Instillation of Bupivacaine With Epinephrine Over Diaphragm to Reduce Postoperative Shoulder Pain Following Benign Gynecologic Laparoscopic Surgery: A Randomized Control Trial
Phase: PHASE4
Conditions: Postoperative Pain, Shoulder Pain
Sponsor: Cedars-Sinai Medical Center

 
 
 
 
 
 
Placing Numbing Medication Over Diaphragm to Reduce Shoulder Pain After 
Gynecologic Surgery: A Randomized Control Trial 
 
 
NCT Number: 
Not yet assigned 
 
Protocol ID: 
STUDY00003947 
 
Document Date: 
23 January 2026 
 

Instillation of bupivacaine with epinephrine over 
diaphragm to reduce postoperative shoulder pain 
following benign gynecologic laparoscopic surgery: 
A randomized control trial 
 
Short Title: Bupivacaine with epinephrine over diaphragm in laparoscopy 
 
Protocol Number: 00003947 
Principal Investigator: Kelly Wright, MD 
Sponsor: N/A 
Funded by: Internal Funding 
Version Number:  v3 
23 January 2026 
 
 
Summary of Changes from Previous Version: 
V 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
2.0 
1.2 Schema 
-sample size updated to 94 
-IRB biostatistics recommended 
sample size of 47 per group 
3.0 
1.2 Schema 
 
6.3 Measures to minimize bias 
 
6.5 Concomitant therapy  
 
 
 
 
General 
-sample size updated to 100 
 
Addressed research coordinators role in 
study randomization  
 
Addressed that patients with history of 
chronic pain or regular pain medication 
use will not be eligible for the study 
 
-inconsistencies in study drug have been 
corrected 
-study drug measurement has been 
clarified 
-addressed “off-label” use of study drug 
and updated language from “sprayed” 
to “instilled” to improve clarity 
-preoperative and postoperative drug 
regimen addressed  
-IRB recommended sample size of 100 
to account for study drop out 
 

  
Table of Contents 
STATEMENT OF COMPLIANCE 
1 
1 
PROTOCOL SUMMARY 
1 
1.1 
Synopsis 
1 
1.2 
Schema 
3 
1.3 
Schedule of Activities (SoA) 
4 
2 
INTRODUCTION 
4 
2.1 
Study Rationale 
4 
2.2 
Background 
4 
2.3 
Risk/Benefit Assessment 
5 
2.3.1 
Known Potential Risks 
5 
2.3.2 
Known Potential Benefits 
5 
2.3.3 
Assessment of Potential Risks and Benefits 
5 
3 
OBJECTIVES AND ENDPOINTS 
6 
4 
STUDY DESIGN 
7 
4.1 
Overall Design 
7 
4.2 
Scientific Rationale for Study Design 
7 
4.3 
Justification for Dose 
7 
4.4 
End of Study Definition 
8 
5 
STUDY POPULATION 
8 
5.1 
Inclusion Criteria 
8 
5.2 
Exclusion Criteria 
8 
5.3 
Lifestyle Considerations 
8 
5.4 
Screen Failures 
8 
5.5 
Strategies for Recruitment and Retention 
9 
6 
STUDY INTERVENTION 
9 
6.1 
Study Intervention(s) Administration 
9 
6.1.1 
Study Intervention Description 
9 
6.1.2 
Dosing and Administration 
9 
6.2 
Preparation/Handling/Storage/Accountability 
10 
6.2.1 
Acquisition and accountability 
10 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
10 
6.2.3 
Product Storage and Stability 
11 
6.2.4 
Preparation 
11 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
11 
6.4 
Study Intervention Compliance 
11 
6.5 
Concomitant Therapy 
11 
6.5.1 
Rescue Medicine 
11 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/ WITHDRAWAL 
11 
7.1 
Discontinuation of Study Intervention 
11 
7.2 
Participant Discontinuation/Withdrawal from the Study 
11 
7.3 
Lost to Follow-Up 
12 
8 
STUDY ASSESSMENTS AND PROCEDURES 
12 
8.1 
Efficacy Assessments 
12 
8.2 
Safety and Other Assessments 
13 
8.3 
Adverse Events and Serious Adverse Events 
13 
8.3.1 
Definition of Adverse Events (AE) 
13 

  
8.3.2 
Definition of Serious Adverse Events (SAE) 
13 
8.3.3 
Classification of an Adverse Event 
14 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up 
15 
8.3.5 
Adverse Event Reporting 
15 
8.3.6 
Serious Adverse Event Reporting 
15 
8.3.7 
Reporting Events to Participants 
16 
8.3.8 
Events of Special Interest 
16 
8.3.9 
Reporting of Pregnancy 
16 
8.4 
Unanticipated Problems 
16 
8.4.1 
Definition of Unanticipated Problems (UP) 
16 
8.4.2 
Unanticipated Problem Reporting 
16 
8.4.3 
Reporting Unanticipated Problems to Participants 
16 
9 
STATISTICAL CONSIDERATIONS 
17 
9.1 
Statistical Hypotheses 
17 
9.2 
Sample Size Determination 
18 
9.3 
Populations for Analyses 
18 
9.4 
Statistical Analyses 
18 
9.4.1 
General Approach 
18 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) 
18 
9.4.3 
Analysis of the Secondary Endpoint(s) 
19 
9.4.4 
Safety Analyses 
20 
9.4.5 
Baseline Descriptive Statistics 
20 
9.4.6 
Planned Interim Analyses 
20 
9.4.7 
Sub2020 
9.4.8 
Tabulation of Individual participant Data 
20 
9.4.9 
Exploratory Analyses 
20 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
21 
10.1 
Regulatory, Ethical, and Study Oversight Considerations 
21 
10.1.1 
Informed Consent Process 
21 
10.1.2 
Study Discontinuation and Closure 
21 
10.1.3 
Confidentiality and Privacy 
22 
10.1.4 
Future Use of Stored Specimens and Data 
22 
10.1.5 
Key Roles and Study Governance 
23 
10.1.6 
Safety Oversight 
23 
10.1.7 
Clinical Monitoring 
23 
10.1.8 
Quality Assurance and Quality Control 
23 
10.1.9 
Data Handling and Record Keeping 
23 
10.1.10 Protocol Deviations 
24 
10.1.11 Publication and Data Sharing Policy 
24 
10.1.12 Conflict of Interest Policy 
25 
10.2 
Additional Considerations 
25 
10.3 
Abbreviations 
25 
10.4 
Protocol Amendment History 
25 
11 
REFERENCES 
26 
 

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9.3 STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
Clinical trial site staff who are responsible for the conduct, management, or oversight of clinical trials 
have completed Human Subjects Protection Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study. In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Instillation of bupivacaine with epinephrine over diaphragm to reduce 
postoperative shoulder pain following benign gynecologic laparoscopic 
surgery: A randomized control trial 
Study Description: 
Postoperative pain is a significant area of interest in laparoscopic 
gynecologic surgery. Postoperative shoulder pain is often reported to be 
particularly bothersome after laparoscopy. The benefits of local anesthetic 
applied to subcutaneous tissue for postoperative pain management after 
surgery is well established. However, there have been no studies on 
instillation of bupivacaine with epinephrine over the diaphragm to reduce 
shoulder pain in laparoscopic surgery. We hypothesize that instilling infra-
diaphragmatic bupivacaine with epinephrine compared to no intervention 
will improve postoperative shoulder pain in benign laparoscopic 
gynecologic surgery.  
Objectives: 
Primary Objective: To evaluate the impact of instilled infra-diaphragmatic 
bupivacaine with epinephrine on post-operative pain scores for shoulder 
pain. 
Secondary Objectives: To evaluate the impact of instilling infra-
diaphragmatic bupivacaine with epinephrine on postoperative overall 
pain, opioid use, length of stay in PACU, and surgical outcomes.  

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Endpoints: 
Primary Endpoint:  
● Reported shoulder pain score using visual analog score (VAS) on 
postoperative day 1 (POD1) 
 
Secondary Endpoints:  
● Maximum reported shoulder pain in PACU using VAS 
● Daily reported shoulder pain using VAS for 5 days postoperatively 
● First reported generalized pain score in PACU using the numerical 
rating scale (0-10). 
● Last reported generalized pain score in PACU prior to discharge 
using the numerical rating scale (0-10). 
● Total analgesic requirements in PACU (opioids to be reported in 
morphine milligram equivalents) 
● Total opioid requirements in the 1 week following discharge 
● Operative time 
● Estimated blood loss 
● Intraoperative complications 
● Conversion to laparotomy 
● Length of stay (from arrival to PACU to discharge home) 
 
Study Population: 
Individuals 18 years and older undergoing conventional laparoscopic or 
robotic-assisted laparoscopic surgery within the Minimally Invasive 
Gynecologic Surgery Division at Cedars-Sinai Medical Center. We 
anticipate 50 patients will be included in each arm.   
Phase: 
Phase 4 
Description of 
Sites/Facilities Enrolling 
Participants: 
Enrollment will occur at one site at Cedars-Sinai Medical Center   
Description of Study 
Intervention: 
30 ml of 0.25% bupivacaine with epinephrine  (1:200,000) instilled over 
the diaphragm at the conclusion of the surgery 
Study Duration: 
12 months 
Participant Duration: 
2 weeks (from randomization to study completion) 

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1.2 
SCHEMA 
Flow diagram 
 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Operating  
room 
 
 
PACU 
 
 
 
 
 
Post-operative 
assessment via  
secure message  
or phone call 
 
 
 
Further data  
collection  
and analyses 
 
 
 
Total 100:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, document. Can be done over video visit or phone. 
 
Randomize 
No intervention 
 
N = 50 participants 
Bupivacaine with 
epinephrine 
N = 50 participants 
Administer study intervention at end of the procedure 
 
PACU RN to document shoulder pain score using VAS and generalized pain scores using 
numerical rating scale (0-10) in the electronic health record as per usual routine post-
operative assessment. Post-operative analgesia will be administered per usual anesthesia 
protocol. 
Assessment of post-operative opioid use and shoulder pain scores using VAS 
following discharge from PACU through 7 days post-op.  
Abstraction of 
operative outcomes (EBL, 
operative time, 
complication rate, etc.). 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Day -30 to -1 
Enrollment/Day 
of Surgery 
Final Study Visit   
Post-operative day 7-14 
(secure message or 
phone call)  
Informed consent 
X 
 
 
Demographics 
X 
 
 
Medical history 
X 
 
 
Randomization 
X 
 
 
Administer study intervention 
 
X 
 
Height 
 
X 
 
Weight 
 
X 
 
Adverse event review and 
evaluation 
 
X 
X 
Pain assessment in PACU 
 
X 
 
Assessment of post-operative oral 
opioid use 
 
 
X 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
To investigate the effect of infra-diaphragmatic instilled bupivacaine with epinephrine over diaphragm 
on postoperative pain of patients undergoing laparoscopic gynecologic surgery.  
 
2.2 
BACKGROUND  
Laparoscopy as the route of major gynecologic surgery has been increasing over the last decade (1-3). 
The laparoscopic approach to gynecologic surgery is preferred over other approaches due to less 
postoperative complications, less associated pain, less blood loss, and rapid recovery (4). However, 
postoperative pain remains a significant area of interest. In particular, patients often report pain in the 
shoulder after laparoscopy. Acute postoperative pain in laparoscopic surgery is thought to be caused by 
local injury, traction and tension of the peritoneum and diaphragm, increased intra-abdominal pressure, 
intraperitoneal inflammatory reactions, and traumatic and/or neuropathic pains (5-6). Lack of pain 
control can lead to issues, such as longer hospital stays, chronic pain, and opioid dependence (7-8). 
Although opioids are effective in providing analgesia, extensive use can lead to increased side effects 
including dependence, respiratory depression, urinary retention, nausea, vomiting, etc. (9). Therefore, it 
is important to obtain both safe and effective postoperative analgesia while reducing opioid use.  
 
There are other nonopioid alternatives utilized in gynecologic laparoscopy to reduce pain and opioid use 
(10). Anesthetics, such as bupivacaine delivered via superior hypogastric plexus block has not been 
shown to reduce postoperative pain after laparoscopic hysterectomy while intraperitoneal infusion of 
bupivacaine has been demonstrated to improve quality of recovery in patients undergoing laparoscopic 
hysterectomy (11,12). Similar intraperitoneal use of lidocaine was found to improve pain management 
after cesarean delivery and reduced the number of opioids received in the postpartum period (13). 
 
Instilling local anesthetics intraperitoneally under laparoscopy has been shown to be an effective 
method for post-operative pain control (14-16).  Increased intraabdominal pressure from laparoscopic 

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surgery has been known to cause referred shoulder pain postoperatively. Both bupivacaine and 
ropivacaine are safe methods for abdominal instillation following surgery and are long-acting compared 
to their local counterparts. There have been multiple randomized control trials that investigate use of 
intraperitoneal local anesthesia with differing outcomes (14-16). For example, in a randomized control 
trial, Cho et al demonstrated that intraperitoneal bupivacaine significantly reduced shoulder pain 
following up to 24 hours following gynecologic laparoscopy (14). On the other hand, Sutchritpongsa et al 
found that subdiaphragmatic instillation of bupivacaine with morphine had no effect on reducing 
postoperative shoulder pain up to 24 hours after gynecologic laparoscopy (15). Majority of these studies 
do not specify location of bupivacaine administration, include other medications, or do not 
longitudinally follow patients postoperatively.  
 
In this study, we hypothesize that infradiaphragmatic instillation of bupivacaine with epinephrine 
compared to no intervention will improve postoperative pain, specifically shoulder pain following 
laparoscopic gynecologic surgery. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 
KNOWN POTENTIAL RISKS  
The risks are minimal in our study given the low dosage and amount of bupivacaine with epinephrine we 
plan on utilizing. The risks of use often are associated with the dose used and overall, extremely rare. 
Risks include potential interactions between ergot medications, blood thinners, antidepressants, or 
monoamine oxidase inhibitors. There are exceedingly rare immunologic reactions. Allergic reactions to 
amide-type local anesthetics are also rare and not often reported but are possible. There is also a risk of 
methemoglobinemia described in rare case reports. Other extremely rare adverse effects include 
nausea, vomiting, chills, shivering, headache, back pain, dizziness, tremors, coma, and cardiovascular 
collapse. 
 
2.3.2 
KNOWN POTENTIAL BENEFITS  
Bupivacaine with epinephrine is a commonly used drug for local or regional anesthesia or analgesia for 
surgeries. It is approved by the Food and Drug Administration for local infiltration (20). It is commonly 
used before, during and after surgery to aid in postoperative pain management. The onset of action is 
rapid while the anesthesia is long lasting. It is also known to be safe depending on proper dosage, 
correct technique, adequate precautions, and readiness for emergencies.  
 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Our study utilizes a lower dose of bupivacaine with epinephrine, thus the aforementioned risks are 
extremely rare. Multiple studies have demonstrated safety and efficacy of use for both local infiltration 
and abdominal instillation following laparoscopic surgery (18-19). Administration of local anesthesia 
before, during or after laparoscopic surgery is also quite common. Typically, opioids are used for 
analgesia postoperatively and given they are dose dependent, extensive use can cause unnecessary side 
effects, including respiratory depression, excessive sedation, nausea, vomiting, etc. Bupivacaine has 
nearly none of those side effects and provides a safe alternative to help reduce the amount of 
postoperative opioids required.  
 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To assess the effectiveness of 
instilled bupivacaine with 
epinephrine under the diaphragm 
on pain in the immediate 
postoperative period  
 
 
The primary endpoint is reported 
shoulder pain score using visual 
analog score (VAS) on POD1 
 
Decreases in immediate 
post-operative pain 
scores may increase 
patient satisfaction, 
decrease postoperative 
opioid use, and shorten 
hospital stay. We chose 
the reported shoulder 
pain score in PACU as our 
primary endpoint as we 
believe this to be the 
most clinically relevant 
data point for this 
medication intervention 
in the immediate 
postoperative period for 
laparoscopic surgery.   
 
Secondary/Exploratory 
 
 
To evaluate the impact of instilled 
bupivacaine with epinephrine 
under the diaphragm on pain 
scores at other time points in PACU 
and in the first week of recovery, 
post-operative opioid use, length 
of stay in PACU, and surgical 
outcomes.  
● Maximum reported shoulder pain 
in PACU using VAS 
● Daily reported shoulder pain 
score using VAS for 5 days 
postoperatively 
● First-reported pain score in PACU 
using numerical rating score 
(NRS)  
● Last reported pain score in PACU 
using NRS 
● Total analgesic requirements in 
PACU (in morphine equivalents)  
● Total opioid requirements in the 
7 weeks following discharge 
● Surgical safety outcomes 
(operative time, estimated blood 
loss, complications, conversions 
to laparotomy) 
● Length of stay in PACU 
We chose to examine 
pain scores at additional 
points in the PACU and 
at home to assess how 
our intervention may 
impact pain scores over 
time.  Post-operative 
opioid use (in PACU and 
at home) will be 
examined both as a 
proxy for post-operative 
pain at various time 
points, and to examine 
the potential for our 
intervention to decrease 
opioid use and prevent 
dependency. The 
remaining secondary 
endpoints were chosen 
as a means of evaluating 
the safety and 
acceptability of our 
intervention.  

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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This will be a single-center, single-blinded randomized controlled trial evaluating the impact of instilled 
infradiaphragmatic bupivacaine with epinephrine on post-operative pain and surgical field visualization 
among patients undergoing laparoscopic gynecologic surgery.  We hypothesize that instilled bupivacaine 
with epinephrine on the diaphragm will decrease postoperative pain, specifically shoulder pain in the 
immediate postoperative period. The study will include 2 groups: patients receiving bupivacaine with 
epinephrine instilled over the diaphragm at the end of the procedure and patients who do not receive 
the intervention.  
To minimize bias, the following measures will be taken to standardize pain management: 
● Preoperative acetaminophen and celecoxib (or equivalent) per standard of care with Enhanced 
Recovery After Surgery (ERAS) protocol. 
● Local subcutaneous infiltration of all port sites with 0.25% bupivacaine with epinephrine 
(1:200,000) will be performed prior to each incision. Remaining local anesthetic will be 
administered into the incision sites prior to the conclusion of the case (30cc total). This volume 
was selected as the bupivacaine that is typically used for surgery at our institution comes in 30 
cc vial, and it is common practice to give the entire vial’s worth. The maximum dosage in 24 
hours is 400 mg; we use well below the maximum dosage. 
● To evacuate residual carbon dioxide at the conclusion of the procedure, three positive pressure 
breaths will be administered with simultaneous compression of the abdomen prior to trocar 
removal.  
● General anesthesia and post-operative analgesia will be administered per the standard of care 
at our hospital and not altered in any manner given participation in the study. 
● In the post-anesthesia care unit, intravenous opioids (morphine, fentanyl or hydromorphone) 
will be administered at the discretion of the nursing and anesthesia teams as per routine care. 
● Patients will be instructed to take extra strength acetaminophen and ibuprofen in a scheduled 
manner, with oxycodone as needed, following discharge as per current and routine post 
operative care. All patients will be prescribed a total of 10 pills of oxycodone 5mg to be taken 
every 6 hours as needed in the immediate postoperative period, which is the standard amount 
that our practice prescribes for patients after laparoscopic surgery. Additional pills may be 
prescribed during their postoperative course at the discretion of the surgical team if the patient 
is having greater than expected pain and runs out of the prescribed pain medication, per the 
standard of care and current practice of our division. 
Study participants will be blinded to the study intervention. The surgical team and the post-operative 
care unit nurses will not be blinded to the intervention.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This is a superiority trial with respect to the primary outcome (pain scores).  
 
4.3 
JUSTIFICATION FOR DOSE 
The planned maximum dosage is 30mL of 0.25% bupivacaine with epinephrine 1:200,000, which is 
already approved for use for local infiltration and therefore is routinely used for infiltration at incision 

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sites during laparoscopic cases. Our study utilizes a very low dose as typically, the maximum dose is up 
to 400 mg in 24 hours. We plan to provide only one dose at 75 mg.  
 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study once all phases of the study including the last 
visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 1.3, are 
complete. 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study 
3. 18 years of age or older 
4. Undergoing laparoscopic surgery at Cedars-Sinai Medical Center with a surgeon in the Minimally 
Invasive Gynecologic Surgery division 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Pregnancy  
2. Urgent/non-scheduled surgery 
3. Scheduled for planned or possible concomitant non-gynecologic surgery (e.g., urologic or 
colorectal procedure) 
4. Baseline shoulder pain 
5. Baseline opioid use 
6. Baseline of chronic pain syndrome 
7. Conversion to open surgery 
8. Allergy or intolerance to bupivacaine, lidocaine (or amide class of anesthetics), oxycodone, 
acetaminophen, or ibuprofen 
9. Planned post-operative admission  
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 

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respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
We do not anticipate any modifiable factors that would initially exclude participation in the trial but 
later allow a patient to become eligible for participation (allowing for re-screening). 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
● Patients who are scheduled for laparoscopic gynecologic surgery at Cedars-Sinai Medical Center 
with a surgeon in the minimally invasive gynecologic surgery division will be identified. 
● We anticipate needing to screen approximately 200 patients for eligibility to achieve our sample 
size. 
● Anticipated accrual rate = 8 people per month 
● Anticipated number of sites = 1 (Cedars-Sinai Medical Center) 
● Potential participants will be identified in the outpatient setting prior to surgery. Eligible 
participants will be notified about the study at their preoperative visit or via secure message by 
their surgeon or study team member prior to their surgery (see recruitment template) 
● Given the nature of our specialty, all patients in our study population were assigned female sex 
at birth and most identify as women. Our patient population is racially and ethnically diverse, 
thus we will be actively recruiting historically under-represented populations. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
i.DOSING AND ADMINISTRATION 
 
The study intervention includes 30 ml of 0.25% bupivacaine with epinephrine instilled over the 
diaphragm at the conclusion of the surgery. Prior to desufflation of the abdomen during the procedure, 
the surgeon will instill the drug laparoscopically aiming to cover the diaphragm with liquid. Our study 
utilizes a very low dose as typically; the maximum dose is up to 400 mg and can be repeated once every 
three hours. We plan to provide only one dose at 75 mg. 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
Per standard care. 0.25% bupivacaine with epinephrine is already approved for use for local infiltration 
and therefore is routinely used for infiltration at incision sites during laparoscopic cases. Thus, the study 
intervention will be readily available for use at bedside. 
 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Per standard care. 
 

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The following description was obtained from the package insert:  
“Sensorcaine ® (bupivacaine HCl) injections are sterile isotonic solutions that contain a local anesthetic 
agent with and without epinephrine (as bitartrate) 1:200,000 and are administered parenterally by 
injection.  
Sensorcaine-MPF with Epinephrine 1:200,000 (as bitartrate) is a sterile isotonic solution containing 
sodium chloride. Each mL contains bupivacaine hydrochloride and 0.005 mg epinephrine, with 0.5 mg 
sodium metabisulfite as an antioxidant and 0.2 mg citric acid (anhydrous) as stabilizer.” 
 
 
 
 
6.2.3 
PRODUCT STORAGE AND STABILITY 
Per standard care. Bupivacaine with epinephrine is to be stored at 20 to 25°C (68 to 77°F); excursions 
permitted between 15° to 30°C (59° to 86°F). 
 
6.2.4 
PREPARATION 
Per standard care. Preparation required is minimal. Operating room staff are well-versed in drawing up 
bupivacaine with epinephrine with a syringe. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Participants will be 1:1 allocated to the bupivacaine with epinephrine and no intervention groups 
(parallel design) by block randomization and assigned a serial study identification number. 
Randomization groups will be allocated to each study identification number using an online tool and 
concealed until the time of enrollment. Once the patient is consented and enrolled, the surgeon will be 
informed which group the patient is randomized to by the research coordinator.  
Only patients will be blinded to the intervention group. The surgeons, OR nurses performing the 
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Since we do not anticipate plausible serious adverse events related to using bupivacaine with 
epinephrine, there will not be a reason to unblind the intervention group to the patient. Any 
unintentional breaking of the blind will be reported to the principal investigator of the study. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
The entire surgical team will be notified of the assigned group. Completion of the provider survey and 
patient reporting of postoperative opioid use will be tracked by the study coordinator. 
 
6.5 
CONCOMITANT THERAPY 
Not applicable. Patients who routinely take pain medications or have chronic pelvic or shoulder pain are 
not eligible for the study. This screening will occur prior to enrollment.  
 
6.5.1 
RESCUE MEDICINE 
Not applicable. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Indications for discontinuing the study intervention (i.e., refraining from additional use of bupivacaine 
(with epinephrine) are the same as indications for refraining from additional use of bupivacaine with 
epinephrine during any laparoscopic surgery (i.e., local anesthetic toxicity including seizures, cardiac 
arrhythmias, and hypotension). These indications are incredibly rare. Bupivacaine with epinephrine will 
already be utilized per protocol at the beginning of the procedure and therefore, if there is a reaction at 
that time, the patient will be withdrawn from the study. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
● Patient randomized but did not receive assigned intervention at any point (e.g., failed to 
remember to distribute medication at the end of the case) 
● Procedure aborted, e.g., due to physiologic intolerance of bupivacaine with epinephrine 
● Conversion to laparotomy (will included in all intra-operative variable analyses but omitted from 
all postoperative analyses) 
● Patients with unplanned admission post-operatively (will be omitted only from postoperative 
opioid analysis) 
● Patients unable to report pain scores post-operatively (i.e., unplanned transfer to intensive care 
unit while still intubated) 
● If any clinical adverse event (AE) other medical condition or situation occurs such that continued 
participation in the study would not be in the best interest of the participant 
● If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
● Following enrollment, participant does not undergo scheduled surgery  
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
REDCap data collection form. Subjects who sign the informed consent form and are randomized 

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but do not receive the study intervention may be replaced. Subjects who sign the informed 
consent form, and are randomized and receive the study intervention, and subsequently 
withdraw, will not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if the participant fails to return for the post-operative 
visit and is unable to be contacted by the study site staff to report postoperative opioid use.  
The following actions must be taken if a participant fails to attend their postoperative visit: 
● The site will attempt to contact the participant and ascertain if the participant wishes to and/or 
should continue in the study. 
● Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, a secure patient message, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file.  
● Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
The following data points will be obtained through review of data in the electronic medical record, as 
this information is collected and documented in the electronic medical record as part of regular 
standard of clinical care. 
Baseline/Operative Data:  
● Medical Record Number 
● Age at time of surgery 
● Body mass index at time of surgery 
● Race 
● Ethnicity  
● Prior abdominal surgeries  
● American Society of Anesthesiology class  
● Procedure type (endometriosis resection, adnexal surgery, hysterectomy, myomectomy, other) 
● Specimen weight 
● Number of port sites 
● Size of all ports 
Safety data: 
● Operative time  
● Estimated blood loss 
● Intraoperative complications  
Efficacy data: 
● Postoperative pain scores on numerical rating score (documented by nursing team per routine 
protocol) 
● Daily reported shoulder pain using visual analog score for 7 days postoperatively 

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● Quantity of analgesics administered in the PACU (opioids reported in morphine milligram 
equivalents) 
● PACU length of stay 
 
The remaining study data will be obtained via questionnaires as follows: 
Efficacy Data: 
● The study staff will ask patients about the quantity of postoperative opioids taken via secure 
message using the patient portal or via a telephone call.  An instrument will not be used for 
collecting pain medication usage information, as the study staff will just ask the patients how 
many pain pills they took.  
● Postoperative pain scores (shoulder specific and generalized) will be collected in a similar 
fashion by nurses via secure message or phone call.  
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Safety outcomes will be gathered from the electronic medical record and via questionnaires as indicated 
above (section 8.1). 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the 
investigator, it results in any of the following outcomes: death, a life-threatening adverse event, 
inpatient hospitalization (other than for routine post-operative care) or prolongation of existing 
hospitalization, or a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. Important medical events that may not result in death, be life-threatening, or 
require prolonged hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
1.1.1.1 
SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious.” 
 

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1.1.1.2 
RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study intervention must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
OR 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
1.1.1.3 
EXPECTEDNESS  
The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 

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8.3.4     TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel at the time of surgery, in the immediate postoperative period, or at the patient's 2-
week post-operative visit.  
All AEs will be documented on the patient data collection tool in REDCap. Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
A co-investigator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5  
ADVERSE EVENT REPORTING  
The investigator will record any adverse events on the REDCap data collection tool and if indicated, will 
report them to the IRB. 
 
8.3.6  
SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report any serious adverse event to the IRB if indicated (i.e., the 
adverse event is unexpected and there is a reasonable possibility that is related to participation in the 
study).   
 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS  
Any AEs or SAEs that occur during surgery will be promptly disclosed to the patient, as would be the 
case with any complication that could occur during surgery.   
 
8.3.8 
EVENTS OF SPECIAL INTEREST  
Not applicable. 
 
8.3.9 
REPORTING OF PREGNANCY  

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Not applicable 
 
   
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied. 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 
UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number. 
• 
A detailed description of the event, incident, experience, or outcome. 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP. 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the Cedars-Sinai IRB within 30 
days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB within 10 days of the investigator becoming aware of 
the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 10 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 

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ii.8.4.3 
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Not applicable. 
 
10. STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
● Primary Efficacy Endpoint(s):  
o Post-operative shoulder pain scores (superiority): Null hypothesis = pain scores will not 
differ among the bupivacaine with epinephrine vs no intervention group; Alternative 
hypothesis= pain scores will be lower among the bupivacaine with epinephrine group  
 
● Secondary Efficacy Endpoint(s): 
o Post-operative shoulder pain scores at home (superiority): Null hypothesis = pain 
scores will not differ among the bupivacaine with epinephrine vs no intervention group; 
Alternative hypothesis= pain scores will be lower among the bupivacaine with 
epinephrine group  
o Post-operative generalized pain scores (superiority): Null hypothesis = pain scores will 
not differ among the bupivacaine with epinephrine vs no intervention group; Alternative 
hypothesis= pain scores will be lower among the bupivacaine with epinephrine group  
o Post-operative opioid use (superiority): Null hypothesis = post-op opioid use will not 
differ among the bupivacaine with epinephrine vs no intervention group; Alternative 
hypothesis= post-op opioid use will be lower among the bupivacaine with epinephrine 
group 
o Surgical outcomes (EBL, operative time): Null hypothesis = each of these outcomes will 
not differ between groups; Alternative hypothesis = each of these outcomes will be 
improved in bupivacaine with epinephrine group 
o Length of stay in PACU (superiority): Null hypothesis = PACU length of stay will not 
differ among the bupivacaine with epinephrine vs no intervention group; Alternative 
hypothesis= PACU length of stay will be shorter in the bupivacaine with epinephrine 
groups 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
Prior studies have cited a clinically significant reduction in pain on the numerical rating scale to be 1.3-
1.5 [14,15]. We estimated the standard deviation on the numerical rating scale to be 2.5 for post-
operative shoulder pain following minimally invasive gynecologic surgery, based on a prior similar study 
[9]. To detect a difference of at least 1.5 between groups on the 11-point VAS with 80% power and a 
significance level of .05, a total of 50 participants per group (100  total) would be required. To account 
for protocol deviations, we added approximately 10% to the number of participants, resulting in a 
sample size of 100 (50 per group). We anticipate needing to recruit and screen approximately 200 
patients to reach this sample size. Sample size calculation was performed using G*Power version 3.1.9.7 
(Heinrich-Heine-Universität, Düsseldorf, Germany).  
The above sample size calculation was powered specifically for the primary outcome (reported shoulder 
pain score 24 hours postoperatively). The sample size was not powered for the secondary endpoints of 
daily shoulder pain scores at home, maximum, first, and last reported pain scores in PACU, post-
operative opioid use, PACU length of stay, and surgical outcomes. 

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10.3 
POPULATIONS FOR ANALYSES 
An intention-to-treat analysis of all randomized participants will be conducted. 
 
9.4 
STATISTICAL ANALYSES 
i.9.4.1 
GENERAL APPROACH 
● Descriptive statistics will be presented with standard descriptive summaries (mean/standard 
deviation for normal data, median/range for non-normal data, and frequency/percentage for 
categorical variables. 
● Checks of normality will be performed, and non-parametric tests will be used to analyze non-
normal data.   
● Chi-square and Fisher’s exact test will be used for categorical variables as appropriate. 
Continuous variables will be analyzed using analysis of variance for variables with normally 
distributed data and the Kruskal Wallis test for variables with non-normally distributed data.  
● A 2-sided p-value of <.05 will be considered statistically significant.  
 
ii.9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Primary endpoint: Reported right shoulder pain score using visual analog score (VAS) 24 hours 
postoperatively. 
● Assessed using the validated 100-mm scale with a range of 0-10 (11-point numerical rating 
scale), an ordinal scale. 
● Analyzed using the Kruskall Wallis test (as the data from the scale is typically not normally 
distributed); pairwise analyses will then be conducted using the Dunn post-hoc test if 
statistically significant. 
● Assuming non-normality, data will be presented as median (range). 
● Patients without any postoperative documentation of pain scores will be withdrawn from the 
study and thus excluded from the analysis. 
iii.9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary outcomes 
● Maximum reported shoulder pain in PACU using VAS 
● Daily reported shoulder pain score using visual analog scale for 5 days postoperatively 
o Assessed using the validated 100-mm scale with a range of 0-10 (11-point numerical 
rating scale), an ordinal scale. 
o Analyzed using the Kruskall Wallis test (as the data from the scale is typically not 
normally distributed); pairwise analyses will then be conducted using the Dunn post-hoc 
test if statistically significant. 
o Assuming non-normality, data will be presented as median (range). 
o Patients without any postoperative documentation of pain scores will be withdrawn 
from the study and thus excluded from the analysis. 
● First and last reported generalized pain score in PACU using numerical rating score 

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o Assessed using the validated 11-point numerical rating scale (0-10), an ordinal scale. 
o Analyzed using the Kruskall Wallis test (as the data from the scale is typically not 
normally distributed); pairwise analyses will then be conducted using the Dunn post-hoc 
test if statistically significant. 
o Assuming non-normality, data will be presented as median (range). 
o Patients without any postoperative documentation of pain scores will be withdrawn 
from the study and thus excluded from the analysis. 
● Total analgesic requirements in PACU (in morphine equivalents)  
o Calculated in morphine milligram equivalents (continuous data) 
o Analyzed using the Kruskall-Wallis test (assuming non-normal data) 
o Data will be presented as median (range) 
● Total opioid requirements in the 1 week following discharge 
o Number of pills used reported by patient (interval data) 
o Analyzed using the Kruskall-Wallis test  
o Data will be presented as median (range) 
● Surgical safety outcomes  
o Continuous variables: operative time, estimated blood loss 
▪ 
Analyzed using ANOVA if normally distributed, Kruskall-Wallis test if not 
normally distributed 
o Binary data: Surgical complications, conversions to laparotomy 
▪ 
Analyzed using chi-square test 
● Length of stay in PACU 
o Documented in minutes (continuous data) 
o Analyzed using ANOVA if normally distributed, Kruskall-Wallis test if not normally 
distributed 
 
 
iv.9.4.4 
SAFETY ANALYSES 
 
Surgical safety outcomes will be analyzed as above (section 9.4.3.) 
 
v.9.4.5 
BASELINE DESCRIPTIVE STATISTICS 
 
The following baseline characteristics will be collected, with the corresponding descriptive statistics 
reported: 
● Age (mean/SD or median/range depending on normality) 
● Body Mass Index (mean/SD or median/range depending on normality) 
● Race/ethnicity (n, %) 
● Prior abdominal surgery (median, range) 
● American Society of Anesthesiology Class (n, %) 
 
Additionally, the following operative variables will be collected (in addition to secondary endpoints as 
above), with the corresponding statistics reported: 
● Surgery type (endometriosis resection, adnexal surgery, hysterectomy, myomectomy, other) (n, 
%) 

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● Specimen weight (median, range) 
● Number of port sites (median, range) 
● Size of all ports (median, range) 
 
vi.9.4.6 
PLANNED INTERIM ANALYSES  
 
Not applicable. 
 
vii.9.4.7 
SUBGROUP ANALYSES 
 
There is no indication to perform subgroup analyses for the primary or secondary outcomes based on 
demographic characteristics. We have no reason to suspect that the study intervention will differentially 
impact patients of different age, race, or ethnicity.  
 
viii.9.4.8 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will not be tabulated. 
 
ix.9.4.9 
EXPLORATORY ANALYSES 
 
Not applicable. 
 
 
 
 
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
x.10.1.1 INFORMED CONSENT PROCESS 
 
1.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol: 
● Consent Form (HRP 610-A) – to be uploaded onto REDCap (plan for electronic informed consent 
per IRB protocol) 

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1.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants will be encouraged to discuss the study with their family or think about 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
Given that most pre-operative patient visits conducted in our division are virtual, the verbal explanation 
of the study and potential risks will be discussed virtually or by phone. Consent forms will be made 
available to the patient and signed via REDCap as part of the electronic informed consent process.   
xi.10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
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 the study participants and investigator.  If the study 
is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
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 with protocol requirements 
● Data that is not sufficiently complete and/or evaluable 
● Determination that the primary endpoint has been met 
● Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the IRB. 
 
xii.10.1.3 CONFIDENTIALITY AND PRIVACY  

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Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
all be maintained securely within REDCap electronic data capture tools and on Box, HIPAA-compliant 
secure storage systems within the Cedars-Sinai network with access restricted to approved members of 
the research team. Patient identifiers (i.e., medical record number) will be linked to participant data in 
order to allow for data abstraction from the electronic medical record. At the end of the study, all study 
databases will be de-identified. 
 
10.1.4 
FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be stored on REDCap electronic data capture tools and on Box. Study 
data will not be used for further analyses following completion of the study.  
xiii.10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
Kelly Wright, MD 
N/A 
Cedars-Sinai Medical Center  
N/A 
444 S San Vicente Blvd #1003 
Los Angeles, CA 
N/A 
310-423-9268 
N/A 
Kelly.Wright@cshs.org 
N/A 
The principal investigator will be responsible for the oversight of the trial, including safety monitoring 
and handling of unforeseen adverse events.  
 

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xiv.10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of the principal investigator. 
 
xv.10.1.7 CLINICAL MONITORING 
 
All study participants will be monitored clinically by the surgical team as part of their routine 
perioperative care. 
 
xvi.10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The principal investigator will be responsible for ensuring that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigation site will provide direct access to all source data/documents, and reports for the 
purpose of monitoring and inspection by local and regulatory authorities. 
 
xvii.10.1.9 DATA HANDLING AND RECORD KEEPING  
 
1.1.1.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All study data will be documented electronically using REDCap electronic data capture tools, a HIPAA-
compliant secure storage system within the Cedars-Sinai network with access restricted to approved 
members of the research team. 
Data recorded in the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents.  
Clinical data (including surgical complications, adverse events (AEs) and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system hosted at Cedars-Sinai Medical Center. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appears inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
 
1.1.1.2 
STUDY RECORDS RETENTION  
 
Records will be retained for a minimum of 3 years following completion of the study.  
 

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10.1.10 
   PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or the International Conference 
on Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 30 working days of identification of the protocol deviation, or within 30 working days 
of the scheduled protocol-required activity. Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements.  
 
10.1.11    PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
This study will comply with the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 3 years after the 
completion of the primary endpoint by contacting the investigator or co-investigator.  
10.1.12    CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest among people who have a role in the 
design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. 
Furthermore, people who have a perceived conflict of interest will be required to have such conflicts 
managed in a way that is appropriate to their participation in the design and conduct of this trial. The 
study leadership in conjunction with Cedars-Sinai Medical Center has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
10.2 
ADDITIONAL CONSIDERATIONS 
None 
 
10.3 
ABBREVIATIONS 
 

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AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CONSOR
T 
Consolidated Standards of Reporting Trials 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability 
Act  
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MOP 
Manual of Procedures 
MME 
Morphine milligram equivalent 
OHRP 
Office for Human Research Protections 
PACU 
Post-anesthesia recovery unit 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
11. 
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