21 
12.1 
STATISTICAL DESIGN ...................................................................................................... 21 
12.2 
INTERIM ANALYSES ......................................................................................................... 21 
12.3 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS .................................... 21 
12.4 
PRIMARY ANALYSIS ....................................................................................................... 21 
12.5 
SECONDARY ANALYSIS .................................................................................................. 22 
13. REFERENCES ................................................................................................................... 24 
APPENDICES .............................................................................................................................. 25 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST ........ ERROR! BOOKMARK NOT DEFINED. 


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PROTOCOL SYNOPSIS 
In the table below summarize the basic aspects of this research. This is to be used as a quick 
reference guide. Remove any section that is not relevant to the research.  
 
 
TITLE 
A Randomized Double-blinded, Placebo-
Controlled 
Trial: 
Use 
of 
Transversus 
Abdominis Plane (TAP) Block in Breast 
Cancer Patients Undergoing Microsurgical 
Breast Reconstruction with Abdominal Free 
Flap  
STUDY PHASE 
Phase III 
INVESTIGATIONAL 
PRODUCT 
OR 
PROCEDURE 
Pre-operative Transversus Abdominis Plane 
Block with Nimbus Ambulatory Infusion 
System 
PRIMARY OBJECTIVE(S) 
Post-operative narcotic usage 
SECONDARY OBJECTIVE(S) 
i. Post-operative pain scores 
ii. Post-operative anti-emetic usage 
iii. Time to ambulation 
iv. Time to first bowel movement 
v. Patient-perceived quality of life 
TREATMENT SUMMARY 
Two study arms:  
• Intervention: infusion of 0.125% 
bupivacaine through TAP catheter  
• Control: infusion of saline through 
TAP catheter 
SAMPLE SIZE  
128  
 
 




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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
The primary objective is to determine if pre-operative transversus abdominis plane (TAP) blocks 
with continued infusion of local anesthetic post-operatively affect post-operative narcotic usage 
as compared to a placebo TAP block. 
 
1.2. 
Secondary Objectives 
 
 
1.2.1 To determine if pre-operative TAP blocks with continued infusion of local anesthetic 
post-operatively affect post-operative pain scores as compared to a placebo TAP block. 
 
1.2.2 To determine if pre-operative TAP blocks with continued infusion of local anesthetic 
post-operatively affect anti-emetic usage as compared to a placebo TAP block. 
 
1.2.3 To determine if pre-operative TAP blocks with continued infusion of local anesthetic 
post-operatively affect time to ambulation post-operatively as compared to a placebo TAP block. 
 
1.2.4  To determine if pre-operative TAP blocks with continued infusion of local anesthetic 
post-operatively affect time to first bowel movement as compared to a placebo TAP block. 
 
1.2.5  To determine if pre-operative TAP blocks with continued infusion of local anesthetic 
post-operatively affect patient-reported quality of life as compared to a placebo TAP block. 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
Patient enrolled in our study with have a known or presumed diagnosis of breast cancer or are 
pursuing prophylactic treatment for which they are undergoing post-mastectomy breast 
reconstruction with abdominal free flap. 
 
2.2 
Study Agent/Device/Procedure 
2.2.1  Nimbus Ambulatory Infusion System: 
 
Product Description: 
• Adjustable volume to be infused (VTBI), variable basal rate and bolus delivery 
• Single patient use. 
The Nimbus Ambulatory Infusion System is capable of carrying: 
• Time stamped infusion parameters 
• Incidences of bolus requests vs. bolus delivered 
 
2.2.2 Transversus abdominis plane (TAP) block 
 


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The transversus abdominis plane (TAP) block is a peripheral nerve block that targets nerve roots 
T6 to L1, which innervate the anterior abdominal wall. The block is placed by administering 
local anesthetic into the fascial plane between the internal oblique muscle and the transversus 
abdominis muscle.1, 2 TAP blocks have previously been show to improve immediate post-
operative patient comfort and reduce post-operative narcotic usage in a variety of other 
abdominal surgeries including abdominoplasty, laparotomy, and cesarean section.3-7 
 
2.2.3 Bupivacaine (Bupivacaine Hydrochloride) 
 
Bupivacaine hydrochloride is an amide-type local anesthetic metabolized primarily in the liver 
via conjugation with glucuronic acid. Peak levels of bupivacaine in the blood are reached in 30 
to 45 minutes following peripheral nerve block injection, followed by a decline to insignificant 
levels during the next three to six hours. The half-life of Bupivacaine Hydrochloride in adults is 
2.7 hours. When administered in recommended doses and concentrations, Bupivacaine 
Hydrochloride does not ordinarily produce irritation or tissue damage.8 
 
For clinicaltrials.gov compliance 
Both the Nimbus Ambulatory Infusion System and the local anesthetic bupivacaine have been 
FDA approved for use for analgesia in patient in the United States. 
 
2.3 
Rationale 
There are many options for post-mastectomy breast reconstruction including implants, pedicled 
muscle flaps, and free muscle flaps. With the development of advanced microsurgical 
techniques, free abdominal muscle flaps have become a popular option for breast 
reconstruction.9, 10 For these patients, the speed of recovery and hospital length of stay following 
surgery are largely determined by the abdominal flap donor site rather than the breast recipient 
and resection site.9 
 
Successful post-operative analgesia has been reported to decrease the incidence of both 
cardiopulmonary complications, in-hospital mortality, and healthcare costs, and it may also 
contribute to lower odds of death after surgery.11, 12 In addition, when examining factors leading 
to expedited discharge following abdominal-based breast reconstruction surgery, use of a 
multimodal pain regimen was found to be predictive of successful early discharge.13 Though 
post-operative opioids can decrease pain scores, opioids can also lead to adverse side effects 
including sedation, nausea, vomiting, constipation, and respiratory depression.14 Because patients 
undergoing abdominal flap-based breast reconstruction have had abdominal muscle tissue 
manipulation, postoperative vomiting can increases the risk of incisional hernias and other 
surgical complications.  
 
An increasingly utilized option for post-surgical pain management is a pre-operative nerve block 
targeting anesthetic directly to the nerve roots innervating the surgical field. In the setting of 
abdominal flap-based breast reconstruction, a transversus abdominis plane (TAP) nerve block 
accomplishes this goal for the abdominal incision. Several studies have evaluated the TAP block 
in abdominal flap-based breast reconstruction. Hivelin et al. evaluated bilateral ultrasound-
guided TAP block in patients undergoing unilateral deep inferior epigastric perforator (DIEP) 
flap reconstruction and found that patients reported lower pain scores post-operatively and 
demonstrated lower narcotic usage in the first 24 hours, but not in subsequent time periods out to 


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48 hours after surgery. However, in this study only a single injection of local anesthetic was 
given intra-operatively, and this injection was performed by a surgeon in the operating room, 
rather than by an anesthesiologist in the pre-operative waiting area. The duration of block 
placement varied between 18 and 24 minutes, increasing the overall length of time in the 
operating room. In addition, Hivelin et al. only followed patients to 48 hours after 
reconstruction.15 Furthermore, Wheble et al. performed a retrospective review of intra-
operatively placed TAP blocks and found patients receiving the block had a shorter hospital 
length of stay, lower overall morphine usage, and less post-operative nausea and vomiting. 
However, this was a retrospective study with a small number of patients in each group (12 in the 
TAP group, and 15 in the non-TAP group).16 
 
In addition, Zhong et al. conducted a prospective cohort study with TAP block catheters placed 
intra-operatively under direct visualization of fascial planes, and the anesthetic infusions 
continued until post- operative day 3. Zhong et al. compared this group of patients to a 
retrospective cohort from the same institution and found that patient who received TAP blocks 
had significantly less opioid usage than those who did not.17 The group conducted a subsequent 
randomized double-blinded controlled trial with TAP catheters placed under direct vision, this 
time administering either local anesthetic or saline for controls and found similar results.18 
 
A limitation of both studies by Zhong et al. is that patients undergoing both unilateral and 
bilateral reconstruction were combined, as were patients undergoing immediate and delayed 
reconstruction. Given that patients are subjected to twice the surgical insult in bilateral versus 
unilateral reconstruction, combining these patients into one cohort for analysis of post-operative 
pain may confound the results attained. Similarly, in delayed reconstruction, a repeat surgical 
incision is made at the site of the breast, whereas in immediate reconstruction, the same incision 
at the breast is used for both mastectomy and reconstruction.  
 
In our study design, patients undergoing unilateral and bilateral reconstruction will be separated 
for both randomization and statistical analysis. We aim to further elucidate if the specific type of 
surgery changes the efficacy of the pre-operative TAP nerve block.  
 
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
• State the primary purpose for the protocol: 
o Supportive Care: protocol designed to evaluate one or more interventions 
where the primary intent is to maximize comfort, minimize side effects or 
mitigate against a decline in the subject’s health or function.  In general, 
supportive care interventions are not intended to cure a disease.  
•  State the interventional model: 
o Parallel: one of two groups in parallel for duration of study.  
• State the number of intervention arms: 
o Two intervention arms. 
• State whether the study will be masked: 
o Double Blind: both parties unaware of intervention assignment 
• State whether the study is randomized: Yes. 


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• State type of primary outcome or outcome that the protocol is designed to 
evaluate: Efficacy 
 
2.5 
Correlative Studies Background 
There are no planned correlative studies. 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 Refer to the Participant Eligibility Checklist in Appendix A.  
 
3.1 
Inclusion Criteria 
 
3.1.1 Prior diagnosis or presumed diagnosis of breast cancer or undergoing prophylactic 
treatment. 
 
3.1.2 Greater than 18 years old. 
 
3.1.3 Female. 
 
 
3.1.4 Undergoing microsurgical breast reconstruction with abdominal free flap. 
 
 
3.1.5 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria. 
 
3.2.1 True allergy to local anesthetics or opioids. 
 
3.2.2 History of addiction to narcotics within the last 24 months 
 
3.2.3 History of chronic pain on opioids within the last 24 months. 
 
3.2.4 Specific mental health issues such as schizophrenia or bipolar disorder. 
 
3.2.5 Patients who are pregnant.  
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure. 
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.  
 
3.4       Randomization Procedures 
Patients will be randomized within their surgery subtype (unilateral or bilateral) by the Stanford 


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Pharmacy to receive TAP catheters infusing either bupivacaine or saline. Randomization will 
occur using a computer software program to be implemented by the Pharmacy. The anesthetist 
placing the block, the surgeon performing the surgery, the nurses caring for the patient while 
hospitalized, and the research coordinators collecting data will be blinded to the randomization 
status.  
 
 
3.5 
Study Timeline 
Primary Completion: 
The study will reach primary completion approximately 48 months from the time the study opens 
to accrual. 
 
Study Completion: 
The study will reach study completion approximately 52 months from the time the study opens 
to accrual. 


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4. 
TREATMENT PLAN 
 
4.1  
Pre-operative clinic visit 
4.1.1  All patients undergoing microsurgical breast reconstruction for breast cancer with 
abdominal free flap are screened for enrollment. 
4.1.2 Patients meeting inclusion criteria and not meeting exclusion criteria are enrolled. (See 
Appendix A for further details on inclusion and exclusion criteria.) 
4.1.3 Consent forms for study enrollment are signed. 
4.1.4  BREAST-Q19 questionnaire filled out.  
 
4.2  
Hospitalization for reconstructive surgery 
4.2.1  TAP Catheter Placement and Dosing: 
On the day of surgery, bilateral TAP catheters will be placed using ultrasound guidance by the 
anesthesiologist in the pre-operative staging area prior to entering the operating room. Patients in 
the experimental group will receive an infusion of 0.125% bupivacaine and patients in the 
control group will receive an infusion of saline. Both groups will receive the following dosing:  
• Initial bolus of 15mL pre-operatively 
• 10mL bolus q4h intraoperatively with an option of 1-2mL per hour basal rate 
• 10mL bolus q4h post-operatively with an option of 1-2mL per hour basal rate 
TAP catheters will be discontinued on post-operative day (POD) 2, and the time will be 
recorded. 
 
4.2.2 Post-Operative Pain Medication Regimen: 
All patients will be provided with a patient controlled analgesia (PCA) infusion post- operatively 
providing IV hydromorphone. The PCA will be discontinued on POD2. Other pain medications 
available immediately after leaving the operating room will include the following:  
• Acetaminophen IV or PO around the clock, per physician preference 
• IV hydromorphone (dilaudid) 0.5 mg every 4 hours as needed for breakthrough pain, 
with an option to titrate up dose or frequency, per physician preference 
• PO oxycodone 5-10 mg every 3 hours as needed for pain, with an option to titrate up dose 
or frequency, per physician preference 
• Any pre-operative medications may be continued 
 
4.2.3  Post-Operative Anti-Emetic Medication Regimen: 
All patients will have available IV ondansetron (zofran) 4 mg every 4 hours as needed for 
nausea. Patients unable to take ondansetron will be given metocloprmiade (reglan). 
 
4.2.4 Post-Operative Measurements: 


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Patients will be asked to rate their pain level on the Visual Analog Scale (VAS) every 4 hours 
while hospitalized unless they are sleeping. The total dosage of IV hydromorphone administered 
(via both the PCA and the as needed medications for breakthrough pain) will be recorded in 8-
hour periods (midnight to 8am, 8am to 4pm, 4pm to midnight). The use of other pain 
medications, as well as anti-emetic medications, will be recorded in the same 8-hour periods. 
Time to ambulation, time to first bowel movement after surgery, and time to discharge will be 
recorded. 
 
4.2.5 Evaluation for Discharge: 
Patients will be evaluated daily for meeting discharge criteria as per normal Institution guidelines 
that are standard of care for patients undergoing flap-based breast reconstruction. That is, 
discharge criteria for patients on this study are the same as Institutional discharge criteria. 
 
4.3  
Post-operative follow-up (1-6 months post-operatively) 
4.3.1  The post-operative BREAST-Q questionnaire19 will be administered at a clinic visit 1-6 
months after surgery. If the study subject is unable to attend clinic in person during this time 
period, they will be asked to return the post-operative BREAST-Q questionnaire via email or fax. 
If the study subject does not return the post-operative BREAST-Q survey after 3 attempts by 
phone or email, the subject will be considered lost to follow-up and no futher attempts will be 
made to have the patient complete the questionnaire. 
 
4.4 
General Concomitant Medication and Supportive Care Guidelines 
Please refer to Section 4.2 above for details on concomitant medications. 
 
4.5 
Criteria for Removal from Study 
Patients will be removed from the study if the study proves harmful to patient’s health, if there is 
recurrence of cancer during study enrollment, if the patient withdraws consent at any time, 
and/or if the study protocol director deems it necessary to remove the patient from the study for 
any reason. 
 
4.6 
Alternatives 
Sterile surgical technique and precautions will be utilized for placement of each TAP catheter. 
Alternative treatments for patients will include all pain medications offered for post-operative 
pain (detailed in Section 4.2). 
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
Investigational Agent/Device/Procedure   
5.1.1 Nimbus Ambulatory Infusion System 
 
Product Description: 
• Adjustable volume to be infused (VTBI), variable basal rate and bolus delivery 


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• Single patient use. 
• Basal rate 0 – 14 mL/hr. Rate may be titrated during therapy delivery 
• Optional keypad lockout function 
• Kit comes with a pump, fanny pack, 10-day lithium ion battery, Clinician Guide and 
Patient Quick Reference Guide 
 
Nimbus Infusion Pump IV Administration Set: 
 
Product Description: 
• 1 Each 67" (170cm) Long 
• Priming Volume: 3mL (approx.) 
• Fluid path is sterile, non-Pyrogenic 
• One bag spike (1) 
• One Cassette (3) 
• One 1.2 Micron, air-eliminating Filter (4) One Slide Clamp (5) 
• One Male Luer Lock Adaptor (6) 
 
  
 
The Nimbus Ambulatory Infusion System is intended to deliver medications and/or fluids to a 
patient under the direction or supervision of a physician or other certified healthcare provider. 
The device is indicated for subcutaneous, epidural, perineural, and intravenous infusion. 
For the purposes of the Implementation, the Nimbus Ambulatory Infusion System will be 
customized to the Institution protocol presently: 
• Deliver a 15 mL bolus to establish the primary block 
• Deliver a 10 mL auto-bolus every four hours intraoperatively, with the option for 
• a 1 or 2 mL per hour basal rate 
• Deliver a 10 mL per hour auto-bolus post-operatively, with the option for a 1 or 2 mL per 
hour basal rate  
 
The Nimbus Ambulatory Infusion System is capable of carrying: 
• Time stamped infusion parameters 
• Incidences of bolus requests vs. bolus delivered 
to provide Institution with access to infusion history data and patient interactions as a uniquely 
designed data carrier device. 
 
The Nimbus Ambulatory Infusion System is intended to be used in an environment where patient 
care is provided by Healthcare Professionals, i.e. Physicians, Nurses, and Technicians, who will 
determine when use of the device is indicated, based upon their professional assessment of the 


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patient's medical condition. 
 
5.1.2  Transversus abdominis plane (TAP) Nerve Block 
 
The transversus abdominis plane (TAP) nerve block is a peripheral nerve block that targets nerve 
roots T6 to L1, which innervate the anterior abdominal wall. The block is placed by 
administering local anesthetic into the fascial plane between the internal oblique muscle and the 
transversus abdominis muscle.1, 2 TAP nerve blocks have previously been show to improve 
immediate post-operative patient comfort and reduce post-operative narcotic usage in a variety of 
other abdominal surgeries including abdominoplasty, laparotomy, and cesarean section.3-7 
 
5.1.3 Bupivacaine (Bupivacaine Hydrochloride) 
 
As reported on FDA-approved drug products website:  
<http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018053s055lbl.pdf> 
 
“The onset of action with Bupivacaine Hydrochloride is rapid and anesthesia is long lasting. The 
duration of anesthesia is significantly longer with Bupivacaine Hydrochloride than with any 
other commonly used local anesthetic. 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. After injection of Bupivacaine Hydrochloride for caudal, epidural, or peripheral nerve 
block in man, 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. The half-life of 
Bupivacaine Hydrochloride in adults is 2.7 hours. 
Amide-type local anesthetics such as Bupivacaine Hydrochloride are metabolized primarily in 
the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those 
with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type 
local anesthetics. Pipecoloxylidine is the major metabolite of Bupivacaine Hydrochloride. The 
kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary 
excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of 
bupivacaine is excreted unchanged in the urine.  
When administered in recommended doses and concentrations, Bupivacaine Hydrochloride does 
not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.  
Bupivacaine Hydrochloride 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.  
Bupivacaine Hydrochloride is contraindicated in patients with a known hypersensitivity to it or 
to any local anesthetic agent of the amide-type or to other components of Bupivacaine 
Hydrochloride solutions.  
Maximum dosage limit must be individualized in each case after evaluating the size and physical 
status of the patient, as well as the usual rate of systemic absorption from a particular injection 
site. Most experience to date is with single doses of Bupivacaine Hydrochloride up to 225 mg 




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7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
As reported on FDA-approved drug products website:  
<http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018053s055lbl.pdf> 
 
“The most commonly encountered acute adverse experiences which demand immediate counter 
measures are related to the central nervous system and the cardiovascular system. These adverse 
experiences are generally dose related and due to high plasma levels which may result from over 
dosage, rapid absorption from the injection site, diminished tolerance, or from unintentional 
intravascular injection of the local anesthetic solution. In addition to systemic dose-related 
toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal 
or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and 
neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension 
due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad 
extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest 
if untreated. Patients over 65 years, particularly those with hypertension, may be at increased risk 
for experiencing the hypotensive effects of Bupivacaine Hydrochloride. Factors influencing 
plasma protein binding, such as acidosis, systemic diseases which alter protein production, or 
competition of other drugs for protein binding sites, may diminish individual tolerance.”8 
 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse Event 
(AE) to determine whether it is unexpected according to the Informed Consent, Protocol 
Document, or Investigator’s Brochure, and related to the investigation. All Serious Adverse 
Events (SAEs) will be tracked until resolution, or until 30 after the last dose of the study 
treatment.  
 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation. Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the 
IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences. 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
There are no planned correlative studies. 


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9. 
STUDY CALENDAR 
 
   
Pre-Study 
POD 0 POD 1 POD 2 
POD 3-Discharge 
1-6 months post-
operatively 
 
Investigational Treatment 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
TAP catheter  
 
 
 
X 
 
X 
 
X 
 
  
 
PCA 
 
X 
X 
X 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
 
Evaluation for dischargea 
 
X 
X 
X 
X 
 
Pain evaluation 
 
X 
 
X 
 
X 
 
X 
 
X 
 
BREAST-Q questionnaire 
 
X 
 
 
 
 
X 
aPatients will be evaluated daily for meeting discharge criteria and discharged when all criteria are met (detailed in 
Section 4.2.5).


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10. MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
Primary Outcome Measure: Total oral morphine equivalents of narcotic used in first 48 
hours post-operatively after breast reconstruction. 
• Title: Post-operative Narcotic Usage 
• Time Frame: First 48 hours post-operatively.  
• Safety Issue: No 
 
Note: Each outcome measure listed within the protocol will necessitate legally 
required results reporting to clinicaltrials.gov within one year after the completion 
of the primary outcome measure.   
 
10.1  Primary Outcome Measure: Post-operative Narcotic Usage 
10.1.1 Measurement Definition 
Post-operative Narcotic Usage will be measured in total oral morphine equivalents (OME) 
calculated by summing all narcotics used in the first 48 hours post-operatively. 
 
10.1.2 Measurement Methods 
Post-operative Narcotic Usage will be measured by review the patient’s chart and medication 
administration history and totaling all narcotics administered. 
 
10.1.3 Measurement Time Points 
Post-operative Narcotic Usage will be measured in 8-hour time intervals (midnights to 8am, 8am 
to 4pm, 4pm to midnight) while the patient is hospitalized. The primary outcome will evaluate 
total narcotic usage in the first 48 hours post-operatively. 
 
10.2  Secondary Outcome Measure: Post-operative Pain Score 
10.2.1 Measurement Definition 
Post-operative Pain Score is defined using Visual Analog Scale (VAS), a patient reported pain 
score on a scale of 0-10. 
 
10.2.2 Measurement Methods 
Post-operative Pain Score will be measured by asking patient to rate their pain on the VAS. 
 
10.2.3 Measurement Time Points 
Post-operative Pain Score will be measured every 4 hours post-operatively unless the patient is 
sleeping. 
 
10.3 
Secondary Outcome Measure: Post-operative Anti-emetic Usage 
 
10.3.1 Measurement Definition 
Post-operative Anti-emetic Usage is defined as the total amount of IV ondansetron administered 
to a patient during the first 48 hours post-operatively. 


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10.3.2 Measurement Methods 
Post-operative Anti-emetic Usage will be determined by examining the patient’s chart and 
medication administration history. 
 
10.3.3 Measurement Time Points 
Post-operative Anti-emetic Usage will be examined during the first 48 hours post-operatively. 
 
10.4 
Secondary Outcome Measure: Time to Ambulation 
 
10.4.1 Measurement Definition 
Time to Ambulation is defined as the time to the first instance a patient is able to stand up and 
walk a few steps post-operatively.  
 
10.4.2 Measurement Methods 
The time of first ambulation will be recorded by the nurse on shift. Time to Ambulation will be 
calculated from midnight on POD 1. 
 
10.5 
Secondary Outcome Measure: Time to First Bowel Movement 
 
10.5.1 Measurement Definition 
Time to First Bowel Movement is defined as the time to the first instance a patient passes stool 
post-operatively. 
 
10.5.2 Measurement Methods 
The time of first bowel movement will be recorded by the nurse on shift. Time to First Bowel 
Movement will be calculated from midnight on POD 1.  
 
10.6 
Secondary Outcome Measure: Quality of Life 
 
10.6.1 Measurement Definition 
Quality of Life is defined as the calculated score from the BREAST-Q questionnaire.19 
 
10.6.2 Measurement Methods 
Quality of Life will be measured by having the patient fill out the BREAST-Q questionnaire pre-
operatively, as well as post-operatively between 1-6 months after surgery. 
 
10.6.3 Measurement Time Points 
Quality of Life will be measured 1-6 months after surgery. 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 


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to implementation.  The Protocol Director will disseminate the protocol amendment information 
to all participating investigators. 
 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study. The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study: regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
 
11.3 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document treatment outcomes for data analysis.   Case report forms 
will be maintained by Stanford Box account, a secure data storage platform, or in a locked office 
accessible only to the research team. 
 
12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
This study is a randomized double-blind, placebo-controlled clinical trial. 
 
12.1.1 Randomization 
Patients will be randomized within their group (unilateral or bilateral reconstruction) to receive 
either a true TAP catheter or a sham TAP catheter with saline infusion. The Stanford Pharmacy 
will randomize patients into the two groups.  
 
12.2 
Interim analyses 
There are no planned interim analyses. 
 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
If applicable, describe plans for descriptive statistics and exploratory data analysis. 
 
12.4 
Primary Analysis  
Post-operative Narcotic Usage 
 
12.4.1 Analysis Population 
Subjects will be grouped according to laterality of breast reconstruction (i.e., unilateral vs. 
bilateral). Within each group, experiment subjects will be compared to control subjects. A first 


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sensitivity analysis will explore the impact of missing data by replacing missing data with the 
more extreme values that favor the null hypothesis. A second sensitivity analysis will replace 
missing values with an extreme value that favors the alternative hypothesis.  In both cases 
"extreme" is the largest or smallest value as applicable. 
 
12.4.2. Analysis Plan 
Differences between the two arms will be evaluated using an analysis of covariance model. The 
comparison of the two arms will be made adjusting for the variables used in the stratified 
randomization. The primary analysis will be a modified intent-to-treat principle (using recorded 
values where available regardless of compliance). 
 
12.5 
 
Secondary Analysis 
 
12.5.1  
Post-operative Pain Score 
 
12.5.1.1 
Analysis Population 
Subjects will be grouped according to laterality of breast reconstruction (i.e., unilateral vs. 
bilateral). Within each group, experiment subjects will be compared to control subjects. Missing 
data will be dropped, and subjects who were non-adherent to the protocol will be excluded. 
 
12.5.1.2 
Analysis Plan 
Data will be compared between the two groups using a two-tailed t-test.  
 
12.5.2  
Post-operative Anti-emetic Usage 
 
12.5.2.1 
Analysis Population 
Subjects will be grouped by study intervention, with experimental subjects being compared to 
control subjects. Missing data will be dropped, and subjects who were non-adherent to the 
protocol will be excluded. 
 
12.5.2.2 
Analysis Plan 
Differences between the two arms will be evaluated using an analysis of covariance model. The 
comparison of the two arms will be made adjusting for the variables used in the stratified 
randomization.  
 
12.5.3  
Time to Ambulation 
 
12.5.3.1 
Analysis Population 
Subjects will be grouped by study intervention, with experimental subjects being compared to 
control subjects. Missing data will be dropped, and subjects who were non-adherent to the 
protocol will be excluded. 
 
12.5.3.2 
Analysis Plan 
Time to ambulation will be evaluated using a Cox proportional hazards model. The comparison 
of the two arms will be made adjusting for the variables used in the stratified randomization. 
 
12.5.4  
Time to First Bowel Movement 


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12.5.4.1 
Analysis Population 
Subjects will be grouped by study intervention, with experimental subjects being compared to 
control subjects. Missing data will be dropped, and subjects who were non-adherent to the 
protocol will be excluded. 
 
12.5.4.2 
Analysis Plan 
Time to first bowel movement will be evaluated using a Cox proportional hazards model. The 
comparison of the two arms will be made adjusting for the variables used in the stratified 
randomization. 
 
12.5.5  
Quality of Life 
 
12.5.5.1 
Analysis Population 
Subjects will be grouped by study intervention, with experimental subjects being compared to 
control subjects. Missing data will be dropped, and subjects who were non-adherent to the 
protocol will be excluded. 
 
12.5.5.2 
Analysis Plan 
Data will be compared between the two groups using a two-tailed t-test.  
 
12.6  Sample Size 
12.6.1 Accrual estimates  
 
Based on data from prior years of patients undergoing post-mastectomy breast reconstruction, we 
estimate a total of 40 patients will be eligible for study enrollment each year. This number was 
determined by counting the number of patients who underwent eligible surgeries in 2014 at 
Stanford Hospital and Clinics. If study accrual falls short of what is expected, we will apply for 
IRB extension and continue study enrollment until the target sample size is reached. Our target 
sample size is 64 patients in each the experimental and control groups for a total of 128 patients.  
 
 
 
 
 
 
12.6.2 Sample size justification 
The target sample size was determined by the two-tailed t-test power calculation. The estimated 
standard deviation of total oral morphine or equivalents is 20 mg. A difference of 10 mg between 
the two arms is considered clinically relevant. To detect a difference of 10mg of morphine (or 
oral morphine equivalents) between the experimental and control groups with a power of 80%, 
we calculated a target enrollment of 64 patients in each group. The null hypothesis is that the 
experiment and control groups will not have significantly different Post-operative Narcotic 
Usages in the first 48-hour period post-operatively. The alternative hypothesis is that the 
experiment and control groups will have significantly different Post-operative Narcotic Usages 
in the first 48-hour period post-operatively 
 


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13. 
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