Clinical trial NCT04897841
Conditions: Cesarean Section Complications Pain Opioid Use
Keywords: cesarean
Sponsor: University of Wisconsin, Madison
Start date: 2021-10-11; Completion date: 2022-10-13
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study seeks to identify whether the addition of liposomal bupivacaine to regular bupivacaine and saline administered via surgical transversus abdominis plane (TAP) block will reduce the cumulative opioid dose in the first 48 hours after cesarean. 60 women scheduled for cesarean at Unity-Point Health Meriter Hospital in Madison, Wisconsin will be enrolled and can be expect to be on study for up to 6 weeks post-partum.

Detailed description:
The purpose of this study is to determine whether liposomal bupivacaine administered via surgical TAP block at the time of Cesarean delivery will reduce the total dose of opioids received. The hypothesis is that liposomal bupivacaine will reduce the total dose of opioids received in the immediate 48 hours post-delivery.

Secondary outcomes will include participant self-reported pain scores, participant-reported incidence of side effects, and development of objective complications such as dysrhythmias. Other outcomes collected will include length of stay, time to first rescue analgesic medication, total dose of opioids at 12, 24, 36, 72 hours and during the hospital stay, use of supplemental oxygen during hospitalization, breastfeeding rates, both exclusive and in combination with formula use, amount of opioid prescribed at discharge and whether refills were requested or administered, rates of chronic pain at six weeks postpartum, and six week Edinburgh Depression Screen scores. Neonatal outcomes such as fetal weight, five-minute Apgar scores and development of adverse outcomes such as neonatal intensive care unit (NICU) admission will also be collected because NICU admission can impact maternal opioid use.

Primary Objective:

* To determine whether liposomal bupivacaine administered via surgical TAP block at the time of cesarean delivery will reduce the total dose of opioids received in the first 48 hours after surgery.
* Hypothesis: The hypothesis is that liposomal bupivacaine administered via surgical TAP block at the time of cesarean delivery will reduce the total dose of opioids received in the first 48 hours after surgery.
* Developmental Sub Aim: If liposomal bupivacaine administered via surgical TAP block does reduce the total dose of opioids received, to determine the degree of the reduction in order to allow for an adequately powered randomized-controlled trial.

Secondary Objective:

* To determine whether liposomal bupivacaine administered via surgical TAP block at the time of cesarean delivery will reduce patient-reported pain scores and opioid-related side effects, including respiratory compromise.
* Hypothesis: The hypothesis is that liposomal bupivacaine administered via surgical TAP block at the time of cesarean will reduce patient-reported pain scores and opioid related side effects.

Arms: arm 1: The control arm will receive 30 mL of bupivacaine HCl plus 50 mL of saline injected into the lateral transversus abdominis plane via surgical approach (abdominal approach). arm 2: The intervention arm will receive 30 mL of bupivacaine HCl plus 30 mL of saline plus 20 mL of liposomal bupivacaine injected into the lateral transversus abdominis plane via surgical approach (abdominal approach).
Interventions: intervention 1: Liposomal bupivacaine intervention 2: Bupivacaine Hydrochloride intervention 3: saline
Intervention descriptions: intervention 1: 20 mL prior to closing fascia, the active drug (bupivacaine) is encapsulated in a liposomal platform and released slowly over the course of days with an approximate 72 hour duration. intervention 2: 30 mL bupivacaine hydrochloride 0.25 percent, local post-surgical anesthetic intervention 3: post-surgical saline

Protocol documents:
Prot_SAP_000.pdf: 
Obstetric Liposomal Bupivacaine Via Surgical Transversus Abdominis Plane Block for Post Cesarean 
Pain
Control: a Single-blind Pilot Randomized Controlled Trial
NCT04897841
PI: Kathleen Antony, MD, MSCI
Version Date 9/11/2022


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Obstetric Liposomal Bupivacaine via Surgical Transversus 
Abdominus Plane Block for Post Cesarean Pain Control:  
a single-blind pilot randomized controlled trial 
 
The OBstetric Liposomal Bupivacaine Trial  
(ObLiBupi Trial) 
 
Protocol Number: UnityPoint Health-Meriter IRB#: 2021-005 
Principal Investigator: Kathleen M. Antony, MD, MSCI 
 
 
 
This document is confidential. 
No part of it may be transmitted, reproduced, published, or used by other persons without prior 
authorization from the Sponsor or Principal Investigator. 
 
 
 
 
 
 
Protocol Version History 
Protocol Version 
Version Date 
Brief description of protocol modification/actions requested, if any 
Version 1.7 
06/20/2021 
***Do not update version # until final draft*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1. 
Statement of Compliance ................................................................................................................................................. 4 
2. 
List of Abbreviations ......................................................................................................................................................... 5 
3. Study Summary ................................................................................................................................................................... 6 
3.1 Synopsis ........................................................................................................................................................................ 6 
4. Key Roles ............................................................................................................................................................................ 9 
5. Introduction ....................................................................................................................................................................... 10 
5.1 Background ................................................................................................................................................................. 10 
5.2 Rationale ..................................................................................................................................................................... 12 
6. Study Objectives and Endpoints ....................................................................................................................................... 13 
6.1 Objectives .................................................................................................................................................................... 13 
6.2 Endpoints ..................................................................................................................................................................... 14 
7. Study Design ..................................................................................................................................................................... 15 
7.1 General Design ............................................................................................................................................................ 15 
7.2 End of Study Definition ................................................................................................................................................ 16 
8. Subject Selection .............................................................................................................................................................. 16 
8.1 Target Study Sample Size ........................................................................................................................................... 16 
8.2 Inclusion Criteria .......................................................................................................................................................... 16 
8.3 Exclusion Criteria ......................................................................................................................................................... 17 
8.4 Recruitment ................................................................................................................................................................. 18 
8.5 Retention Strategies .................................................................................................................................................... 18 
8.6 Early Termination and Withdrawal .............................................................................................................................. 18 
9. Study Intervention ............................................................................................................................................................. 18 
9.1 
Study Intervention Description .............................................................................................................................. 18 
9.2 Source ......................................................................................................................................................................... 19 
9.3 Packaging and Labeling .............................................................................................................................................. 19 
9.4 Preparation .................................................................................................................................................................. 20 
9.5 Storage and Stability ................................................................................................................................................... 20 
9.6 Accountability .............................................................................................................................................................. 20 
9.8 Randomization and Blinding ........................................................................................................................................ 23 
9.9 Study Intervention Compliance ................................................................................................................................... 24 
9.10 Concomitant Therapy ................................................................................................................................................ 25 
9.11 FDA IND Compliance ................................................................................................................................................ 25 
10. Study Visits and Procedures ........................................................................................................................................... 26 
10.1 Study Calendar .......................................................................................................................................................... 26 
10.2 Screening and Enrollment ......................................................................................................................................... 26 
10.3 On-Study/Follow-up Activities ................................................................................................................................... 31 
10.4 Unscheduled Visits .................................................................................................................................................... 32 
10.5 Early Termination and Withdrawal ............................................................................................................................ 32 


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11. Data Collection, Handling and Record Keeping ............................................................................................................. 33 
11.1 Data Collection .......................................................................................................................................................... 33 
11.2 Record Retention ....................................................................................................................................................... 33 
11.3 Handling of Data to Ensure Confidentiality................................................................................................................ 33 
11.4 Data collection forms ................................................................................................................................................. 34 
11.5 Data Confidentiality ................................................................................................................................................... 34 
11.6 Records Retention ..................................................................................................................................................... 34 
12. Assessment of Safety ..................................................................................................................................................... 35 
12.1 Risk/Benefit Assessment ........................................................................................................................................... 35 
12.2 Unanticipated Findings .............................................................................................................................................. 35 
12.5 Adverse Event (AE) Definition ................................................................................................................................... 36 
12.6 Serious Adverse Event (SAE) Definition ................................................................................................................... 36 
12.7 Documenting and Reporting of AEs, SAEs & Ups .................................................................................................... 37 
12.8 Stopping Rules .......................................................................................................................................................... 38 
13. Study Analysis ................................................................................................................................................................. 38 
13.1 Statistical Hypothesis ................................................................................................................................................ 38 
13.2 Sample Size Justification........................................................................................................................................... 39 
13.3 Statistical Methods .................................................................................................................................................... 39 
13.4 Planned Interim Analysis ........................................................................................................................................... 39 
14. Regulatory, Ethical, and Study Oversight Considerations .............................................................................................. 40 
14.1 Safety Oversight ........................................................................................................................................................ 40 
14.2 Protocol Deviations .................................................................................................................................................... 40 
14.3 Publication Plan ......................................................................................................................................................... 40 
References ............................................................................................................................................................................ 41 
 
 
 
 


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1. Statement of Compliance 
 
The signature below constitutes that the research will be conducted in accordance with the approved protocol, 
applicable regulations, guidelines, laws and institutional policies.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitment.  
 
 
 
 
PRINTED OR TYPED NAME 
 
 
 
SIGNATURE 
 
 
 
DATE 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
 


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2. List of Abbreviations 
 
AE 
Adverse event 
ANOVA 
Analysis of variance 
CFR 
Code of Federal regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CoC 
Certificate of Confidentiality 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data & Safety Monitoring Board  
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data & Safety Monitoring Plan 
DMC 
Data Monitoring Committee 
EDC 
Electronic Data Capture 
HER 
Electronic Health Record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH E6 
International Council on Harmonisation Guidance for Industry, Good Clinical Practice: Consolidated 
Guidance 
ICTR 
Institute for Clinical and Translational Research 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
OHRP 
Office for Human Research Protections 
Ob/Gyn 
Department of Obstetrics and Gynecology 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PRC 
Pharmaceutical Research Center 
QA 
Quality Assurance 
QC 
Quality Control 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SRC 
Scientific Review Committee 
UP 
Unanticipated Problem 
 
 
 


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3. Study Summary 
3.1 Synopsis 
Title 
Obstetric Liposomal Bupivacaine via Surgical Transversus Abdominus 
Plane Block for Post Cesarean Pain Control: Single Blind RCT 
Protocol Number 
UnityPoint Health-Meriter IRB#: *** 
ClinicalTrials.gov 
Identifier  
ClinicalTrials.gov Identifier: *** 
Number of Site(s) 
Single center 
Main Inclusion 
Criteria 
o Singleton or multifetal pregnancy  
o Able to receive neuraxial analgesia 
o Planned/ scheduled Cesarean delivery OR non-urgent Cesarean 
delivery with adequate time to consider and consent to the study 


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Main Exclusion 
Criteria 
o Known hypersensitivity to bupivacaine (defined as a history of a reaction or 
allergy to bupivacaine (injectable, intravenous, or transdermal) reported by 
patient or documented in the medical record 
o Contraindication to regional analgesia 
o Positive urine drug screen at admission to the hospital, if ordered for clinical 
purposes. 
o Current opioid use or opioid use disorder per patient report or documented in the 
medical record 
o Chronic opioid use or opioid use disorder, either patient reported or documented 
in the medical record, defined as opioid use on most days for >3 months 
o Planned cesarean hysterectomy (excluded due to anticipated blood loss and 
alternative pain control measures, possible prolonged intubation) 
o Planned vertical midline incision (excluded due to possible different postpartum 
pain) 
o Presence of renal dysfunction precluding the use of NSAIDs (NSAIDs are part 
of the usual postpartum pain regimen/ hospital protocol) per discretion of the 
treating physician or PI 
o Ischemic heart disease, congestive heart failure, or cardiomyopathy of 
pregnancy precluding the use of NSAIDs (NSAIDs are part of the usual 
postpartum pain regimen/ hospital protocol) per discretion of the treating 
physician or PI 
o Significant liver dysfunction precluding the use of acetaminophen 
(acetaminophen is part of the usual postpartum pain regimen/ hospital 
protocol) per discretion of the treating physician or PI 
o Coagulopathy 
o Planned discharge from the hospital less than 48 hours postpartum 
o Unable to receive post-operative scheduled acetaminophen for any reason, 
such as allergy to acetaminophen or elevated liver function tests precluding 
acetaminophen use 
o Unable to receive post-operative scheduled NSAIDs for any reason, such as 
allergy to ketorolac or ibuprofen, or renal dysfunction precluding NSAID use 
o Seizure disorder: Specifically, poorly controlled seizure disorder defined as 
having had a seizure within the last three years despite antiepileptic use or 
poorly managed seizure disorder due to medication non-compliance.  
o Cardiac disease or arrhythmia: Defined as ischemic heart disease, 
peripartum cardiomyopathy, heart failure (with reduced or preserved ejection 
fraction, compensated or decompensated). Patients with a remote history of 
non-cyanotic pediatric cardiac surgery (like a VSD closure or PDA ligation as a 
child) do not need to be excluded. History of adult cardiac surgery without 
ongoing problems or treatments other than chronic anticoagulation (mitral valve 
repair for MVP or aortic valve replacement for bicuspid aortic valve for 
example) would not need to be excluded. History of repaired congenital 
cyanotic heart disease should be considered for exclusion, ultimately up to the 
anesthesiologist that day. A patient with a history of arrhythmias not requiring 
medication or ablation would NOT need to be excluded and could be included 
in the study. History of ablation or active anti-arrhythmic medication should be 
considered for exclusion.  
o Hypoxia: Defined as requiring supplemental oxygen during the day. 
o Acidosis. This will be uncommon in our population, but if someone has active 
diabetic ketoacidosis will exclude.  


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Primary Objective 
To reduce the total dose of opioids received in the first 48 hours post-op after 
cesarean delivery. All opioid doses will be converted into oral morphine equivalents 
for standardization purposes 
Study Design 
This study will be a single-center, single blind, randomized controlled trial. The 
study will be conducted at UnityPoint-Health Meriter Hospital under investigators 
from the University of Wisconsin-Madison. Obstetric patients undergoing scheduled 
Cesarean delivery at UnityPoint-Health Meriter will be eligible. 
Study Intervention 
The control arm will receive 30 mL of bupivacaine HCl plus 50 mL of saline injected 
into the lateral transversus abdominus plane via surgical approach (abdominal 
approach).  
The intervention arm will receive 30 mL of bupivacaine HCl plus 30 mL of saline 
plus 20 mL of liposomal bupivacaine injected into the lateral transversus 
abdominus plane via surgical approach (abdominal approach).  
Total Number of 
Subjects 
60 Subjects 
Study Population 
Pregnant women undergoing scheduled cesarean delivery 
Statistical 
Methodology 
The primary outcome of total opioid dose (in OME) will be compared via Student’s t-
test or Mann-Whitney U test if the distribution is non-normally distributed, and 
additional outcomes will be assessed via Student’s t-test, Chi-squared, or non-
parametric tests, as appropriate. Statistics will be performed by Scott Hetzel.  
Estimated 
Enrollment Period 
24 months from initial subject enrollment 
Estimated Study 
Duration 
24 months from initial subject enrollment 
 
 
 
 


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4. Key Roles 
The following is a list of all key personnel and roles: 
 
Principal Investigator
 
 
Kathleen M. Antony, MD, MSCI 
Department of Obstetrics & Gynecology 
Division of Maternal-Fetal Medicine 
University of Wisconsin School of Medicine and Public Health 
1010 Mound Street, 4th Floor, MFM 
Madison, WI 53715 
kantony@wisc.edu 
Tel: 608-417-6099 
Fax: 608-417-4270 
UnityPoint Health-Meriter Hospital, Madison, WI 
 
Participating Site(s) 
UnityPoint Health, Meriter Hospital 
202 S. Park Street, Madison, WI 53715 
Co-Investigator(s) 
Luther Gaston, MD 
Division of Academic Specialists in General Obstetrics and Gynecology 
1010 Mound Street, 4th Floor, MFM 
Madison, WI 53715 
UnityPoint Health-Meriter Hospital, Madison, WI 
 
Ryan McDonald, MD 
Division of Academic Specialists in General Obstetrics and Gynecology 
1010 Mound Street, 4th Floor, MFM 
Madison, WI 53715 
UnityPoint Health-Meriter Hospital, Madison, WI 
Medical Monitor 
To be determined. 
 
Data and Safety 
Monitoring Board 
Contact 
To be determined. 
 
Funding Sponsor 
Meriter Foundation 
Funding Point of 
Contact 
Kathleen M. Antony, MD, MSCI (above) 
kantony@wisc.edu 
 
Lisa Grady 
lgrady@wisc.edu 
Biostatistician 
Scott Hetzel, MS 
Biostatistics and Medical Informatics 
207G WARF  
hetzel@biostat.wisc.edu 
608-265-4311 
 


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5. Introduction 
 
5.1 Background  
Cesarean birth is the most common major surgical procedure performed in the United States, with rate of 
about 31.9% of deliveries.(1) Pain management following cesarean birth involves a combination of opioid and 
non-opioid analgesia. Prescription opioid abuse and dependence has increased rapidly in the United States 
over the past two decades, with a four-fold increased rate of unintentional overdose using prescription opioids 
from 2000-2010.(2) 
 
An evaluation by the Centers for Disease 
Control and Prevention found that many 
patients become addicted to opioids following 
treatment of acute pain, including after 
cesarean delivery.(3,4) Between 1 in every 50 
and 1 in every 300 women undergoing 
cesarean delivery become chronic opioid 
users.(4,5) If this rate holds true for women 
delivering 
at 
UnityPoint 
Health-Meriter, 
between 4 and 27 women delivering at Meriter 
would potentially become chronic opioid users 
every year. Women delivering at UnityPoint 
Health-Meriter also use more opioids in the 
immediate postpartum period than women 
delivering elsewhere in this country. During 
2016-2017, 
the 
per-woman 
average 
cumulative oral morphine milligram equivalent 
(MME) dose in the first 24 hours postpartum 
for opioid-naive women undergoing cesarean 
delivery was 104.4 mg. Based upon this high 
cumulative opioid dose, a standardized 
analgesia regimen was created in 2018 which 
prioritized scheduled acetaminophen and 
nonsteroidal 
anti-inflammatory 
drugs 
(NSAIDs). 
After 
this 
protocol 
was 
implemented, 
the 
per-woman 
average 
cumulative MME dose was reduced to 82.1 
mg in the first 24 hours postpartum. While 
successful at reducing the cumulative MME 
dose, the dose of 82.1 mg MMEs within the 
first 24 hours postpartum exceeds the opioid 
dose used by other institutions with a range of 
MMEs in the literature of 2.5-35 mg.(6–9)  
 
Efforts to reduce opioid exposure postoperatively may reduce the potential for addiction. There is a nationwide 
opioid crisis, and the Madison community is no exception; any intervention to decrease future opioid use 
disorder is of interest to the healthcare community. For the purpose of this protocol, the term “opioids” refers 
to both natural opiates such as morphine and codeine and synthetic opioids, such as fentanyl. The rate of 
respiratory events is related to the total opioid dose,(10) so efforts to decrease the total dose may decrease 
the frequency of such events.  
 
0
20
40
60
80
100
120
Meriter
2016-2017
Meriter Q3
2018-2019
Other
institution,
Cincinnati
Other
institution,
California
Multi-site
study
Multi-site
study
Average MME used first 24 hours post-
cesarean


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In order to address the high cumulative MME dose received by postpartum women delivering at UnityPoint 
Health-Meriter Hospital, we have formed a committee to create an enhanced recovery after surgery protocol 
which is a multimodal approach to pain control. This multipronged approach incorporates patient educational 
videos and handouts with nursing education and has representatives from nursing, nursing leadership, the 
obstetrical residency program, pharmacy, the anesthesia department, nutrition, and information technology. 
We have formed such a group at Meriter aimed at enhancing recovery after cesarean surgery (ERACS) and 
we are developing an evidence based protocol to achieve these aims.   
 
However, the experience of other institutions has shown that, while 
these efforts reduce cumulative MME dose, even with these ERACS 
protocols in place that there is additional benefit to the use of 
liposomal 
bupivacaine 
when 
administered 
via 
transversus 
abdominus plane (TAP) block. The rationale for additional benefit of 
bupivacaine via TAP block is because neuraxial morphine (one 
portion of the ERACS protocol) has effect up to 12-24 hours whereas 
liposomal bupivacaine has effect up to 72 hours. A TAP block 
comprises of injection of local anesthesia into the plane between the 
internal oblique muscle and transversus abdominis muscle in the 
area of the iliohypogastric and ilioinguinal nerves (Figure).  
 
 
Liposomal bupivacaine is a long-acting local anesthetic which is FDA approved for single dose infiltration into 
a surgical site or for nerve blocks. With liposomal bupivacaine, the active drug (bupivacaine) is encapsulated 
in a liposomal platform and released slowly over the course of days with an approximate 72 hour duration.(11)  
One prior retrospective study conducted in a center with a fully implemented obstetrical enhanced recovery 
after surgery protocol already in place found that when they added liposomal bupivacaine administered via 
transversus abdominus plane (TAP) block, they found a 47% reduction in total post-cesarean opioid 
consumption, a 46% reduction in pain scores, and a decreased length of hospital stay from 4.3 days to 3.1 
days (P <0.001).(12) As noted, this center already had implemented intrathecal morphine, scheduled 
acetaminophen and NSAIDs, and other components that we are aspiring to add to our multimodal enhanced 
recovery after cesarean protocol. Thus, the benefit they demonstrated to the liposomal bupivacaine TAP 
block was in addition to an existing enhanced recovery after surgery protocol. More recently, a 
randomized controlled trial utilizing liposomal bupivacaine as the intervention in addition to regular bupivacaine 
and intrathecal morphine (in both the intervention and control arm) found a 51.6% reduction in opioid use in 
the first 72 hours after cesarean (P=0.0002) and also found that 54% of women in the intervention arm used 
less than 15 mg of MME total compared to 24.7% in the control arm (P=0.0012).(9) 
 
TAP plane blocks via the usual anesthesia-administered technique, however, require placement by an 
anesthesiologist.(13) The anesthesiologist needs specialized training, and ultrasound guidance is required to 
ensure proper placement.(13) Placement by the anesthesia team with ultrasound guidance carries the risk of 
complications such as inadvertent peritoneal penetration and bowel injury.(12,14–16) Placement of this block 
is also more challenging in the setting of obesity,(17) and 60% of the patients undergoing cesarean birth at 
UnityPoint Health-Meriter have obesity.  
 
Therefore, a surgical, or abdominal, approach to the transversus abdominus plane block has been proposed. 
In 2011 Owen et al. piloted this approach on 16 women undergoing cesarean delivery.(15) They used 0.5% 
bupivacaine and fentanyl and found their surgical TAP block decreased the average 24 hour MME from 23.4 
mg to 14.1 mg and increased the time to the first request for opioid medications.(15) Thus, the surgical 
approach to TAP block was effective. An RCT then compared surgeon-administered TAP block compared to 
anesthesiologist-placed TAP block and found no significant differences in opioid consumption or pain scores, 
therefore, the mode of administration does not appear to impact the efficacy of the block.(14) The RCT 


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comparing surgeon-administered TAP block to anesthesiologist-administered TAP block also found the time 
was significantly less for the surgeon-administered TAP block (2.4 minutes versus 12.1 minute, P <0.001) and 
the time spent in the operating room was also significantly lower (55.3 versus 77.9 minutes, P <0.001).(14) 
Finally, the patient satisfaction with pain scores was not different (satisfaction 7.8 with surgical TAP versus 6.7 
with conventional TAP, P 0.11).(14) Finally, a study that sought to assess the feasibility of surgical TAP block 
on a larger scale found that the procedure was safe, easy, and effective and did not require any specialized 
equipment.(16) So placement of the TAP block via a surgical or abdominal approach by the obstetrical-surgeon 
is feasible, equally effective, and faster than placement by the anesthesia team. However, the studies 
demonstrating the effectiveness of this approach used bupivacaine or ropivacaine, both of which have a 
relatively short duration of action. Additionally, none of these three studies utilized intrathecal (neuraxial) 
morphine.(14–16)  
 
Intrathecal, or neuraxial, morphine is a long acting spinal anesthetic with efficacy up to 24 hours after spinal 
injection.(18) The effect of neuraxial morphine would be expected to exceed the effect of regular bupivacaine 
which has an effect up to 7 hours.(19) Therefore, only liposomal bupivacaine would be expected to have an 
ongoing effect after the effect of neuraxial morphine has worn off.  
 
There is a strong interest in reducing post-cesarean opioid consumption at our institution. Collaborators in the 
department of anesthesia, nurses, and the pharmacy are all committed to reducing opioid consumption, 
particularly given the risk of post-operative respiratory depression related to opioid use. The rate of moderate 
to severe respiratory compromise at our institution is 184/10,000 deliveries compared to 1.6/10,000 in the 
general obstetrical population. This is 112-fold higher than reported in the literature.(20) In our population we 
found the risk of respiratory compromise to be higher among women using more opioids.(20) If successful, 
this project will decrease post-operative opioid use and may therefore reduce post-operative respiratory 
morbidity and opioid exposure leading to future addiction. Future efforts will focus on continuing to reduce 
opioid use in our post-cesarean population.  
 
This study will be conducted in compliance with this protocol, good clinical practice, and under the supervision 
of the Meriter Institutional Review Board (IRB). The population studied will include pregnant women who are 
at least 18 years old who are pregnant who will be delivered via cesarean delivery at UnityPoint Health-Meriter 
Hospital. This study will also not start until the multidisciplinary obstetrical enhanced recovery after cesarean 
surgery (ERACS) protocol is completed and fully operational and implemented to reduce confounding by pre 
and post-protocol implementation on patient pain and opioid use.  
 
5.2 Rationale 
The current standard of care for post-Cesarean pain control consists of a combination of opioids and non-
steroidal anti-inflammatory analgesics, such as ibuprofen. Patients can become addicted to opioids following 
treatment of acute post-Cesarean pain and are acutely at risk of moderate to severe respiratory 
compromise.(3,4) The rate of respiratory events is related to the total opioid dose, efforts to decrease the 
opioid dose may decrease the frequency of such events. (10) Reducing the opioid dose may also reduce the 
risk of addiction. There are many ongoing completed and ongoing studies nationwide seeking to reduce post-
cesarean opioid use, some of which could be integrated into practice once completed.(8)  
 
This study seeks to identify whether the addition of liposomal bupivacaine to regular bupivacaine and saline 
administered via surgical TAP block will reduce the cumulative opioid dose in the first 48 hours after 
cesarean. The liposomal bupivacaine and control arm (bupivacaine plus saline) will both also receive the 
current standard of care, which at UnityPoint Health-Meriter consists of scheduled NSAIDs, acetaminophen, 
and “rescue” opioids. This study will also be started after the enhanced recovery after cesarean (ERAC) 
protocol has started and therefore all women will have received intrathecal or neuraxial morphine.  
 


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This study is novel in its surgical approach to the TAP block which has not previously been performed in 
women receiving intrathecal morphine and also is novel in that it will be using liposomal bupivacaine. The 
average BMI of our cesarean delivery population is also higher than reported in the existing investigations 
utilizing surgical TAP block, thus while we are not specifically targeting women with obesity, our study will 
likely include a significant proportion of women with obesity.(14–16) 
 
If successful, this pilot randomized controlled trial will be used to justify a larger randomized controlled trial. 
The effect size found via this pilot will be used to ensure that the larger randomized controlled trial will be 
adequately powered. If that second trial successfully demonstrates that surgical TAP block with liposomal 
bupivacaine indeed reduces post-cesarean opioid use, pain, and length of stay compared to women 
receiving regular bupivacaine, then a cost-benefit analysis will be performed and it may be considered for 
more routine use at UnityPoint Health-Meriter and possibly elsewhere.  
 
Bupivacaine is safe to use in the immediate peripartum and postpartum period. However, it does have risks. 
Bupivacaine is highly potent and lipid soluble and can cause central nervous system toxicity.(11) Giving higher 
doses of bupivacaine HCl (regular bupivacaine) in hopes of prolonging anesthesia can be harmful.(11) In 
contrast, liposomal bupivacaine has lower maximum plasma concentrations compared to an equivalent dose 
of bupivacaine, thus allows for a longer duration of effect without increasing plasma concentrations.(11) 
Several publications utilizing regular bupivacaine for injection into the cesarean incision, for incision 
infiltrations, and for TAP blocks. These studies have demonstrated its safety when used in the operating room 
and with lasting effect into the immediate postpartum period.(13,16,21–26) Its safety has also been 
demonstrated with lactation.(27) Liposomal bupivacaine has also been demonstrated to be safe when injected 
into the cesarean incision and when utilized for TAP block.(9,12,28,29)  
 
For the purpose of this study, the control arm and intervention arm will receive the following medications via 
surgical TAP block:  
Control Arm 
Intervention Arm 
30 mL bupivacaine HCl 0.25% 
50 mL saline 
 
 
Total: 80 mL  
Inject 40 mL on each side 
30 mL bupivacaine HCl 0.25% 
30 mL saline 
20 mL (266 mg) liposomal bupivacaine  
 
Total: 80 mL 
Inject 40 mL on each side 
 
These injections will be performed once during this surgery itself. Because liposomal bupivacaine has a hazy 
appearance and is not clear due to the presence of liposomes, this study will be single blind as there is no 
equivalent appearing control.   
 
6. Study Objectives and Endpoints 
 
6.1 Objectives 
The purpose of this study is to determine whether liposomal bupivacaine administered via surgical TAP block 
at the time of Cesarean delivery will reduce the total dose of opioids received. Our hypothesis is that 
liposomal bupivacaine will reduce the total dose of opioids received in the immediate 48 hours post-delivery.  
 
Secondary outcomes will include  
• 
patient self-reported pain scores. 
• 
patient-reported incidence of side effects. 
• 
development of objective complications such as dysrhythmias.  


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• 
Percentage of postpartum people who are "opioid free" at each timepoint (12, 24, 48, 72 hours, and 
during the hospitalization) with “Opioid free” defined as not receiving any opioid medication after 
surgery.  
Percentage of postpartum people who are “Opioid spared” at each timepoint (12, 24, 48, 72 hours, and 
during the hospitalization) with "Opioid spared" defined a priori as taking ≤15 mg oral morphine equivalent 
dose at that timepoint after surgery 
Other outcomes collected will include: 
• 
length of stay 
• 
time to first rescue analgesic medication 
• 
total dose of opioids at 12, 24, 36, 72 hours and during the hospital stay 
• 
use of supplemental oxygen during hospitalization 
• 
breastfeeding rates, both exclusive and in combination with formula use 
• 
amount of opioid prescribed at discharge and whether refills were requested or administered 
• 
rates of chronic pain at six weeks postpartum 
• 
six week Edinburgh Depression Screen scores 
• 
% subjects who use 0 MME in each group for each time period  
• 
% subjects who used 15 MME or less 
• 
% subjects who report pain score of 7 or higher at each time point 
 
Neonatal outcomes such as fetal weight, five-minute Apgar scores and development of adverse outcomes 
such as NICU admission will also be collected because NICU admission can impact maternal opioid use.  
 
6.1.1 Primary Objective: 
• 
To determine whether liposomal bupivacaine administered via surgical TAP block at the time of 
cesarean delivery will reduce the total dose of opioids received in the first 48 hours after surgery.  
• 
Hypothesis: Our hypothesis is that liposomal bupivacaine administered via surgical TAP block at the 
time of cesarean delivery will reduce the total dose of opioids received in the first 48 hours after 
surgery.  
• 
Developmental SubAim: If liposomal bupivacaine administered via surgical TAP block does reduce 
the total dose of opioids received, to determine the degree of the reduction in order to allow for an 
adequately powered randomized-controlled trial. 
 
6.1.2 Secondary Objective:  
• 
To determine whether liposomal bupivacaine administered via surgical TAP block at the time of 
cesarean delivery will reduce patient-reported pain scores and opioid-related side effects, including 
respiratory compromise.   
• 
Hypothesis: Our hypothesis is that liposomal bupivacaine administered via surgical TAP block at the 
time of cesarean will reduce patient-reported pain scores and opioid related side effects.  
 
6.2 Endpoints 
 
6.2.1 Primary Endpoint: 
• 
The primary endpoint or primary objective is to reduce the total dose of opioids received in the first 48 
hours post-op after cesarean delivery. All opioid doses will be converted into oral morphine equivalents 
for standardization purposes.  
 
6.2.2 Secondary Endpoint(s): 
• 
Median postoperative pain score for the first 24 hours post-operatively measured by the Numeric 
Rating Scale (NRS) which rates pain on a 0-10 scale, collected routinely on the postoperatively floor 
by nurses as per their standardized routine. UnityPoint Meriter’s Assessment of the Postpartum Patient 


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Standard of Care Document #29 (UnityPoint-Health Meriter Nursing Policy Document) states that pain 
assessment documentation should be done every shift and before and after giving pain medication to 
ensure that patients are getting adequate relief. Thus, pain will be assessed approximately every 4-6 
hours. This outcome, therefore, will be recorded from the EMR.  
• 
Maximum and minimum pain scores every 6 hours throughout the whole hospital stay as measured 
by the NRS above extracted manually from the electronic health record.  
• 
Frequency of patient-reported opioid-related side effects, such as pruritis, constipation, nausea, and 
mental clouding.  
• 
Incidence of complications of bupivacaine, such as local burning, nausea, dizziness, drowsiness, 
serious skin reactions such as blistering, confusion, blurred vision, ringing in the ears, arrhythmias, 
methemoglobinemia, and allergies and hypersensitivities. 
• 
Post-operative anti-emetic use and number of recorded episodes of emesis. 
• 
Return of bowel function (measured in hours from completion of surgery to passage of flatus) 
• 
Length of hospital stay, measured in hours from admission to time of discharge order placement 
• 
Time to first rescue analgesic medication, measured in minutes from arrival in the post-anesthesia 
care unit (PACU) until the first as needed opioid dose is administered 
• 
Total dose of opioids used in the first 48 hours post-operatively. All opioid doses will be converted into 
oral morphine equivalents.  
• 
Total dose of opioids during the whole hospitalization. All opioid doses will be converted into oral 
morphine equivalents. 
• 
Postoperative complications, such as urinary tract infections, thromboembolic events, pneumonia, 
postpartum blood transfusions, falls, myocardial infarctions. 
• 
Amount of opioid prescribed at discharge, measured as both the number of pills and the dose of 
opioids.  
• 
Routine obstetric/ maternal outcomes will be collected. 
• 
Neonatal outcomes, including Apgar scores, NICU admission and reason, birthweight, gestational age 
at delivery, and other routine neonatal outcomes. 
• 
A secondary analysis will also be performed analyzing the effect of the liposomal bupivacaine 
administered via surgical TAP block on opioid dose and pain score stratified by BMI.  
• 
We will also analyze the overall cost effectiveness of liposomal bupivacaine administered via surgical 
TAP block in terms of overall hospital costs, if it is proved to reduce pain and opioid dose.  
 
6.2.3 Correlative objectives: 
• 
Breastfeeding rates, both exclusive and breastfeeding with supplementation at the time of discharge.  
• 
Readmission rate. 
• 
Whether opioid refills were requested, assessed at 2 and 6 weeks postpartum. 
• 
Number of remaining opioid pills (of those prescribed), assessed at 2 and 6 weeks postpartum.  
• 
Rates of ongoing pain at 2 and 6 weeks postpartum. Edinburgh Depression Screen (EDS) Scores 
assessed at 2 and 6 weeks postpartum.  
• 
Satisfaction scores at 2 and 6 weeks postpartum as measured by two pain satisfaction questions taken 
from the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS survey) 
 
7. Study Design 
 
7.1 General Design  
• 
This study will be a single-center, single blind, randomized controlled trial. The study will be 
conducted at UnityPoint-Health Meriter Hospital under investigators from the University of 
Wisconsin-Madison. Obstetric patients undergoing Cesarean delivery at UnityPoint-Health Meriter 
will be eligible.  


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• 
The rationale for this study being a pilot randomized controlled trial is that the liposomal 
bupivacaine has never been administered via surgical TAP block at the time of cesarean, therefore 
an effect size cannot be estimated from the literature. 
• 
The rationale for this study being single blind is that a control with a similar appearance to the 
liposomal bupivacaine is not available from the drug manufacturer or another pharmaceutical 
company. Because the injections will not be available, the providers will be able to identify whether 
the control or intervention is being utilized.  
• 
The injection will occur one time and will be administered via surgical TAP block at the time of 
cesarean delivery.  
• 
The study groups will consist of two arms: 
o One arm will receive the intervention injection which comprises 30 mL of bupivacaine HCl 
0.25%, 30 mL of saline, and 20 mL of liposomal bupivacaine (266 mL) for a total of 80 mL 
with 40 mL injected on each side. 
o The other arm will receive the control injection which comprises 30 mL of bupivacaine HCl 
0.25%, and 50 mL of saline for a total of 80 mL with 40 mL injected on each side.  
 
7.2 End of Study Definition 
A subject is considered to have completed the study when she has completed all phases of the study. 
Primary endpoints occur at 48 hours after cesarean completion. Additional outcomes will be collected at two 
and six weeks post-Cesarean.  
 
8. Subject Selection 
 
8.1 Target Study Sample Size 
• 
The target sample size for a pilot RCT was determined to be 50 with 25 subjects per arm. However, in 
order to account for up to a 20% dropout, we seek to randomize 60 subjects with 30 per arm.  
• 
We anticipate that maximum number of subjects screened to reach this sample size will be 3000. This 
approximates the number of women who undergo Cesarean delivery at UnityPoint-Health, Meriter in a 
24 month period. The most likely scenario is that less subjects will need to be screened because many 
unplanned or urgent cesarean births would not be eligible.  
• 
The anticipated goal is 60 subjects randomized.  
• 
Subjects will be counted once they are randomized, not at the time of consent. This is because many 
subjects who are planning for a cesarean delivery do not ultimately have their surgery performed on the 
day that it is scheduled due to either going into labor prior to the scheduled date or having another 
indication for delivery prior to the scheduled date. When this occurs, randomization may or may not 
occur depending upon staff availability around the time of delivery.  
• 
Subjects will be enrolled and randomized while pregnant but when delivery via cesarean is imminent. 
The intervention will occur immediately after delivery while the surgery is ongoing. This intervention, 
since it will occur postpartum, will not impact the fetus because at the time of intervention the 
pregnancy will have been completed.  
 
8.2 Inclusion Criteria  
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Maternal age greater than or equal to 18 
• 
Singleton or multifetal pregnancy  
• 
Able to receive neuraxial analgesia 
• 
Planned/ scheduled Cesarean delivery OR non-urgent Cesarean delivery with adequate time to 
consider and consent to the study 
• 
Able to provide consent in English 


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8.3 Exclusion Criteria 
An individual who meets any of the following criteria is not eligible to participate in this study and is excluded: 
• 
Known hypersensitivity to bupivacaine or liposomal bupivacaine (defined as a history of a reaction 
or allergy to bupivacaine (injectable, intravenous, or transdermal) reported by patient or 
documented in the medical record) or patient report 
• 
Plan by the obstetrical provider to inject bupivacaine or other local anesthetic into the cesarean 
incision due to potential differences in pain levels. 
• 
Contraindication to regional analgesia 
• 
Positive urine drug screen at admission to the hospital, if ordered for clinical purposes. 
• 
Current opioid use or opioid use disorder per patient report or documented in the medical record or 
the ePDMP (reviewed by PI 1-14 days prior to surgery) 
• 
Chronic opioid use or opioid use disorder, either patient reported or documented in the medical 
record or the ePDMP (reviewed by PI 1-14 days prior to surgery), defined as opioid use on most 
days for >3 months 
• 
Planned Cesarean hysterectomy (excluded due to anticipated blood loss and alternative pain 
control measures, possible prolonged intubation) 
• 
Planned vertical midline incision 
• 
Presence of renal dysfunction precluding the use of NSAIDs  
• 
Ischemic heart disease, congestive heart failure, or cardiomyopathy of pregnancy 
• 
Coagulopathy 
• 
Planned discharge from the hospital less than 48 hours postpartum 
• 
Unable to receive post-operative scheduled acetaminophen for any reason, such as allergy to 
acetaminophen or elevated liver function tests precluding acetaminophen use 
• 
Unable to receive post-operative scheduled NSAIDs for any reason, such as allergy to ketorolac or 
ibuprofen, or renal dysfunction precluding NSAID use. 
• 
Due to an adverse event where a patient experienced local anesthetic systemic toxicity, the 
anesthesiology group at UPH-Meriter proposes additional exclusion criteria for this study protocol. 
These patients are still able to receive local anesthetics and bupivacaine and liposomal 
bupivacaine, but because they are the team that would manage a toxicity reaction, they would feel 
more comfortable placing these TAP blocks themselves rather than having them be in this study 
protocol.  
• 
Seizure disorder: Specifically, poorly controlled seizure disorder defined as having had a seizure 
within the last three years despite antiepileptic use or poorly managed seizure disorder due to 
medication non-compliance.  
• 
Cardiac disease or arrhythmia: Defined as ischemic heart disease, peripartum cardiomyopathy, 
heart failure (with reduced or preserved ejection fraction, compensated or decompensated). 
Patients with a remote history of non-cyanotic pediatric cardiac surgery (like a VSD closure or PDA 
ligation as a child) do not need to be excluded. History of adult cardiac surgery without ongoing 
problems or treatments other than chronic anticoagulation (mitral valve repair for MVP or aortic 
valve replacement for bicuspid aortic valve for example) would not need to be excluded. History of 
repaired congenital cyanotic heart disease should be considered for exclusion, ultimately up to the 
anesthesiologist that day. A patient with a history of arrhythmias not requiring medication or ablation 
would NOT need to be excluded and could be included in the study. History of ablation or active 
anti-arrhythmic medication should be considered for exclusion.  
• 
Hypoxia: Defined as requiring supplemental oxygen during the day.  
• 
Acidosis. This will be uncommon in our population, but if someone has active diabetic ketoacidosis 
will exclude.  


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8.4 Recruitment 
• 
Primary obstetric providers will be made aware of this study using IRB-approved study posters, fliers, 
and brochures. 
• 
Providers will provide the woman with information and a consent form and have the patient sign a 
“Permission to Contact” form, performing a preoperative examination on a woman who meets criteria for 
enrollment in the study 
• 
The study coordinator or study staff will call the patient and read a prepared script about the study.  
• 
If the patient is interested, the study coordinator or study staff will review the informed consent document 
during the telephone call.  
• 
At a following clinical appointment or on the day of surgery, the research coordinator or study staff will 
review again the informed consent document and the patient will sign it if they would like to participate.  
• 
Preliminarily eligible subjects will be invited to the Meriter Center for Perinatal Care or their assigned 
room in triage or the antepartum or intrapartum ward for informed consent and formal screening. 
 
8.5 Retention Strategies 
• 
Subjects will not be compensated for participating in this project.  
• 
After enrollment, there will be an in-person randomization and the surgical TAP block will be 
administered at the time of their cesarean delivery. 
• 
Two week postpartum follow-up will comprise questions about breastfeeding, number of opioid pills 
remaining (of those prescribed) and questions about satisfaction with care.  
• 
Six week postpartum follow-up will comprise questions about breastfeeding, number of pills left and 
questions about satisfaction with care.  
• 
These questions will be sent via email message link to a secure survey for the participant to complete.  
 
8.6 Early Termination and Withdrawal 
Subjects will be informed that they have the right to withdraw from the study at any time for any reason, 
without prejudice to their medical care. The investigator also has the right to withdraw patients from the study 
for any of the following reasons: 
• 
If study procedures are discontinued due to AE 
o After the intrapartum period, if the subject develops serious skin reaction, or hypersensitivity/ allergy.  
• 
Protocol violation 
• 
Study terminated 
• 
If the subject meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation] 
 
Subjects who sign the informed consent form and are randomized but do not receive the study intervention 
will be replaced. Subjects who sign the informed consent form, are randomized and receive the study 
intervention, then subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced. 
 
9. Study Intervention 
 
9.1 Study Intervention Description 
The study intervention will consist administering the study injection (either the intervention injection which 
comprises 30 mL of bupivacaine HCl 0.25%, 30 mL of saline, and 20 mL of liposomal bupivacaine 
(266 mL) for a total of 80 mL with 40 mL injected on each side or the control injection which 
comprises 30 mL of bupivacaine HCl 0.25%, and 50 mL of saline for a total of 80 mL with 40 mL 


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injected on each side) at the time of cesarean delivery. This injection will occur only once and will 
occur at the time of cesarean.   
 
9.2 Source 
The intervention drug and control drug will be purchased by and supplied to the investigator via the 
Pharmaceutical Research Center (PRC) pharmacy research center at the University of Wisconsin-Madison. 
Hospitals and Clinics (UWHC). The PI has corresponded with the PRC regarding obtaining these 
medications and has received confirmation that they can be obtained and the cost. 
 
9.3 Packaging and Labeling 
• 
The intervention drug will be supplied by Pacira Biosciences, Inc. (NDC 65250-266-29).(30)  
• 
It is labeled as “Exparel (Bupivacaine liposome injectable suspension).  
• 
The instructions indicate that vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F).  
• 
The intervention drug 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.   
• 
Do not re-refrigerate vials.  
• 
Do not freeze or expose liposomal bupivacaine to high temperatures (greater than 40°C or 104°F) for an 
extended period.   
• 
Do not administer liposomal bupivacaine if it is suspected of having been frozen or exposed to high 
temperatures.  
• 
Do not use the vial if the stopper is bulging.   
• 
Handling 
• 
Invert vials of liposomal bupivacaine to re-suspend the particles immediately prior to withdrawal from 
the vial.   
• 
Multiple inversions may be necessary to re-suspend the particles if the contents of the vial have 
settled.  
• 
Visually inspect vials for particulate matter and discoloration before use.  
• 
Do not filter.  
• 
Do not heat before use.  
• 
Do not autoclave.  
• 
Following withdrawal from the vial, store liposomal bupivacaine at controlled room temperature of 
20°C to 25°C (68°F to 77°F) for up to 4 hours prior to administration.  
• 
Discard any unused portion in an appropriate manner.  
The control drug will be handled as per the usual protocol as it is already in semi-routine use for injections into 
other sites at the time of cesarean.  
 
 
 


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9.4 Preparation 
Both the intervention and the control injections will be prepared by mixing with regular bupivacaine HCl 
0.25% and saline as follows:  
 
Control Arm 
Intervention Arm 
30 mL bupivacaine HCl 0.25% 
50 mL saline 
 
 
Total: 80 mL  
Inject 40 mL on each side 
30 mL bupivacaine HCl 0.25% 
30 mL saline 
20 mL (266 mg) liposomal bupivacaine  
 
Total: 80 mL 
Inject 40 mL on each side 
 
These medications will be mixed in the operating room by study staff or nursing staff who have been 
educated on the handling of liposomal bupivacaine.  
 
9.5 Storage and Stability 
 
UW PRC will create study drug kits containing either the intervention or the control. These will be labeled 
sequentially with ascending sequential randomization numbers and will contain the medications for the 
control arm (bupivacaine and saline) or the intervention arm (bupivacaine, saline, and liposomal 
bupivacaine). Ancillary supplies (syringes, needles) will be in a separate package. Kits stored at room 
temperature will need to be utilized within 30 days. Kits stored in a refrigerator will not need to be used 
within 30 days.  
 
Kits stored in a refrigerator will be located within a locked refrigerator in a locked room.  Kits stored at room 
temperature will be within a locked cabinet in a locked room and will need to be used within 30 days.  
 
After a participant is consented and randomized, we will pull the next unused kit for use with that 
participant. The participants study ID information will be recorded on a log created by the UW pharmacy to 
ensure that all regulatory information is documented.  
 
The kit will then be brought to the operating room to use at the end of the cesarean surgery.  
 
The physician performing the surgery will open the contents of the “kit” as described above while handling 
all drugs appropriately. The products will be mixed as above, and administration of the “study drug” will be 
documented in the operative note and the medication administration record within the electronic health 
record.  
  
Measures will be taken to ensure limited access as well as measures to prevent accident damage or 
destruction.  
 
If “kits” are not able to be used, we will plan to store the components separately at the temperature at 
which they are most stable and will assemble the kits as needed based upon the randomization 
sequence with the assembling providers blinded until the allocation envelope is opened.  
 
9.6 Accountability 
Quality review activities related to the receipt, storage, dispensing, tracking, and destruction are performed to 
ensure proper accountability of the investigational product. The MOP describes the processes for the 
ordering, maintenance, and dispensing of the study drug. Investigator(s) and study team members ensure 


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that informed consent is obtained before the investigational product is administered to study subjects, and 
the investigational product is only administered to those subjects eligible for and enrolled in the clinical trial. 
 
9.7 Dosing and Administration 
The liposomal bupivacaine will be administered via surgical TAP block after delivery of the fetus and 
closure of the hysterotomy but prior to closure of the fascia. Only providers trained on performing this 
procedure may perform it for the study protocol. All patients in both arms will be administered 
additional analgesia in accordance with post-
cesarean pain control as per hospital guidelines. 
The expected “Study Drug Schedule” is included in 
this documentation.  
 
The administration will occur as follows1,2:  
 
Having closed the uterus and established 
hemostasis at the incision, the rectus muscle is 
gently elevated superiorly using a retractor (figure) 
and the surgeon palpates its lateral border. This 
indirectly locates the inferior epigastric vessels 
which ascend between the rectus abdominis and 
posterior lamella of its sheath. The nerves that 
supply the anterior abdominal wall travel through the 
neurofascial plane between internal oblique and 
transversus abdominis muscles. Access to this 
plane can be achieved by inserting an 18-22 gauge blunted 
needle through the parietal peritoneum and with further 
advancement there is a loss of resistance and the correct 
plane has been entered. The presence of resistance to 
injection suggest the needle tip is too deep and is within the 
internal oblique muscle. Formation of a bleb in the peritoneum 
suggests the needle is too superficial and had not penetrated 
the transverse abdominis. If the needle is not in the correct 
plane, reposition it by retracting or advancing, respectively. 
After aspiration to ensure no vascular injury, 40 mL of 
bupivacaine is slowly introduced via two 20 mL injections into 
the area of interest. The surgical TAP block is then performed 
on the opposite side using an identical technique which may 
be performed by the other surgeon or by having the first 
surgeon move to the contralateral side of the table.  
By directly visualizing the injection site, the surgeon ensures 
no inadvertent damage to the viscera.  
Following surgical TAP block, the fascia, subcutaneous tissue, 
and skin are closed in the usual fashion per the usual surgical protocol.  
Tip: a sponge may be inserted in the paracolic gutter to pack the bowel away if they impede access.  
 
 
 


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Dosing location:  
 
 
 
 
 


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9.7.1 Dose Schedule 
 
  
Enrolled 
  
Randomization 
  
Intervention arm 
Control arm 
Intraoperative  
Standard regional analgesia 
Standard regional analgesia 
Prior to closing fascia 30 mL bupivacaine HCl 0.25% 
30 mL saline 
20 mL (266 mg) liposomal bupivacaine  
  
 
Total: 80 mL 
Inject 40 mL on each side 
30 mL bupivacaine HCl 0.25% 
50 mL saline 
  
  
  
Total: 80 mL  
Inject 40 mL on each side 
At arrival to PACU 
15 mg IV ketorolac  
+ 
975 mg PO acetaminophen 
15 mg IV ketorolac 
+ 
975 mg PO acetaminophen 
Anytime post-op 
Morphine IR PO 7.5-15 mg Q 4 hours 
PRN for moderate to severe pain* 
  
*CAN increase to 15-30 mg Q4 hours 
PRN if pain is not controlled 
  
*CAN also use Hydromorphone IV 0.5-
1 mg Q2 hours PRN for moderate to 
severe pain for breakthrough pain or if 
not yet tolerating PO 
 
OR any other opioid medications on 
formulary 
Morphine IR PO 7.5-15 mg Q 4 hours 
PRN for moderate to severe pain* 
  
*CAN increase to 15-30 mg Q4 hours 
PRN if pain is not controlled 
  
*CAN also use Hydromorphone IV 0.5-
1 mg Q2 hours PRN for moderate to 
severe pain for breakthrough pain or if 
not yet tolerating PO 
 
OR any other opioid medications on 
formulary 
Every 6 hours postop 15 mg IV ketorolac (or 600 mg ibuprofen 
after 24 hours postop) 
+ 
975 mg PO acetaminophen 
+ 
Resume postoperative pain regimen 
15 mg IV ketorolac (or 600 mg 
ibuprofen after 24 hours postop) 
+ 
975 mg PO acetaminophen 
+ 
Resume postoperative pain regimen 
 
9.7.2 Dose Adjustments/Modifications/Delays 
If a study participant experiences an allergic reaction to bupivacaine or does not tolerate it for any 
reason including, but not limited to, pain, irritation, desire to discontinue, the study team will be notified.  
 
9.8 Randomization and Blinding 
A randomization schedule will be created by the study statistician and will follow a block randomization with random 
block sizes of 4 or 6.  This method will ensure balance in sample size per arm throughout the entire study. Ultimately, 
there will be 30 subjects per arm for a total of 60 subjects. The study ID numbers will be sequentially assigned to 
participants in the order that they are enrolled and consented. Randomization IDs will be sequentially assigned on the 
day of or the day before their surgery by the research coordinator or physician performing the procedure. The patient/ 
participant will be blinded to the subject’s allocation. However, because the injections are not identical in appearance, 
the clinical team and research coordinators will not be blinded. Therefore, since the research coordinators are not 


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blinded, they may perform the randomization and will know the subject’s allocation. Outcome measures are objectively 
measured and participants will be blinded to allocation.  
 
9.9 Study Intervention Compliance 
 
This section describes the strategy, responsibilities, and quality management activities in place to 
demonstrate that there is adequate monitoring of the clinical trial by the Principal Investigator (PI) to ensure:  
• 
The trial is conducted according to the investigational plan, protocol and applicable laws, regulations, 
policies and guidance 
• 
The rights, welfare, and safety of human subjects are protected 
• 
Proper reporting of study data to the FDA and IRB 
• 
The PI is providing adequate oversight of the clinical trial 
 
The plan includes both internal quality and external, independent safety management processes used 
throughout the study, including but not limited to staff training, standardized procedures, methods for data 
collection, study and data monitoring, and routine team meetings to review the study progress and isolate 
any compliance issues and/or trends. 
 
9.9.1 Study Team Training 
Members of the study team are trained on the protocol and/or study procedures applicable to their roles 
and responsibilities. When the protocol and/or study procedures are updated, staff will be trained on the 
revisions prior to implementation, as applicable.  
 
Per University of Wisconsin-Madison policy, all personnel engaging in human subjects research must 
complete Human Subjects Protection, and Health Insurance Portability and Accountability Act (HIPAA) 
training. In addition, those engaged in applicable clinical trials must also complete the Good Clinical 
Practice (GCP) training.]  
 
Training is documented and maintained in the study files. 
 
9.9.2 Investigator/Study Team Member Agreement 
All members of the study team are informed of their responsibilities specific to their role(s) in this study, 
their obligation to follow the approved clinical research protocol, the applicable regulations, guidelines 
and institutional policies. Documentation of this agreement is maintained in the study files. 
 
9.9.3 Financial Disclosure 
Financial disclosure information is collected for all members of the study team that make a direct and 
significant contribution to the data. Financial disclosure documentation is maintained in the study files. 
 
9.9.4 Routine Study Team Meetings  
Routine study team meetings ensure on-going supervision and oversight of the study and study 
personnel involved in the conduct of the study will be held on a weekly and then bi-weekly basis: 
weekly in the weeks before and immediately after study initiation and bi-weekly once the team has 
determined that weekly meeting are no longer needed by any study personnel. In the meetings, the 
sponsor, sponsor-investigator, and/or the principal investigator (PI) (if not one in the same) and study 
team members discuss evaluations of study-related activities (as applicable): identification of deviations 
or noncompliance, review of adverse events, and overall study progress. Training on protocol, 
procedure and/or form updates may also be performed during routine meetings.  
 
9.9.5 Standardized Procedures 
 


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9.9.5.1 Standard Operating Procedures (SOPs) 
Study teams are trained on and must follow the Department of Obstetrics & Gynecology (Ob/Gyn) 
Clinical Research SOPs to ensure consistent performance of procedures by all team members and 
across protocols within the clinical research office. SOPs are periodically reviewed and updated (as 
necessary). 
 
9.9.5.2 Manual of Procedures (MOP) 
The MOP is a supplemental guide to the study protocol and complements Department SOPs to 
provide additional details on the conduct of the study. It is routinely updated to ensure consistent 
performance of study activities. 
 
9.9.6 Additional Measures in place.  
Refer to the following section(s) of the protocol for additional quality assurance measures that will be 
taken.  
11. Data Collection, Handling and Record Keeping 
12. Assessment of Safety 
14. Regulatory, Ethical, and Study Oversight Considerations 
14.1 Safety Oversight 
14.2 Protocol Deviations 
 
9.10 Concomitant Therapy 
All patients in this study will be receiving the standard post-cesarean analgesia regimen as detailed above. 
Unless specifically listed in the exclusion criteria (above), other concomitant medications will be recorded on 
the CRF but will be permitted. Concomitant therapy might affect the outcome due to drug-drug interactions or 
altered metabolism.  
 
9.11 FDA IND Compliance 
The liposomal bupivacaine intervention used for the purposes of this study is for the indication of pain 
control, which is its listed indication. This medication has also been used for TAP blocks at cesarean. The 
subjects being studied are not considered a vulnerable population, posing no additional risks regarding the 
use of the study intervention. This study does not need to be conducted under an Investigational New Drug 
(IND) application with the FDA, rather is considered IND Exempt as it is being used in the context in which it 
was approved.   
 
This study meets the IND Exemption criteria as defined by 21 CFR 312.2(b) Exemptions.  
(1) The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from 
the requirements of this part if all the following apply: 
(i) 
The investigation is not intended to be reported to FDA as a well-controlled study in support of a 
new indication for use nor intended to be used to support any other significant change in the 
labeling for the drug; The results of this study will not be reported to the FDA to support a new 
indication or use, or change in labeling of the drug.  
(ii) 
If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the 
investigation is not intended to support a significant change in the advertising for the product; The 
study intervention is lawfully marketed and is not intended to support a significant change in the 
advertising of the product.  
(iii) 
The investigation does not involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of the 
risks) associated with the use of the drug product; The study intervention will be administered using 
the dosage and route of administration as well as the patient population (in need of pain relief) that 
is approved.  
(iv) The investigation is conducted in compliance with the requirements for institutional review set forth 


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in part 56 and with the requirements for informed consent set forth in part 50; and the investigation 
will be conducted in compliance with the requirements for institutional review set forth in part 56 and 
with the requirements for informed consent set forth in part 50.  
(v) 
The investigation is conducted in compliance with the requirements of 312.7. The intervention used 
in the study will not presented as safe or effective for the purposes for which it is under investigation 
or otherwise promote the drug. 
 
10. Study Visits and Procedures 
 
10.1 Study Calendar 
 
Event 
Activity 1 
Activity 2 
Activity 3 
Activity 4 
Timing 
Clinic, ultrasound 
unit, triage, via 
telephone, or labor 
and delivery prior 
to Cesarean 
delivery. 
May occur on 
same day as 
activity 2 or may 
occur prior. 
At the time of 
Cesarean delivery 
2 weeks 
postpartum 
6 weeks 
postpartum 
Location 
See 10.2.1   
OB triage, 
antepartum unit, or 
labor and delivery 
(L&D) room  
 
L&D OR (for 
Cesarean delivery) 
Pt’s home:  
Email message 
link to survey + 
(Emails x up to 4) 
Telephone 
reminder (If no 
prior response) 
Pt’s home:  
Email message 
link to survey + 
(Emails x up to 4) 
Telephone 
reminder (If no 
prior response) 
Events 
Consent 
-Randomization (to 
occur day of or day 
before surgery) 
-Cesarean delivery 
(clinical event) 
-Liposomal 
bupivacaine 
administered via 
surgical TAP block 
Survey completed 
Survey completed 
 
10.2 Screening and Enrollment 
The Screening and Enrollment activities and procedures are described in detail below. 
 
10.2.1 Prescreening 
Potentially eligible subjects will be identified and approached at different time points during pregnancy and 
at various locations. Women may be approached or consented at any of the time periods below (to allow for 
many possible opportunities to have the study discussed, but once they indicate they are not interested they 
will not be re-approached.) For each scenario, the initial approach will be done by nurses, residents, providers 
or other clinical staff not on the study or study coordinators. Clinical staff will only approach the patients about 


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participation in a research study, but not include specifics about this study. These scenarios and mechanisms 
are described below: 
 
General Recruitment and Enrollment Mechanism:  
1. Providers: 
Primary obstetric providers will be made aware of this study and IRB-approved study posters, fliers, and 
brochures will be made available to interested primary obstetric providers.  
a. When providers perform a preoperative examination on a woman who meets criteria for enrollment in the 
study, they will provide the woman with information and a consent form and have the patient sign a 
“Permission to Contact” form.  
b. Physicians or other clinical care team member can also obtain verbal permission from the potential 
subject to be approached by the coordinator. 
 
2. Study Coordinators: 
Inpatient Only: Coordinators work with nursing staff to identify a time when patient is not sleeping or 
involved in a medical procedure to approach the patient. 
 
The study coordinator or study staff will then call the patient and read a prepared script about the study. If 
the patient is interested, the study coordinator or study staff will review the informed consent document during 
the telephone call. At a following clinical appointment or on the day of surgery, the research coordinator or 
study staff will review again the informed consent document and the patient will sign it if they would like to 
participate. Consent may also occur via a virtual visit.  
 
Preliminarily eligible subjects will be invited to the Meriter Center for Perinatal Care or their assigned room 
in triage or the antepartum or intrapartum ward for informed consent and formal screening. 
 
Randomization will occur the day before the planned surgery or the day of the planned surgery.  
 
Inclusion of Patients who speak Spanish 
The study will enroll subjects who speak and read either English or Spanish. 
 
All documents, including the consent and HIPPA authorization form are translated into Spanish by a 
certified medical interpreter in the UW Hospital Interpreter Services Department.   
 
An interpretation service, LanguageLine, will be used during the informed consent process, telephone 
conversations or other verbal interactions with subjects. Non-English-speaking patients who require a 
Spanish interpreter may only be consented if a language line representative is available. 
 
**First Approach and Permission to Contact 
The coordinator will use LanguageLine in all scenarios for first approach.  The coordinator will call 
LanguageLine to go over the consent form or permission to contact with the patient. 
 
If there is no interpreter present, permission to contact will be delayed. The patient needs to be able to 
understand and communicate with the coordinator. No communication will be done for research purposes 
until LanguageLine is available. 
 
Every effort will be made to approach Spanish speaking subjects at the same locations/circumstances as 
non-Spanish speaking patients. 
 
 
 


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Fetal anatomic examination ultrasound: Meriter Center for Perinatal Care 
Initial Approach: Patients undergoing a detailed fetal anatomic examination ultrasound (CPT code 76811) at 
the Meriter Center for Perinatal Care will be provided with an information about this study. This sonogram 
typically occurs at 18-22 weeks gestational age, which is approximately five months prior to delivery. (CPT 
code 67811 examinations occurring at other gestational ages will also be permitted.) However, this sonogram 
may occur at later gestational ages and information will be provided at this visit regardless of gestational age.  
 
The initial approach will be done by nurses, residents, providers other clinical staff or study coordinators. Clinical 
staff will only approach the patients about participation in a research study, but not include specifics about this 
study. Physicians or other clinical care team member can also obtain verbal permission from the potential 
subject to be approached by the coordinator. 
 
Follow-up and Informed Consent: Research coordinators or study staff will contact subjects by telephone 
who give permission to contact, and they will read a prepared script to the patients to describe the study. If 
the patient is interested, an informed consent document will be mailed to the patient to review. The research 
coordinator or study staff will re-connect with the patient when the patient presents for a third trimester growth 
sonogram or any other visit to Meriter or the day of surgery and they will review study eligibility criteria and 
whether a Cesarean delivery is planned. If a Cesarean delivery is planned, then the coordinator or study staff 
will have the patient sign an informed consent document at that time. Consent may also occur via a virtual 
visit. Then, 0-3 days prior to the Cesarean delivery, the research coordinator or study staff will re-connect 
with the patient to confirm eligibility and desire to be in the study. 
 
Third Trimester: Anesthesia preoperative consultation 
Initial Approach: At Meriter Center for Perinatal Care, some patients complete an anesthesia consultation 
during the antepartum period. This is a clinical protocol and is not related to this study. Of note, these patients 
would not constitute a separate cohort, but the existence of this clinic does allow providers another 
opportunity to identify eligible patients.  
 
The initial approach will be done by nurses, residents, providers other clinical staff or study coordinators. Clinical 
staff will only approach the patients about participation in a research study, but not include specifics about this 
study. Physicians or other clinical care team member can also obtain verbal permission from the potential 
subject to be approached by the coordinator.  
 
Follow-up and Informed Consent: If such patients are scheduled for a Cesarean and have an anesthesia 
appointment, the research coordinator or study staff will approach them for enrollment at their anesthesia 
preoperative appointment. This appointment typically occurs around 32 weeks of gestation; any gestational 
age will technically be eligible for approach and consent. The women, therefore, will sign consent at that time 
and she will be told to expect a telephone call the day before the surgery to confirm eligibility and intent to 
participate in the surgery. Consent may also occur via a virtual visit.  
 
28-38 weeks gestation ultrasound: Meriter Center for Perinatal Care 
Initial Approach: Patients undergoing a growth ultrasound examination (goal 28-38 weeks, but any 
gestational age acceptable) at the Meriter Center for Perinatal Care with a possible plan for scheduled 
cesarean will be provided with an information sheet about this study and a permission to contact form. This 
sonogram typically occurs at 36 weeks gestational age, which is approximately 3-4 weeks prior to delivery, 
but growth ultrasounds occurring at any time will be permitted.  
 
The initial approach will be done by nurses, residents, providers other clinical staff or study coordinators. Clinical 
staff will only approach the patients about participation in a research study, but not include specifics about this 
study. Physicians or other clinical care team member can also obtain verbal permission from the potential 
subject to be approached by the coordinator.  


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Follow-up and Informed Consent: Research coordinators or study staff will contact subjects by telephone 
who give permission to contact, and they will read a prepared script to the patients to describe the study. If 
the patient is interested, an informed consent document will be mailed to the patient to read and review. The 
research coordinator or study staff will also attempt to directly connect with the patient around 36 weeks 
when the patient presents for their growth sonogram, and they will review study eligibility criteria and whether 
a Cesarean delivery is planned. If a Cesarean delivery is planned, then the coordinator or study staff will 
have the patient sign an informed consent document at that time. Consent may also occur via a virtual visit. 
Then, 1-3 days prior to the Cesarean delivery, the research coordinator or study staff will re-connect with the 
patient to confirm eligibility and desire to be in the study.  
 
Antepartum admissions with plan to remain inpatient until delivery via Cesarean 
Initial Approach: Occasionally women are admitted during their pregnancy and need to stay inpatient until 
delivery. Examples of such cases include women with preterm premature rupture of the fetal membranes.  
 
The initial approach will be done by nurses, residents, providers other clinical staff or study coordinators. Clinical 
staff will only approach the patients about participation in a research study, but not include specifics about this 
study. Physicians or other clinical care team member can also obtain verbal permission from the potential subject 
to be approached by the coordinator.  
 
Follow-up and Informed Consent: The research coordinator or study staff will describe the study, give a copy 
of the informed consent document, and allow the patient to consider participation in this study. If the woman 
would like to participate, informed consent will be obtained, the form will be signed. Consent may also occur 
via a virtual visit. 
 
Triage, Labor & Delivery and Main Operating Room Pre-Operative Area: 
Initial Approach: The provider or research coordinator will also review the labor and delivery and main 
operating room schedule for Cesarean deliveries among women who meet inclusion criteria.  
 
The initial approach will be done by nurses, residents, providers other clinical staff or study coordinators. Clinical 
staff will only approach the patients about participation in a research study, but not include specifics about this 
study. Physicians or other clinical care team member can also obtain verbal permission from the potential 
subject to be approached by the coordinator.  
 
Follow-up and Informed Consent: Research coordinators or approved clinical providers will approach 
subjects, the study will be described to subjects, and informed consent will be obtained. Consent may also 
occur via a virtual visit. Randomization will occur that same day prior to the cesarean. Due to the busy nature 
of labor and delivery, this option may be limited to women who remain on labor and delivery for an adequate 
period of time to allow consideration of the study.  
 
10.2.2 Informed Consent 
The informed consent process will be conducted following all federal and institutional regulations relating to 
informed consent. Informed consent will be obtained prior to conducting any study related activities.  
At the baseline study enrollment, the participant’s eligibility will be assessed and the enrollment case report 
form will be completed. No physical examination will be performed. The estimated length of the interaction 
is 10-30 minutes to allow adequate time to review medical history and sign informed consent document. 
The informed consent process may occur in person or via telephone or video visit (remote consent) 
depending upon relevant infectious-disease related clinical and research restrictions in place.  
The informed consent process will be performed as follows: 
1. 
The research coordinator or study staff will review the informed consent form and discuss the study in 
detail with the potential research subject. 


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2. 
The research coordinator or study staff will explain the study, its risks and benefits, and what would be 
required of the research subject. 
3. 
The research subject will be given the opportunity to take the informed consent form home so that he 
or she may discuss it with family members, friends, clergy or others when possible.   
4. 
The subject will have the opportunity to ask questions and have all questions answered by the 
research coordinator and/or PI. 
5. 
The informed consent document must be signed and dated by the research subject. 
6. 
The research coordinator or study staff will review the informed consent document to ensure that all 
fields that require a response are complete (i.e. checkbox marked yes or no, etc.) as applicable. 
7. 
The research subject will be given a copy of the signed and dated informed consent form. The original 
signed informed consent form is kept in the locked OB/GYN research office in a locked file cabinet.  
 
An information sheet about the TAP block is typically used by the surgeon as an illustration tool to describe the 
procedure to the patient.  This might be used prior to consent when describing the study or after consent to 
clarify further questions or as part of the consent process if the surgeon is obtaining the consent. 
 
Example of patient counseling about the drug and study intervention:  
 
Patient counseling:  
We would like to offer you a surgical transverse abdominis plane block with bupivacaine at the time of 
your cesarean. This is sometimes called a “TAP” block for short. This is a nerve block with a local 
anesthetic which should help reduce your pain. Historically, this block was placed by an 
anesthesiologist using an ultrasound to ensure the needle is placed in the correct place. However, we 
as surgeons are able to identify this correct location while we are doing the cesarean before we close 
your abdomen. This eliminates the main risk of the TAP block which is that the needle can 
accidentally puncture into the intestines or liver. Specific risks to all TAP blocks include bruising or 
hematoma formation, pain at the injection site, or inadvertent blockade of additional nerves. Risks of 
local anesthesia include cardiac risks, particularly if injected intravascularly. Other risks include 
neurotoxicity including seizures, blurred vision, ringing in the ears, and also allergic reaction. These 
are overall rare, and we take precautions to avoid intravascular injection by aspirating or pulling back 
on the syringe to ensure we aren’t in a blood vessel before we inject the anesthetic. 
 
 
10.2.3 Baseline 
At the baseline study enrollment, the participant’s eligibility will be assessed, and the enrollment case 
report form will be completed. No physical examination will be performed. The estimated length of the 
interaction is 10-30 minutes to allow adequate time to review medical history and sign informed consent 
document.  
 
10.2.4 Subject Enrollment 
For this study, due to the number of potential time points to obtain consent, and the large potential for 
dropout between consent and randomization, enrollment will be defined as the time of randomization. This 
accounts for women who may potentially present for delivery prior to their scheduled Cesarean date or who 
may no longer require a Cesarean delivery (example: breech presentation at 36 weeks which verts to 
cephalic prior to the scheduled Cesarean).  
 
Procedures 
• 
Informed Consent will be obtained and verified at any of the interactions listed above and by the latest 
on the day of the scheduled surgery 


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• 
Randomization will be performed by the research coordinator or approved clinical providers 
• 
Delivery will occur via Cesarean delivery  
• 
Following delivery of the baby and closure of the hysterotomy but before closing the fascia, the 
surgical TAP block will be administered utilizing liposomal bupivacaine as described above.  
 
Postpartum 
• 
All patients receive either Intervention Injection (liposomal bupivacaine plus bupivacaine HCl and 
saline) or Control Injection (bupivacaine HCl and saline) at the time of cesarean in addition to 
scheduled ketorolac and scheduled acetaminophen with additional opioids available PRN (See Table 
above) 
• 
Pain will be assessed via the Numeric Rating Scale (NRS), which rates pain on a 0-10 scale, by the 
nursing team. Per unit protocol, this occurs every 4-6 hours.  
• 
Outcomes data are collected by research coordinators 
 
10.2.5 Screen Failure and Re-enrollment 
Individuals who do not meet the criteria for participation in this trial (screen failure) due to no longer 
requiring a Cesarean delivery but then later have an obstetric situation change and then do require a 
Cesarean delivery will remain eligible. One example of this happening is a patient who has a breech baby 
who then has an external cephalic version and the baby is no longer breech. Some such patients will have 
a baby who then spontaneously verts to breech again and may ultimately require a Cesarean delivery. 
Therefore, individuals who meet criteria for participation will not be removed from the study until they have 
delivered (vaginally) at which point they will no longer be eligible for participation.  
 
10.3 On-Study/Follow-up Activities 
After subjects have been enrolled, the On-Study/Follow-up activities and the procedures are performed. 
 
Randomization: the day before or day of the Cesarean delivery  
The estimated time for randomization is about 10 minutes of research coordinator or approved clinical 
provider time. The enrollee will then have their Cesarean delivery (clinical) and have the liposomal 
bupivacaine administered via surgical TAP block.  
 
Only the physicians listed on this application (or physicians in training that these physicians are directly 
supervising) will perform the study injections. Physicians in training includes residents and fellows.  
 
A transversus abdominis plane block is not within standard training for OB/MFMs. However, it less 
complicated than many other procedures that we perform, and the technique can easily be learned. The 
physicians listed in this protocol have learned this procedure and have ensured proficiency by performing this 
procedure clinically with regular bupivacaine between October 2020 and February of 2021.  
 
The Cesarean delivery will be performed by the clinical team as per the routine clinical protocol except that 
between closure of the hysterotomy and closure of the fascia the surgical transversus abdominis plane block 
will be placed. This procedure will only be performed by providers trained on the protocol. This procedure will 
occur in the operating room. The estimated time required to place the surgical TAP block is 2.4 minutes.(14) 
The research coordinator will then collect information on the total dose of opioids utilized and other 
outcomes. Study participation will be recorded in the EMR under Care Coordination Plan or Problem List. 
 
Post cesarean follow-up surveys  
Surveys will be emailed at 2 and 6 weeks postpartum, (each sent once if responded to, up to 4 times total 
sent every other day if no response) followed by a telephone call or text if there was no response to the 
emails. Patients who speak Spanish will only receive a phone call and not a text. The surveys can be 


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completed by the patient in the privacy of their own home on either a smart phone or computer. These study 
activities will be completed by the enrollee and if they fail to complete the survey after emails, they will be 
called. Data that will be collected will include the number of opioid pills the patient has remaining (of those 
prescribed) and patient satisfaction scores. Failure to complete these surveys will not be considered a 
protocol violation. Women who respond in the affirmative that they have poor mental/emotional health, are 
feeling depressed or other questions that relate to mental health or opioid addition, will be referred to the 
proper mental health or addiction counselor or provider. 
 
As of this date, we do not have the means to provide non electronic survey copies as the subjects will be at 
home when they complete the surveys. In a future amendment, we will determine the best method for 
subjects without electronic means. 
 
LanguageLine has the ability to do a conference call with the subject and coordinator. We will not be able to 
use text messages for patients who do not speak English. In a future amendment, we will determine the best 
method to communicate via text to subjects who do not speak English. 
 
10.4 Unscheduled Visits 
Unscheduled visits may occur if subjects would like to review the project or review their consent at any time. 
They may also be seen postpartum for any concerns that they think may be related to the study drug. 
(example: SAEs). However, unscheduled visits are not being specifically built into this study protocol.  
 
10.5 Early Termination and Withdrawal 
Subjects will be informed that they have the right to withdraw from the study at any time for any reason, 
without prejudice to their medical care. Such reasons may include (but will not be limited to):  
• 
Subject wishes to stop study involvement or withdraw for any reason. 
• 
Subject has a complication from the Cesarean delivery and wishes to withdraw 
 
The investigator also has the right to withdraw patients from the study for any of the following reasons: 
• 
If study procedures are discontinued due to AE although their data would be retained for intention to treat 
analyses 
• 
Protocol violation 
• 
Study terminated 
• 
If subject has a delayed complication from the cesarean delivery requiring re-operation although their 
data would be retained for intention to treat analyses 
 
All data collected on subjects prior to their withdrawal or discontinuation will be retained. If a subject is 
withdrawn or discontinues study participation prior to their caesarean, the subject will be discontinued and 
replaced. If the subject is withdrawn or discontinues study participation after their caesarean, the subject will 
be followed with intent to treat and will not be replaced. The reason for subject withdrawal or discontinuation 
will be documented in the study records. 
 
If a subject has signed informed consent but does not wish to undergo randomization, this will not count as a 
study discontinuation since they were not formally counted as “enrolled”.  
 
Participants will not be informed of study results, but the results will be available to participants. These 
results would not be expected to be available until 2023 at the earliest. The treatment assignments will also 
not be disclosed to the subjects at the time of the study but will be available if they would like to know after 
the six-week follow-up is complete. If subjects would like to know their treatment allocation, they may call 
research coordinators for unblinding after the 6 week follow-up is complete. 
 


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11. Data Collection, Handling and Record Keeping 
 
11.1 Data Collection  
• 
Standardized data collection forms (e.g., source documents, case report forms, standardized 
assessment forms, etc.) are used to ensure data collected are consistent and compliant with the 
protocol and IRB application.  
• 
Data collection is the responsibility of study team members under the supervision of the principal 
investigator. The principal investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the recorded and reported data. 
• 
All data collection forms must be completed in a legible manner; any missing data will be explained. 
Data entry errors will be corrected with a single line through the incorrect entry and the correct data is 
entered above/near the correction. All changes will be initialed and dated. 
• 
Data collection forms are maintained in the subject files and retained as described in the Record 
Retention section. 
 
11.1.2 Data Collection Forms 
Study team members use standardized data collection forms (e.g., case report forms, source documents, 
etc.) to ensure data collected are consistent and compliant with the protocol and IRB application. Forms 
are updated per protocol amendments (as applicable). Data will be handled in accordance with applicable 
regulations, GCP guidelines, as well as institutional policies.   
 
11.1.3 Study Visit Checklists 
Members of the study team use study visit checklists or worksheets, developed in conjunction with the 
sponsor-investigator and PI (if not one in the same), to ensure that all study required procedures and 
processes are conducted before, during and after the subject has been enrolled. These checklists are 
completed and reviewed by the members of the study team that interact with subjects and/or perform study 
procedures to ensure adherence to the protocol. 
 
11.1.4 Source Documentation 
The source document is defined as the first place the data are recorded. As per present, all source 
documents with patient data (i.e., “clinical metadata”) will be stored as paper records and considered the 
study source documents. All source documents will be maintained as hard copies and thereafter converted 
to electronic copies and secured in a manner accordant with the IRB protocol.  
 
11.2 Record Retention 
Records and documents pertaining to the conduct of this study, including CRFs, source documents, consent 
forms, and laboratory test results, must be retained by the investigator for a minimum of 7 years after study 
completion. Electronic data including clinical information data will be transferred to appropriate database(s). 
No study records shall be destroyed without prior authorization from the study PI (Antony) and/or the funding 
agencies, if applicable. 
 
11.3 Handling of Data to Ensure Confidentiality 
In order to ensure confidentiality of data the following procedures will be followed: 
• 
Label the source documents with code numbers. 
• 
Enter data from the source documents in a controlled-access database on the Internet or site proximal 
server.   
• 
Store all source documents and consent forms in a locked file cabinet(s). Only members of the study team 
will have access to this file cabinet. 
 


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11.4 Data collection forms 
 
11.4 Data Management Software System(s) 
Clinical data (including AEs, concomitant medications, and solicited events data) and clinical laboratory data 
will abstracted from the patient’s electronic medical record (EMR) and entered into the Research Electronic 
Data Capture (REDCap) data management software system(s) to ensure consistent data entry and data 
quality. Clinical data will be entered directly from the source. 
 
REDCap is a largely self-service, secure, web-based application for building and managing data collection 
forms. REDCap provides data management functionality by allowing the development of instrument and 
surveys to support data capture for research studies 
 
11.5 Data Confidentiality 
 
11.5.1 
Confidentiality of Subject Records 
In order to ensure confidentiality of data the following procedures will be followed: 
• 
Label the source documents with code numbers. 
• 
Enter data from the source documents in a controlled-access database on the Internet or site 
proximal server.   
• 
Store all source documents and consent forms in a locked file cabinet(s). Only members of the study 
team will have access to this file cabinet. 
 
All the staff participating in this project have undergone human subjects protection, Good Clinical 
Practice (GCP), and HIPAA training. 
 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act (HIPAA). All subjects will sign an informed 
consent document and HIPAA authorization that includes specific privacy and confidentiality rights. Study 
data will be maintained per federal, state, and institutional data policies. 
 
The Investigator(s) will ensure that the identities of subjects are protected by using coded subject 
information. The log of subject identifying information that links subjects to their study-specific 
identification number will be maintained by the Investigator. The log and all study records will be 
maintained in locked rooms and access will be limited to essential study personnel. Electronic study 
records/files will be stored on REDCap and on a department server and accessed via networked 
computers that are password-protected with access provided only to authorized study personnel.  
 
Authorized representatives of the following groups may need to review this research as part of their 
responsibilities to protect research subjects: the study monitor, representatives of the IRB, DSMB/DMC, 
and DCC staff. The clinical study site will permit access to such records. 
 
Study staff may use e-mail to communicate with research subjects, if the subject has agreed to using 
email in the Informed Consent form. Prior to any email exchanges, the study staff member will review the 
Use of Email for Research Purposes Guidance. The information contained in emails will be limited to 
study activity 3 and 4 which occur at 2 and 6 weeks postpartum. All emails to subjects will be sent from 
UW/wisc.edu accounts; personal, home or Gmail email accounts will not be used. 
 
11.6 Records Retention 
It is the investigator’s responsibility to retain study essential documents for a minimum of period of 7 years 
following completion of the study per UW-Madison institutional policy, or at least 2 years after the last 


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approval of a marketing application in their country and until there are no pending or contemplated marketing 
applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product, whichever comes last. 
 
12. Assessment of Safety 
 
12.1 Risk/Benefit Assessment 
 
12.1.1 Potential Benefits to the Subjects 
• 
There are no anticipated benefits to participating in this study.  
• 
One potential benefit would be reduced pain and reduced need for postoperative opioid medications, if 
in the intervention arm.  
• 
If in the control arm, one potential benefit would be to contribute to generalizable knowledge. There 
would also potentially be benefit from the regular bupivacaine over the standard of care which does not 
include administration of bupivacaine via surgical TAP block.  
 
12.1.2 Known Potential Risks & Risk Minimization 
 
12.1.2.1 
Procedural Risks 
• 
There is a risk of loss of confidentiality. Measures will be taken to prevent loss of confidentiality 
as described in sections 11.3 Handling of Data to Ensure Confidentiality and 11.5 Data 
Confidentiality. 
 
12.1.2.2 
Interventional Risks 
• 
There are risks of allergic reaction to regular bupivacaine HCl or liposomal bupivacaine. There 
are also risks of adverse reactions as delineated above. Subjects with a known allergic reaction 
to bupivacaine of any type will be excluded. Measures, such as aspirating to avoid intravascular 
injection, will also be taken to avoid adverse reactions.  
 
12.1.2.3 
Risk Minimization 
Described below is the rationale for the necessity of exposing subjects to risks and a summary of the 
ways that risks to subjects were minimized in the study design 
o Subjects with a known hypersensitivity or allergy to bupivacaine will be excluded 
o Regarding loss of confidentiality, paper CRF forms and ICF documents will be stored in a locked 
cabinet in the locked research coordinator’s office.  
o Online data will be stored only in secure online servers such as REDCap and Meriter’s secure 
server.  
The risks of participation in the study outweigh the value of the information to be gained. The risks of 
participation in this study are overall minimal as we will not enroll patients with a known hypersensitivity 
or allergy to bupivacaine. There is a potential benefit of pain reduction if the subject is in either arm of 
the study compared to the standard of care which is to not administer any local anesthetic drugs via 
surgical TAP block.  
 
12.2 Unanticipated Findings 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
subjects or others to include, in general, any incident, experience, or outcome that meets all of the following 
criteria:  
• The incidence, experience, or outcome is unexpected given the research procedures described in protocol-
related documents (e.g., the study protocol, the informed consent documents, the Investigator’s Drug 
Brochure) and the characteristics of the subject population being studied. An event may be considered 


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unexpected if it exceeds the nature, severity, or frequency described in the study-related documents, 
Investigator’s Drug Brochure, product labeling, or package insert. 
• The incidence, experience, or outcome is related to or probably related to participation in the research study. 
Probably related means the incidence, experience, or outcome is more likely than not to be caused by the 
research study procedures. 
 
The occurrence of the incidence, experience, or outcome suggests that the research places subjects or 
others at a greater risk of harm (physical, psychological, economic, or social) than was previously known or 
recognized.   
 
12.2.1 Adventitious Findings 
No imaging studies will be obtained as part of the protocol for this study; therefore, we do not anticipate 
any adventitious findings. Other study results will not be reviewed for adventitious findings.  
 
12.3 Clinically Significant Findings 
If there are clinically significant findings that occur during the course of this study, they would usually be 
discovered as part of routine prenatal or postpartum care. Subjects may request this information from the 
lead researcher.  
 
A copy of all notifications provided to the subject is maintained in the subject’s research file. 
 
12.4 Findings of Unknown Significance 
No findings of unknown significance are anticipated as we are not collecting specimens for analysis.   
A copy of all notifications provided to the subject is maintained in the subject’s research file. 
 
12.5 Adverse Event (AE) Definition 
Adverse event (AE) means any untoward or unfavorable medical occurrence in a human subject or others 
that happens during or after participation in a research study. 
 
12.6 Serious Adverse Event (SAE) Definition 
• 
Results in death 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it occurred) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization  
o Does NOT include usual post-partum hospitalization of 2-4 days post-operative stay) 
o DOES include post-op stay >4 days 
o DOES include re-admissions after the usual postpartum hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in congenital anomaly/birth defect: note, the study drug used in this study would be administered 
after delivery of the neonate  
• 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. 
 
12.6.5 Severity of Event 
All AEs will be assessed by the clinician using [specify the defined grading system, e.g., the Common 
Terminology Criteria for Adverse Events (CTCAE), each event searchable using the Safety Profiler website 
(https://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx). For AEs not included in the protocol-defined grading 
system, the following guidelines will be used to describe severity.  


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• Mild (grade 1) – Events require minimal or no treatment and do not interfere with the subject’s daily 
activities.  
• Moderate (grade 2) – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.  
• Severe (grade 3) – Events interrupt a subject’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
• Life threatening (grade 4) - The patient was at risk of death at the time of the event.  
• Fatal (grade 5) - The event caused death. 
 
12.6.6 Relationship to Study, Study Procedure(s) and/or Study Intervention(s) 
For all collected AEs, the clinician who examines and evaluates the subject will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below.  
• 
Definitely Related – Clearly related to the study procedures/intervention and other possible 
contributing factors can be ruled out. 
• 
Probably Related – Likely related to the study procedures/intervention and the influence of other 
factors is unlikely.  
• 
Possibly Related – Possibly related to the study procedures/intervention and there are other 
factors that could be equally likely. 
• 
Unlikely to be related – Doubtfully related to the study procedures/intervention and there is 
another likely cause. 
• 
Unrelated – Clearly not related to the study procedures/intervention and/or evidence exists that the 
event is definitely related to another cause. 
 
12.6.7 Expectedness for Study, Study Procedure(s) and/or Study Intervention(s) 
The PI will be responsible for determining whether an AE is expected or unexpected in relation to the study 
procedures and intervention(s) (as applicable).  
 
For investigational drug and device studies, an AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described in the clinical 
protocol, device manual, investigator’s brochure, investigational drug brochure, the package insert(s), the 
IRB application, or the informed consent document. Expectedness is recorded for both study procedures 
and interventions. 
 
For studies not evaluating an investigational drug or device, an AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information previously described in 
the clinical protocol, the IRB application, or the informed consent document. The expectedness could be 
based on study procedures or the characteristics of the patient population. 
 
12.7 Documenting and Reporting of AEs, SAEs & Ups 
 
12.7.1 Documenting AEs, SAEs & Ups 
Adverse events will be identified by review of the electronic medical record or inquiries with subjects or 
concerns from the nurses on the postpartum floor on a weekly basis or as needed when concerns are 
raised by nurses or subjects. Study subjects will be instructed to contact the research coordinator or PI (K. 
Antony) if any serious or unexpected adverse event occurs. Adverse events will be discussed at weekly 
research team meetings and will be reviewed to determine whether a change in protocol is necessary.   
 


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An abnormal laboratory result will not be assessed as an AE unless that result leads to discontinuation or 
delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be 
clinically significant.  
 
For the purposes of this study, baseline comorbid conditions will be documented prior to the administration 
of the study intervention. Only those symptoms identified as new or worsened compared to the baseline 
assessment and not related to the obstetric course will be recorded as an AE.  
 
AEs will be documented on the appropriate case report form. 
 
12.7.2 Reporting AEs, SAEs & Ups 
AE/SAEs that meet the definition of an unanticipated problem will be reported to the IRB within 14 business 
days of learning of the event. Events that are immediately life threatening, severely debilitating to other 
current subjects or resulted in a death will be reported to the IRB Chair or IRB Director via telephone or 
email within 24 hours (1 business day) of site awareness.  
 
All AEs will also be reported to the ICTR DMC by completing the AE/SAE forms in ICTR REDCap and will 
be reported within the same timeframe as required by the IRB. The DMC co-chairs will review any reported 
SAE and if needed, schedule an ad hoc meeting of the full committee.   
 
12.8 Stopping Rules 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to investigator, funding agency and the regulatory authorities. If the study is 
prematurely terminated or suspended, the PI will promptly inform the IRB and DMC and will provide the 
reason(s) for the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
• 
Determination of futility  
 
13. Study Analysis 
 
13.1 Statistical Hypothesis 
• 
Primary Efficacy Endpoint(s):  
o To determine whether liposomal bupivacaine administered via surgical TAP block at the time of 
cesarean delivery will reduce the total dose of opioids received.  
o Hypothesis: Our hypothesis is that liposomal bupivacaine administered via surgical TAP block at 
the time of cesarean delivery will reduce the total dose of opioids received in 48 hours.  
o Developmental SubAim: If liposomal bupivacaine administered via surgical TAP block at the time of 
cesarean delivery does reduce the total dose of opioids received, to determine the degree of the 
reduction in order to allow for an adequately powered randomized-controlled trial. 
o This will be tested by converting all doses of opioids received into oral morphine equivalents, 
calculating the total dose of opioids received in the first 48 hours, and comparing the mean and 
standard deviation of both groups to determine whether less opioids are used and, if so, what the 
expected effect size would be.  


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o The null hypothesis is that there would be no difference the total dose of opioids used in the first 48 
hours after Cesarean delivery between the subjects randomized to the control injection and 
subjects randomized to the intervention injection. 
 
• 
Secondary Efficacy Endpoint(s): 
o To determine whether liposomal bupivacaine administered via surgical TAP block at the time of 
cesarean delivery will reduce patient-reported pain scores and opioid-related side effects.  
o Hypothesis: Our hypothesis is that liposomal bupivacaine administered via surgical TAP block at the 
time of cesarean delivery will reduce patient-reported pain scores and opioid related side effects.  
o Patient related pain scores will be compared using the Numeric rating scale (NRS) which rates pain 
on a 0-10 scale.  
o Opioid-related side effects will be summed into a composite “Opioid side effects” outcome which will 
either be present or absent and Chi-Square will be used to compare the incidence of these events 
between groups. Individual components of the composite outcome will also be assessed.  
o The null hypothesis is that the patient related pain scores and the rate of opioid related side effects 
would be the same between the two groups.  
 
13.2 Sample Size Justification 
 
This is a pilot study; therefore, sample size is based on effect size estimation of liposomal bupivacaine 
administered via surgical TAP block in reducing post-operative opioid use. With 25 evaluable subjects per 
group we will have a 95% confidence interval precision around the effect size of +/- 60% of a standard 
deviation. This will give us adequate precision in our effect size estimate to move forward with a larger 
randomized clinical trial.  In order to account for up to 20% dropout, we will seek to randomize 60 participants 
(30 per arm).   
 
Within two years we should feasibly be able to recruit 60 women. The limitation will be that the procedure can 
only be performed by providers trained in administering a surgical TAP block.  
 
13.3 Statistical Methods 
The primary outcome of total opioid dose (in OME) will be compared via Student’s t-test or Mann-Whitney U 
test if the distribution is non-normally distributed, and additional outcomes will be assessed via Student’s t-
test, Chi-squared, or non-parametric tests, as appropriate. Statistics will be performed by Scott Hetzel with 
biostatistics. Analysis will be by intention to treat.  
 
No interim analysis is planned. This drug has been demonstrated to be safe, and there is a data safety 
monitoring committee who will review any significant adverse events. The data safety monitoring committee 
will also advise on whether early termination of the study is appropriate.  
 
Regarding missing, unused, or suspected spurious data, there will first be an attempt to validate this data via 
the electronic medical record. If it can be validated, the data will be used. Similarly, data points that are 
missing will be sought in order to have as complete a data set as possible. Otherwise, ongoing missing 
variables will be tabulated as missing. 
 
13.4 Planned Interim Analysis 
No interim analysis is planned. This drug has been demonstrated to be safe, and there is a data safety 
monitoring committee who will review any significant adverse events. The data safety monitoring committee 
will also advise on whether early termination of the study is appropriate. 
 


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14. Regulatory, Ethical, and Study Oversight Considerations 
 
14.1 Safety Oversight 
We will also utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study. The UW ICTR 
DMC is comprised of experienced members with expertise required to oversee this study. In providing 
oversight for the conduct of this study, the ICTR DMC will meet biannually during the time period in which 
participants will have any study procedures.  At these meetings, the DMC members will review protocol-
specific reports created by statisticians using data pulled from the ICTR Research Electronic Data Capture 
(REDCap) data management tool. These standard reports will include an overview of study objectives, a 
review of actual and projected accrual rates, an evaluation of patient demographics for balance of 
randomization, and a summary of the number and seriousness of adverse events. Additional meetings may 
be scheduled as determined by the DMC or as requested by the PI. An interim analysis of study results may 
be performed, and source documents may be reviewed to allow the DMC to independently judge whether the 
overall integrity and conduct of the protocol remain acceptable based on data provided and reported by the 
Principal Investigator. The DMC will make recommendations to the Principal Investigator that could include 
actions of continuation, modification, suspension, or termination.  Refer to ICTR DMC Charter for additional 
details.  
 
14.2 Protocol Deviations 
A protocol deviation is any noncompliance with the IRB approved study protocol, Good Clinical Practice 
(GCP), as adopted by the Food and Drug Administration (FDA), applicable federal regulations or institutional 
policies.  All deviations from the protocol must be documented and reported as required. Notably, failure of 
the subject to complete the online emailed survey in study activity 3 and 4 will not be considered protocol 
deviations because these are to assist with assessing secondary outcomes and are not mandatory to assess 
the primary outcome.  
 
14.3 Publication Plan 
If deemed appropriate, timely communication with the scientific community is one of the essential functions of 
the PI(s) and is accomplished by the publication of manuscripts in scientific literature and oral or poster 
presentations at scientific meetings. The publication policy as it pertains to this is meant to be flexible and to 
facilitate rapid and accurate publication of results. Investigators are responsible for drafting the publications 
and presentations with meaningful input from study sponsors.  Internal review of manuscripts and abstracts 
is deemed necessary to ensure accuracy and consistent representation of concepts and data from the 
clinical trials.  The procedures outlined herein are guidelines and all publications of the must meet the criteria 
for authorship, disclosure, scientific integrity and other requirements of peer-reviewed scientific journals.  
Subject Study IDs are not to be used in any publications.  
 
 


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