Clinical trial NCT03845894
Conditions: Shoulder Arthroplasty
Keywords: Shoulder Replacement Surgery Interscalene Nerve Block Liposomal Bupivacaine Shoulder pain Regional anesthesia Brachial plexus blockade
Sponsor: Wake Forest University Health Sciences
Start date: 2020-03-03; Completion date: 2022-06-25
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether the use of plain bupivacaine with common adjuvants for interscalene block (ISB) provides non-inferior analgesic results compared to the use of liposomal bupivacaine for ISB, in patients undergoing total shoulder arthroplasty.

Detailed description:
The primary objective of this clinical study is to evaluate the comparative efficacy of interscalene block (ISB) using plain bupivacaine with adjuvants vs. liposomal bupivacaine on mean postoperative pain levels in patients who have undergone a total shoulder arthroplasty within the first 48 hours. Principal Investigators hypothesize that ISB using plain bupivacaine with adjuvants will provide similar pain relief as ISB using liposomal bupivacaine.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Liposomal bupivacaine intervention 2: Bupivacaine with adjuvants
Intervention descriptions: intervention 1: Interscalene brachial plexus blockade using liposomal bupivacaine (expanded with plain bupivacaine) intervention 2: Interscalene brachial plexus blockade using plain bupivacaine with adjuvants: clonidine, epinephrine, buprenorphine, dexamethasone.

Protocol documents:
Prot_SAP_001.pdf: 
Official Title:  Single Injection Interscalene Brachial Plexus Nerve Block With Adjuvants 
vs. Liposomal Bupivacaine Interscalene Brachial Plexus Nerve Block for Total Shoulder 
Arthroplasty
NCT03845894
Document Date:  6/9/2020


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Principal Investigator: 
J. Douglas Jaffe, DO
Department of Anesthesiology
Wake Forest School of Medicine
Winston-Salem, NC 27157
jjaffe@wakehealth.edu
336-716-5855
Co-Principal Investigator(s): 
Michael D Font, MD 
Department of Anesthesiology 
Wake Forest School of Medicine 
Winston-Salem, NC 27157 
mfont@wakehealth.edu 
336-716-5855
James D Turner, MD 
Department of Anesthesiology 
Wake Forest School of Medicine 
Winston-Salem, NC 27157 
jturner@wakehealth.edu 
336-716-5855
Biostatistician: 
Hiaying Chen  
Department of Biostatistical Sciences 
Division of Public Health Sciences 
hchen@wakehealth.edu 
336-716-4431


 
 
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Table of Contents 
SCHEMA .................................................................................................................................................. 4 
1.0 
Introduction and Background ....................................................................................................... 5 
2.0 
Objectives ..................................................................................................................................... 6 
2.1 
Primary Objective(s) ................................................................................................................. 6 
2.2 
Secondary Objective(s) ............................................................................................................. 6 
3.0 
Patient Selection ........................................................................................................................... 7 
3.1 
Inclusion Criteria ...................................................................................................................... 7 
3.2 
Exclusion Criteria ..................................................................................................................... 7 
4.0 
Study Outcomes and Study Measures .......................................................................................... 8 
4.1 
Primary Outcome ...................................................................................................................... 8 
4.2 
Secondary Outcomes ................................................................................................................ 8 
5.0 
Treatment Plan .............................................................................................................................. 9 
5.1 
Study-Related Activities ........................................................................................................... 9 
5.2 
Treatment Administration ....................................................................................................... 10 
5.3 
General Concomitant Medication and Supportive Care Guidelines ....................................... 11 
5.4 
Duration of Follow Up ............................................................................................................ 11 
   5.5       Safety Monitoring Plan……………………………………………………………………...12
 
 
6.0 
Statistical Considerations ............................................................................................................ 12 
6.1 
Analysis of Primary Objective................................................................................................ 12 
6.2 
Analysis of Secondary Objective............................................................................................ 13 
6.3 
Power and Sample Size .......................................................................................................... 13 
    6.4      Accrual Rate…………………………….………………..…………………………………..13 
 
6.5 
Estimated Study Length .......................................................................................................... 14 
6.6 
Interim Analysis Plan ............................................................................................................. 14 
7.0 
Adverse Event Reporting 
    
      
 
References ............................................................................................................................................... 18 


 
 
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Appendix A – Eligibility Checklist ........................................................................................................ 20 
Appendix B – Protocol Registration Form ............................................................................................. 22 
Appendix C – Pain Assessment Form .................................................................................................... 23 
Appendix D – Visual Analog Scale ........................................................................................................ 24 
Appendix E – Satisfaction Questionaire ................................................................................................. 25 
Appendix F – Off-Study Form ............................................................................................................... 26 
Appendix G –Pain Medication Diary ..................................................................................................... 28 
Appendix H –Data Collection Form ....................................................................................................... 29 
Appendix I - Adverse Event Grading Definitions……………………………………………………...31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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SCHEMA 
 
 
 
 
 
 
Pre-operative consent and pre-study 
data collection 
Randomization 
ISB using Plain Bupivacaine + 
adjuvants 
ISB using Liposomal Bupivacaine  
 
Shoulder arthroplasty 
Postoperative multimodal analgesia 
 
Pain assessment and opioid consumption tracked by nursing assessments 
and/or diary/phone every 12h.  
 
Satisfaction questionnaire 
Recovery in PACU 
 
Postoperative pain assessment 
and administration of rescue pain 
medications 
Preoperative Multimodal Regimen 


 
 
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1.0 
Introduction and Background 
 
In 2011, liposomal bupivacaine received FDA approval for the use of local surgical site infiltration, 
and its use has become common for a variety of abdominal, gynecological, and orthopedic surgeries, 
with varying efficacy.1,2,3Studies evaluating the efficacy of liposomal bupivacaine for regional 
procedures have also displayed mixed results.4 
 
Liposomal bupivacaine has recently been approved by the FDA for use in brachial plexus blocks for 
patients undergoing major shoulder surgery.5 Per the manufacturer’s data, ISB using liposomal 
bupivacaine provided significant pain reduction in the first 48 hours after surgery compared to ISB 
using placebo, establishing that liposomal bupivacaine has an opioid sparing effect in this patient 
population without significant risk. 
 
A recent study compared the addition of liposomal bupivacaine to plain bupivacaine for interscalene 
blocks in patients undergoing shoulder surgery, and found a modest improvement in pain.6  
 
At a cost of about $300 per administration for liposomal bupivacaine, there are significant economic 
impacts to be considered, given that plain bupivacaine is significantly less expensive.  Data from future 
studies are required to perform a cost-benefit analysis for this new drug.  
 
Common and relatively inexpensive adjuvants have been shown to extend the duration of analgesia 
provided by interscalene nerve blocks (ISB) using plain bupivacaine, with a significant analgesic effect 
extending up to 48 hours postoperatively.7–9  
 
To date, there has been no study comparing the efficacy of ISB using liposomal bupivacaine vs plain 
bupivacaine with these common adjuvants, such as epinephrine, dexamethasone, clonidine, and 
buprenorphine.  
 
The purpose of this study is to determine whether the use of plain bupivacaine with common adjuvants 
for ISB provides non-inferior analgesic results compared to the use of liposomal bupivacaine for ISB, 
in patients undergoing primary total shoulder arthroplasty.  
 
LB= Liposomal bupivacaine 
PBA= Plain bupivacaine + adjuvants 
ISB= Interscalene peripheral nerve block 
 
 
 
 
 


 
 
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2.0 
Objectives 
 
2.1 
Primary Objective(s) 
 
2.1.1 The primary objective of this clinical study is to evaluate the comparative 
efficacy of ISB using plain bupivacaine with adjuvants vs. liposomal 
bupivacaine on mean postoperative pain levels in patients who have undergone 
shoulder arthroplasty within the first 48 hours. We hypothesize that ISB using 
plain bupivacaine with adjuvants will provide similar pain relief as ISB using 
liposomal bupivacaine.  
 
2.2 
Secondary Objective(s) 
 
 
2.2.1 To evaluate the effect of ISB using plain bupivacaine with adjuvants vs. 
liposomal bupivacaine on pain control at the single time point of 48 hours post- 
surgery.  
 
2.2.2 To evaluate the effect of ISB using plain bupivacaine with adjuvants vs. 
liposomal bupivacaine on cumulative postoperative opioid consumption within 
the first 48 hours after shoulder arthroplasty.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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3.0 
Patient Selection 
 
3.1 
Inclusion Criteria  
3.1.1 All patients undergoing primary total shoulder arthroplasty 
3.1.2 Age ≥ 18 years   
3.1.3 Ability to understand and the willingness to sign an IRB-approved informed 
consent document. 
3.1.4 ASA patient status I-III patients 
3.1.5 Weight Greater than or equal to 50 kg 
3.2 
Exclusion Criteria  
 
3.2.1 No contraindications to an interscalene block or phrenic blockade.  
3.2.2 Infection at injection site.  
3.2.3 Pre-existing neurological dysfunction affecting the operative extremity.  
3.2.4 Chronic pain diagnosis or opioid use >40mg oxycodone daily equivalents or use 
of long-acting opioids. 
3.2.5 BMI >40 
3.2.6 Uncontrolled diabetes (A1c >8.0) 
3.2.7 Concurrent painful physical condition requiring analgesic treatment (eg, NSAID 
or opioid) in the postsurgical period for pain not strictly related to the surgery 
3.2.8 Contraindications to any pain-control agents planned for surgical or postsurgical 
use (i.e., bupivacaine, hydromorphone, etc.) 
3.2.9 Patients who are wards of the state  
3.2.10 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to bupivacaine or liposomal bupivacaine. 
3.2.11 Patients with moderate-severe hepatic or renal impairment because of the 
increased risk of toxicity. 
3.2.12 Patients who are pregnant. 
3.2.13 Patients who are lactating. 
3.2.14 Patients with hypersensitivity to any of the study drugs, including 
dexamethasone, clonidine, and buprenorphine. 
3.2.15 Patients with labeled contraindications for the study drugs, such as systemic 
fungal infections. 
3.2.16 Patients undergoing repeat shoulder arthroplasty or reverse total shoulder 
arthroplasty. 
 
 
 


 
 
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4.0 
Study Outcomes and Study Measures 
4.1 
Primary Outcome 
 
4.1.1 The primary outcome of this study is the area-under-the-curve (AUC) of the 
mean visual analog scores numerical rating system (VAS-NRS) within the first 
48 hours postoperatively. Pain levels (with shoulder movement) will be 
measured upon arrival to the PACU, at 6 hours, 12 hours, 24 hours, 36 hours, 
and 48 hours after surgery.   
4.1.1.1 
The mean AUC48 of the liposomal bupivacaine ISB group was 136.4 
with a standard error of 12.09. 10 
4.1.1.2 
There are no existing data to predict the mean AUC48 for ISB using 
plain bupivacaine +adjuvants, but we predict that this value will be 
within 20% of the mean AUC48 of the liposomal bupivacaine group, 
for a value of ~163.0. 
4.2 
Secondary Outcomes 
 
4.2.1 Mean VAS-NRS pain score at 48 hours.  
4.2.1.1 
For patients undergoing ISB with liposomal bupivacaine, the mean 
VAS pain score at 48 hours was 3.39 with a standard error of 0.37.10 
4.2.1.2 
There are no existing data to predict the mean VAS pain score at 48 
hours for patients undergoing ISB with plain bupivacaine + 
adjuvants, however a similar study using plain bupivacaine alone 
demonstrated a mean NRS (similar to VAS) pain score of 5.5 with 
standard error +/-0.56. We expect the mean pain score to be slightly 
below this value, approximately 4.5. 
 
4.2.2 Postoperative opioid consumption  
4.2.2.1 
The mean rescue opioid consumption (in IV morphine equivalents) 
in the first 48 hours after receiving ISB using liposomal bupivacaine 
was 12.0 +/- 2.3 in a previous study.10 
4.2.2.2 
We expect the patients treated with plain bupivacaine and adjuvants 
to use a similar average of 12.0 intravenous morphine equivalents in 
the first 48-hours following surgery. For the purpose of this study, 
we will convert IV morphine equivalents to oral codeine equivalents.  
 
4.2.3 Satisfaction with surgical experience 
4.2.3.1 
At the 48 hour mark, the patient’s satisfaction with the surgical 
experience, satisfaction with pain control, and willingness to 
recommend the procedure to another patient will be assessed via 
Likert scale.  Adverse events will also be evaluated. 
 


 
 
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5.0 
Treatment Plan 
Table 1- Protocol stages 
 
 
Day of 
Surgery- 
Pre-op 
Intraoperative 
15 
departure 
from 
PACU 
6 
hours 
postop 
12 
hours 
postop 
24 
hours 
postop 
36 
hours 
postop 
48 
hours 
postop 
Pre-operative pain 
score 
X 
 
 
 
 
 
 
 
Preoperative 
multimodal 
regimen unless 
contraindicated 
X 
 
 
 
 
 
 
 
Receive ISB with   
Exparel or plain 
bupivacaine + 
adjuvants 
X 
 
 
 
 
 
 
 
Receive short-
acting  IV opioids 
if needed  
 
X 
 
 
 
 
 
 
Rescue opioids if 
needed  
 
 
 
X 
X 
X 
X 
X 
X 
Postoperative 
multimodal 
regimen 
 
 
 
X 
X 
X 
X 
X 
Pain score 
assessment in diary 
 
 
X 
X 
X 
X 
X 
X 
Patent diary of 
narcotic use 
 
 
X 
X 
X 
X 
X 
X 
Study coordinator 
contact via phone 
call 
 
 
 
 
 
X 
 
X 
Patient satisfaction 
assessed via Likert 
scale. Review of 
potential adverse 
events 
 
 
 
 
 
 
 
X 
 
 
5.1 Study-Related Activities  
 
Patients will be recruited from 2 sites- Wake Forest Baptist Health (Main Campus) and WFBH 
Davie. Patient involvement in the study will be initiated upon scheduling of their surgery with the 
Anesthesiology team. Eligible subjects will be identified via eligibility checklist (Appendix A) 
and contacted via phone call to inform them of the study and give them a brief overview. On the 
day of surgery, the consent for the study will be obtained after a pre-operative assessment and 
prior to initiating the regional block by the RAAPM team.  
 


 
 
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The study coordinator will then assign the patients will receive a study number, and the patient 
will be randomized by computer software algorithm to one of the study arms: 
 
1. ISB using liposomal bupivacaine 
2. ISB using plain bupivacaine with adjuvants 
 
The study will be double blinded to patients, the perioperative nurses, the surgeon, and the study 
coordinators contacting the patient post-surgery.  
 
To monitor our primary outcomes, patients will be asked to rate their pain level on a visual 
analog scale (Table 2, Appendix D) upon discharge from the PACU. Following discharge, they 
will continue to get every 12-hour pain assessments performed by research staff in person and/or 
over the phone (if they are discharged) until 48 hours have passed.  
 
 
Table 2: Visual Analog Scale 
 
 
Additionally, upon discharge, patients will be given a sheet to record the amount of narcotics 
and the time that they were used (Appendix G).  At the 48-hour mark, patient’s will be asked to 
rate their satisfaction with the procedure, and their willingness to recommend it, via Likert 
scale (Appendix E).  
 
 
5.2 
Treatment Administration 
 
Patients assigned to the ISB with liposomal bupivacaine group will receive a 20cc solution of 
133mg liposomal bupivacaine (10mL expanded with 10mL 0.25% plain bupivacaine) in an 
interscalene block, conducted via Ultrasound guidance.  
 
Patients assigned to the ISB with plain bupivacaine and adjuvants group will receive a 20cc 
solution of plain bupivacaine 0.25% with adjuvants (clonidine 1.6mcg/mL, epinephrine 


 
 
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2.5mcg/mL, dexamethasone 0.1mg/mL, and buprenorphine 150mcg) in an interscalene block, 
conducted via Ultrasound guidance. 
 
The absolute dosages of medications will be as follows: either 133mg liposomal bupivacaine 
with 25mg plain bupivacaine OR 50mg plain bupivacaine with adjunct medicines: 32mcg 
clonidine, 50mcg epinephrine, 2mg dexamethasone and 150mcg buprenorphine.  
 
The treatment will be administered by either an attending anesthesiologist, or a resident 
anesthesiologist under the supervision of an attending.  
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
This local anesthetic will get delivered at the time of surgery by an attending or resident 
anesthesiologist. Standardized anesthetic criteria will be applied to all patients enrolled in the 
study. Pre-operatively, all patients will receive multi-modal therapy, such as acetaminophen 
1000 mg PO, celecoxib 200 mg PO, and gabapentin 300 mg PO  or pregabalin 150 mg 
PO unless contraindicated based on past medical history.  
 
Intraoperatively, patients will only receive short acting opioids for analgesia, such as fentanyl 
as needed. Intraoperative ketamine and dexamethasone will be avoided. Postoperative non-
opioid medications will supplement as needed opioid mediations for analgesic 
management.  Postoperative pain management for breakthrough pain will include the following 
options: IV fentanyl, IV hydromorphone, or PO oxycodone.  
 
 
Patients will receive full supportive care as medically necessary, including transfusions of 
blood and blood products, antibiotics, antiemetics, etc. Medications considered necessary for 
the patient's well-being may be given as long as they are considered safe in the postoperative 
period and clinically indicated. The reason(s) for treatment, dosage, and dates of treatment will 
be recorded on the flow sheets. 
 
Anesthesia monitoring for the study procedure will following institutional guidelines.  It 
includes the following:  vital signs (blood pressure, heart rate, respiratory rate, and oxygen 
saturation) will be initiated in the regional anesthesia holding room at the time of procedure 
time out, and includes parameters measured every 5 minutes until subject goes to the operating 
room.  At that time routine anesthesia monitoring continues with vital signs every 3 minutes.  
Once the subject enters the post anesthesia care unit the vital sign monitoring is every 15 
minutes until discharge.    
5.4 
Duration of Follow Up 
 


 
 
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Patients will be followed by research personnel upon arrival to the PACU, again 6 hours 
postoperatively, and then at 12, 24, 36 and 48 hours after surgery both in the hospital and at 
home via phone call.   
 
5.5     Safety Monitoring Plan 
 
Any adverse safety events occurring in the perioperative period (pre-op, intra-op, or PACU) 
will be reported by the attending anesthesiologist to the PI and the study coordinator. The PI 
will record these events and contact the patient to determine the result of these events and 
arrange any follow-up care that is necessary.  
 
Patients will be instructed to contact the research team to report any adverse events that occur 
in the postoperative period (after discharge). Patients will be given daytime and evening contact 
numbers for the PI and the Regional Anesthesia team (on call 24/7) via telephone. These events 
will be reported to the PI and the study coordinator. The PI will record these events and contact 
the patient to determine the result of these events and arrange any follow-up care that is 
necessary.  
 
Serious adverse events will be reviewed by the PI and reported to the IRB promptly within 48 
hours.   Adverse events of special interest include the following: local anesthetic systemic 
toxicity, chest pain, shortness of breath, altered sensorium, tinnitus, visual disturbance, and 
severe dizziness. 
 
6 Statistical Considerations 
 
6.1 Analysis of Primary Objective  
 
6.1.1  The VAS-NRS scale is an 11-point scale that assesses pain from 0- “No pain” to 10- “Worst 
possible pain”. For this study, a difference of >=2 points will be considered to be clinically 
significant.  Pain scores will be taken measured on departure from the PACU and at each 12-
hour interval, and average pain scores for each cohort will be calculated. The area under the 
curve (AUC) for each cohort will be calculated using the least squares method. The inferiority 
threshold will be set as >=2 points over 48 hours, which would result in an AUC difference of 
96 point-hours.  
 
Prior studies have found an AUC48 for ISB using liposomal bupivacaine to be 
136.4 with a standard error of 12.09.10 There are no data evaluating the AUC48 
for ISB using plain bupivacaine with adjuvants; however we estimate that the 


 
 
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pain scores will be within 20% of that of liposomal bupivacaine, resulting in an 
AUC48 of 163.0 or below, and a similar standard error of 12.09.  
 
With a 2-sample t test using α = 0.05 and β= 0.1, the study will be powered to 
detect a difference of 96 point-hours between the 2 groups with 36 subjects per 
arm.   
 
To test for differences in these AUC between the 2 arms, an independent t-test 
will be used; if the observed p-value is <0.05, statistical significance will be 
assumed. Two-sided t-test will be performed for statistical analysis once data 
collection is complete.  
 
6.2 Analysis of Secondary Objectives 
 
6.2.1 For the mean VAS-NRS score at 48 hours, prior studies have found an average score of 3.8 
with a standard deviation of 2.88 (standard error of 0.36) for ISB using liposomal 
bupivacaine.10 There have been no studies to evaluate the pain scores after ISB using plain 
bupivacaine with adjuvants. This study will be powered to detect a difference of at least 0.4 on 
the VAS-NRS scale. We will define the threshold for inferiority as a difference of >=2 points 
on the VAS scale. Analysis will be conducted using a two-sample t test with α= 0.05 and β= 
0.1. 
 
6.2.2 For the comparison of post-operative opioid consumption, each patient’s total post-operative 
opioid usage during the first 48 hours will be converted to oxycodone equivalents. The 
geometric mean opioid consumption for each cohort will be calculated, and the two cohorts 
will be compared for statistical difference using a two-sample t test, with α= 0.05 and β= 0.1. 
 
6.2.3 Patient satisfaction will be assessed on POD#2 by 5-point Likert rating scale, and via a binary 
question of “would you recommend this pain relief regiment to the next patient”. The results of 
these questions will be compared with a Fisher’s Exact Test, with α= 0.05. 
 
6.3 Power and Sample Size 
 
We will have a power of 80%, as described in 10.1.1, with a sample size of 36 patients 
in each arm for a total of 72 patients, plus 8 patients to allow for attrition, for a total of 
80 patients.   
 
6.4 Accrual Rate  
 
We plan on accruing 10 new patients per month until the goal of 80 total patients is 
reached.   


 
 
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6.5 Estimated Study Length 
 
Estimated study length will be approximately 1 year.  
6.6 Interim Analysis Plan 
 
We will plan on performing an interim analysis for the primary outcome and secondary 
outcomes after there are at least 10 patients in each treatment group in order to detect 
the evidence of severe side effects in either group.  
 
7.0  
Adverse Event Reporting 
 
 
Adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction. An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
Serious adverse event or serious suspected adverse reaction. An adverse event or 
suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, "reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction implies 
a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 
Unexpected adverse event or unexpected suspected adverse reaction. An adverse event 
or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in 


 
 
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the current application, as amended. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the investigator brochure referred 
only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater specificity) if the 
investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in 
this definition, also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
 
The investigator will assess the relationship/causality of the AE to study drug after 
careful medical consideration on a case-by-case basis. General guidelines for 
determining the causality of an AE to the study drug are provided as follows: 
 
Unrelated: A causal relationship between the study drug and the AE can be easily ruled 
out(e.g., based on the temporal sequence, absence of a reasonable pathophysiological 
mechanism, or direct evidence of actual cause). 
 
Unlikely: A clinical event with a temporal relationship to study drug administration 
which makes a causal relationship improbable and in which other drugs, chemicals, or 
underlying disease provide a plausible explanation. 
 
Possible: A clinical event with a reasonable time sequence to administration of the 
study drug but which could also be explained by a concurrent disease or other drugs or 
chemicals. 
 
Probable: A clinical event with a reasonable time sequence to administration of the 
study drug unlikely to be attributed to a concurrent disease or other drugs or chemicals 
and which follows a clinically reasonable response on withdrawal (dechallenge). 
 
Definite: The pharmacological properties of the study drug(s) or of the substance class, 
and the course of the AE after dechallenge and, if applicable, after rechallenge, and/or 
specific test indicate involvement of the study drug(s) in the occurrence/worsening of 
the AE, and no indication of other causes exists. 
 
The investigator will assess the outcome of the AE after careful medical consideration, 
on a case-by-case basis. General guidelines are provided below: 
 
Recovered/Resolved: The event resolved and the subject recovered from the AE. 
Recovered/Resolved with Sequelae:  The initial event resolved, but has a continuing 
abnormal condition as a result of the AE. 
Not Recovered/Not Resolved:  At the time of the last assessment, the event was 
ongoing, with an undetermined outcome.  


 
 
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Recovering/Resolving: At the time of the last assessment, the event was decreasing in 
frequency, severity, etc., and a resolution was expected. 
Fatal: The AE directly caused death. 
Unknown: There was an inability to access the subject or the subject’s records to 
determine the outcome (e.g., subject withdrew consent or was lost to follow-up). 
 
The subject will receive adequate medical care by the medical provider for any adverse 
events related to the clinical trial.  The investigator will provide any actions taken 
regarding the subject (e.g., treatment, diagnostic tests, laboratory tests, or therapy) for 
each reported AE.  These include the following options: 
 None. 
 Medication. 
 Non-pharmaceutical therapy. (The specific therapy used must be recorded in the data 
collection sheet) 
 Discontinued from study. 
 Other-document specific action taken 
 
Serious and unexpected suspected adverse reaction:  The investigator will report any 
suspected adverse reaction that is both serious and unexpected. The investigator will 
report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as if the 
study participation meets one of the following criteria:  
(A) A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure;  
(B) One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug;  
(C) An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group.   
 
In case a cardiac or neurological AE of special interest (AESI) or serious AE (SAE) 
occurs during the study, if the investigator considers that the event may be related to 
study treatment or suggests the possible occurrence of local anesthetic systemic toxicity 
(LAST; with or without the need for treatment [e.g., intralipids]), or if a plausible 
etiology for the event cannot be found, vital signs, and clinical laboratory tests will be 
performed per institutional standard of care of such occurrence.  Cardiac AESIs include 
chest pain, abnormal/irregular heart rate, and shortness of breath requiring intervention. 


 
 
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Neurologic AESIs include seizure, altered mental status/altered sensorium, tinnitus, 
visual disturbance, and severe dizziness.  
 
This study involves a single administration of the study drug for the analgesic block; 
therefore, subjects should not be withdrawn from the ongoing study assessments as long 
as they are willing and able to continue with the follow-up schedule according to the 
protocol in order to obtain analgesic and safety data.  Any subject exhibiting 
undesirable AESIs will receive appropriate treatment at the discretion of the 
investigator. 
 
Subjects will be monitored for the occurrence of all potential adverse events by research 
personnel.  This clinical research study will be paused after one death where a clear 
alternate cause is not readily apparent.  The study will be paused after 2 non-fatal SAEs 
where a clear alternate cause is not readily apparent; the study will be paused after 3 
moderate or severe adverse events of special interest. The adverse event(s) will be 
assessed by all investigators for causality and relationship prior to the study enrollment 
being resumed.   Assessment of adverse event severity will be assessed and graded as 
per the definitions noted in Appendix I.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.0 Study Costs 
The funding for the medications used in this study is supplied by an internal departmental 
research grant from the WFBH Department of Anesthesiology. The research participants will 
not experience any additional fees or costs for participation in this study outside of the usual 
anesthesiologist’s fee for surgery. The research participant will still incur the cost of the actual 
procedure as it is done as standard of care.  


 
 
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References 
 
1.  
Sakamoto B, Keiser S, Meldrum R, Harker G, Freese A. Efficacy of liposomal bupivacaine 
infiltration on the management of total knee arthroplasty. JAMA Surg. 2017;152(1):90-95. 
doi:10.1001/jamasurg.2016.3474 
2.  
Hamilton TW, Athanassoglou V, Mellon S, et al. Liposomal bupivacaine infiltration at the 
surgical site for the management of postoperative pain. Cochrane Database Syst Rev. 
2017;2017(2). doi:10.1002/14651858.CD011419.pub2 
3.  
Pichler L, Poeran J, Zubizarreta N, et al. Liposomal Bupivacaine Does Not Reduce Inpatient 
Opioid Prescription or Related Complications after Knee Arthroplasty: A Database Analysis. 
Anesthesiology. 2018;(October). doi:https://dx.doi.org/10.1097/ALN.0000000000002267 
4.  
Hamilton TW, Athanassoglou V, Trivella M, et al. Liposomal bupivacaine peripheral nerve 
block for the management of postoperative pain. Cochrane Database Syst Rev. 2016;2016(8). 
doi:10.1002/14651858.CD011476.pub2 
5.  
Rabin T. FDA In Brief: FDA approves new use of Exparel for nerve block pain relief following 
shoulder surgeries. https://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/ucm604021.htm. 
Published 2018. 
6.  
Vandepitte C, Kuroda M, Witvrouw R, et al. Addition of liposome bupivacaine to bupivacaine 
HCl versus bupivacaine HCl alone for interscalene brachial plexus block in patients having 
major shoulder surgery. Reg Anesth Pain Med. 2017;42(3):334-341. 
doi:10.1097/AAP.0000000000000560 
7.  
Vieira PA, Pulai I, Tsao GC, Manikantan P, Kelle B, Connelly NR. Dexamethasone with 
bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus 
blockade. Eur J Anaesthesiol. 2010;27(3):285-288. doi:10.1097/EJA.0b013e3283350c38 
8.  
Baeriswyl M, Kirkham KR, Jacot-Guillarmod A, Albrecht E. Efficacy of perineural vs systemic 
dexamethasone to prolong analgesia after peripheral nerve block: A systematic review and 
meta-analysis. Br J Anaesth. 2017;119(2):183-191. doi:10.1093/bja/aex191 
9.  
Candido KD, Winnie AP, Ghaleb AH, Fattouh MW, Franco CD. Buprenorphine added to the 
local anesthetic for axillary brachial plexus block prolongs postoperative analgesia. Reg Anesth 
Pain Med. 2002;27(2):162-167. doi:10.1053/rapm.2002.30671 
10.  
Patel M, Gadsen J, Bao X, Bendsten T. Brachial Plexus Block With Liposomal Bupivacaine for 
Total Shoulder Arthroplasty or Rotator Cuff Repair: Results from a Randomized Controlled 
Trial. Poster Present NYSORA 16th Annu Symp. 2016:31-32. https://nysorasymposium.com/wp-
content/uploads/2016/02/NYSORA-Sep-2017-all-Abstracts-2017.08.16-revised-1.pdf. 
11.  
US Food and Drug Administration. Indications and Usage of Liposomal Bupivacaine. Silver 
Spring, MD; 2018. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022496s9lbl.pdf. 
12.  
US Food and Drug Administration. Indications and Usage of Bupivacaine Hydrochloride and 
Epinephrine Injection. Vol 000. Silver Spring, MD 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018692s015lbl.pdf. 
 
 
 


 
 
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Appendix A- Eligibility Checklist 
 
 
IRB Protocol No. _00055981__ 
SUBJECT ID:   
Study Title: SINGLE INJECTION INTERSCALENE BRACHIAL PLEXUS NERVE BLOCK WITH ADJUVANTS VS. 
LIPOSOMAL BUPIVACAINE INTERSCALENE BRACHIAL PLEXUS NERVE BLOCK FOR TOTAL SHOULDER 
ARTHROPLASTY 
Principal Investigator:  Doug Jaffe, D.O.  
 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
All patients who are undergoing total shoulder 
arthroplasty 
 
□ 
□ 
 
Age >18 years  
□ 
□ 
 
Ability to understand and willingness to sign IRB-
approved informed consent document  
□ 
□ 
 
Weight Greater than or equal to 50 kg 
□ 
□ 
 
ASA patient status I-III 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
No contraindications to an interscalene block or 
phrenic blockade. 
□ 
□ 
 
Infection at injection site. 
□ 
□ 
 
Pre-existing neurological dysfunction affecting the 
operative extremity. 
□ 
□ 
 
Patients who abuse narcotics or have chronic pain 
(using greater than 40 mg equivalents of oxycodone 
per day) 
 
□ 
□ 
 
Patients who are wards of the state  
 
□ 
□ 
 
BMI >40  
□ 
□ 
 
Uncontrolled diabetes (HbA1c >8.0) 
□ 
□ 
 
Contraindications to any pain-control agents 
planned for surgical or postsurgical use (ie, 
bupivacaine, hydromorphone, etc.) 
□ 
□ 
 


 
 
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History of allergic reactions attributed to 
compounds of similar chemical or biologic 
composition to bupivacaine or liposomal 
bupivacaine or its adjuncts (dexamethasone, 
buprenorphine, or clonidine). 
 
□ 
□ 
 
Patients with moderate-severe hepatic or renal 
impairment. 
□ 
□ 
 
Patient is pregnant or lactating 
□ 
□ 
 
Patient has a labeled contraindication for the study 
drug, such as a systemic fungal infection 
 
□ 
□ 
 
Patients undergoing repeat shoulder arthroplasty or 
reverse total shoulder arthroplasty. 
 
□ 
□ 
 
 
This subject is      
 eligible / 
 ineligible     for participation in this study. 
 
REDCap Assigned PID: ___ ___ ___ ___ ___ ___ ___ ___  
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility: _______________________  
 
Date: ___ ___ / ___ ___ / ___ ___ 
 
Signature of Treating Physician:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
Signature of Principal Investigator**:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, physical exam, etc. When listing 
the source, specifically state which document in the medical record was used to assess eligibility. Also include the date on 
the document. Example: Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed 
 
 
 
 
 
 
 


 
 
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Appendix B – Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name: _____________________ 
First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ 
DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE:  
___ ___ ___ ___ ___ 
 
 
SEX:   
  Male      Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ____________________________________________________________ 
 
 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES   NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by REDCap): 
___ ___ ___ ___ ___ ___ ___ ___ 
 


 
 
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Appendix C – Pain Assessment Form 
Subject Number:___ ___ ___ ___ ___ ___ ___ ___ DATE: __ __/__ __/__ __TIME: __ __:__ __AM/PM 
 
1 - Rate the intensity of your worst pain in the past 12 hours related to your 
operated shoulder 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
2 - Did you take prescription pain pills in the past 24 hours?   YES 
NO 
 
If yes please circle the medication below  
 
 
2a1 – Oxycodone  (Roxicodone)            
 
 
 
 
2a2 - Hydromorphone (Dilaudid)      
 
 
 
  
 
2a3 - Hydrocodone + acetaminophen (Vicodin, Norco)  
  
 
2a4- Oxycodone + acetaminophen (Percocet) 
 
2a5 -Diazepam (Valium)   
 
2a6- Alprazolam (Xanax) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix D- Verbal Numerical Rating Scale 
 
 
 
 
 
 
 
https://www.physio-pedia.com/images/4/47/NRS_pain.jpg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix E – Satisfaction Questionnaire  
 
Subject Number:___ ___ ___ ___ ___ ___ ___ _DATE: __ __/__ __/__ __TIME: __ __:__ __AM/PM 
 
 
 
Instructions: On the second day (48 hours) after surgery, please review the following questions, and 
choose the answer that best corresponds to each question regarding your experience.  
 
 
 
 
 
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly 
Agree 
I believe my pain was well-controlled during 
after surgery. 
 
 
 
 
 
 
 
I would recommend this pain-control treatment 
to another patient. 
 
 
 
 
 
 
Have you had any itching since your surgery 
in your shoulder area? 
YES 
NO 
Have you had any nausea and/or vomiting 
since your surgery? 
YES 
NO 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix F – Off-Study Form  
 
Study Number: __ __ __ __ __ 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
Investigator: J. Doug Jaffe, DO 
Date: __ __/__ __/__ __ 
 
Name of Person Competing form_____________________________ 
 
Did the subject meet eligibility criteria for study enrollment?   Yes 
   No 
 
 
Was the subject withdrawn from the study?  Yes 
   No 
 
 
Reason(s) for withdrawal:  
1. 
 Patient exhibited progression of disease 
 
2. 
 Unacceptable toxicity /adverse event of special interest:  if so, list event/submit as adverse 
event on case report form  
If Yes, Please specify whether the toxicity was: 
 
 
 From Bupivacaine 
 From Liposomal Bupivacaine 
 From BOTH 
 Other _______________________ 
 
Adverse event of special interest and reportable to the IRB? 
If so, date reported:  __________________ 
 
3. 
 Patient withdraw 
 
If Yes, Please specify what portion of the study the subject wishes to withdraw from: 
 
 
 
 For just the Drug A administration only 
 For just the Drug B administration only 
 For both 
 For all components of the research study (including follow up in the medical record)  
 


 
 
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4. 
 Investigator’s discretion to withdraw patient from the study because continued participation 
in the study is not in the patient’s best interest (*Describe below) 
 
5. 
 Undercurrent illness: a condition, injury, or disease unrelated to the intended disease for 
which the study is investigating, that renders continuing the treatment unsafe or regular follow-
up impossible (*Describe below) 
 
6. 
 General or specific changes in the patient’s condition that renders the patient ineligible for 
further investigational treatment (*Describe below) 
 
7. 
 Non-compliance with investigational treatment, protocol-required evaluations or follow-up 
visits (*Describe below) 
 
8. 
 Termination of the clinical trial by the principal investigator 
 
Comment: 
 
If reason for withdrawal includes #4, 5, 6, or 7 then please add comments clarifying this 
information)________________________________________________________________________
__________________________________________________________________________________
__________________________________________________________________________________
__________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix G- Pain Medication Diary.  
Assists patients in recording the amount and time of narcotic and benzodiazepine use. 
 
 
Date 
Pain Medication Used 
(Include dose) 
Number of pills taken 
Time 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 


 
 
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28 
 
 
 
 
29 
 
 
 
 
30 
 
 
 
 
31 
 
 
 
 
32 
 
 
 
 
33 
 
 
 
 
 
 
 
 
 
 
Appendix H- Data Collection Form 
 
  
Assigned Study Number:  
 
Demographics 
WakeOne MRN 
 
Age 
 
Sex 
 
Procedure 
 
Medical Hx 
Comorbidities 
 
 
 
Pre-surgical analgesics 
Preop pain score 
 
Pre-Op  
Pre-op multimodal 
analgesics 
Post-Block assessment 
 
Intraop 
Intra-op Narcotics (PO oxy 
equivalents) 
 
PACU 
Pain score in PACU p/t 
discharge 
PACU block assessment 
 
PACU opioids (PO oxy 
equivalents) 
 
+6hr worst pain score 
(VAS) 
 


 
 
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Post OP 
+12h worst pain score 
(VAS) 
 
+24h worst pain score 
(VAS) 
 
+36h worst pain score 
(VAS) 
 
+48h worst pain score 
(VAS) 
+6hr opioid use (PO oxy 
eq) 
 
+12h opioid use (PO oxy 
eq) 
 
+24h opioid use (PO oxy 
eq) 
 
+36h opioid use (PO oxy 
eq) 
 
+48h opioid use (PO oxy 
eq) 
 
Likert Satisfaction  #1 
 
Likert satisfaction #2 
 
  
Nonopioid Analgesics 
Used 
Side effect evaluation 
(Itching, Nausea/vomiting) 
 
 
Off study 
("OFF" if applicable) 
 
Reasons: 
 
 
Date of study completion:   
 
Evaluable subject? 
 
Protocol deviations? 


 
 
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APPENDIX I:  ADVERSE EVENT GRADING SCALES  
LOCAL REACTION TO 
INJECTABLE PRODUCT 
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Potential life threatening 
(Grade 4) 
Pain
Does not interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room visit or 
hospitalization 
Tenderness
Mild discomfort to touch
Discomfort with 
movement 
Significant discomfort 
at rest 
Emergency room visit or 
hospitalization 
Erythema/Redness
2.5-5 cm
5.1-10 cm
>10 cm 
Necrosis or exfoliative dermatitis 
Induration/Swelling
2.5-5 cm and does not 
interfere with activity 
5.1-10 cm or interferes 
with activity 
>10 cm or prevents 
daily activity 
necrosis 
VITAL SIGNS 
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Potentially Life threatening 
(Grade 4) 
Fever-*F
100.4-101.1
101.2-102.0
102.1-104 
>104 
Tachycardia
101-115
116-130
>130 
ER visit or hospitalization for 
arrhythmia 
Bradycardia
50-54
45-49
<45 
ER visit or hospitalization for 
arrhythmia 
Hypertension-systolic
141-150
151-155
>155 
ER visit or hospitalization for 
malignant hypertension 
Hypertension-diastolic
91-95
96-100
>100 
ER visit or hospitalization for 
malignant hypertension 
Hypotension
85-89
80-84
<80 
ER visit or hospitalization for 
hypotensive shock 
Respiratory rate
17-20
21-25
>25 
Intubation 
SYSTEMIC (GENERAL)
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Potentially Life threatening 
(Grade 4) 
Nausea/vomiting
No interference with 
activity or 1 – 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or hospitalization for 
hypotensive shock 
Diarrhea
2 – 3 loose stools
4 – 5 stools
6 or more watery 
stools or requires IV 
hydration 
ER visit or hospitalization 


 
 
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Headache
No interference with 
activity 
Repeated use of 
nonnarcotic pain reliever 
> 24 hours or some 
interference with activity 
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity 
ER visit or hospitalization 
Fatigue
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or hospitalization 
Myalgia
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or hospitalization 
Illness or clinical adverse 
event (as defined 
according to applicable 
regulations 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or hospitalization 
 

ICF_000.pdf: 
Official Title:  Single Injection Interscalene Brachial Plexus Nerve Block With Adjuvants vs. 
Liposomal Bupivacaine Interscalene Brachial Plexus Nerve Block for Total Shoulder 
Arthroplasty 
NCT03845894
IRB-Approved Date: 4/5/2022


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Department of Anesthesiology
SINGLE INJECTION INTERSCALENE BRACHIAL PLEXUS 
NERVE BLOCK WITH ADJUVANTS VS LIPOSOMAL 
BUPIVACAINE INTERSCALENE BRACHIAL PLEXUS NERVE 
BLOCK FOR TOTAL SHOULDER ARTHROPLASTY
Informed Consent Form to Participate in Research
J. Doug Jaffe, DO, Principal Investigator
SUMMARY
You are invited to participate in a research study. You are invited to this study because you are having a 
shoulder surgery performed. For these types of shoulder surgeries, a regional anesthesia technique is used 
called an interscalene block, which is a way to numb the shoulder by injecting medications directly onto 
the nerves. Nerve blocks are commonly used for shoulder surgeries to decrease pain for several days after 
surgery.  
The purpose of this research is to determine whether the amount of pain after shoulder surgery is the same 
for two types of medication used in the regional anesthesia block. The two types of medications are 
liposomal bupivacaine, which is a commonly used long-acting medicine, or regular bupivacaine with 
other medications added to prolong its effect.
Your participation in this research will involve no additional visits, but will consist of a written form to be 
filled out each day and a telephone call daily with a study coordinator for about 3 days.  
Participation in this study will involve having a nerve block done using one of the two types of 
medications. All research studies involve some risks.  The risks for this study is the same type of risk that 
you would have regardless of the medication used to block the nerves. These risks include lasting 
irritation to the nerves, infection at the injection site, bleeding, difficulty breathing, injury to the lung, or 
allergic reaction. These risks, however, are small. 
Your participation in this study is voluntary.  You do not have to participate in this study if you do not 
want to.  There may be other choices available to you.  Some other choices may include undergoing 
regional anesthesia with plain bupivacaine alone.  You will not lose any services, benefits, or rights you 
would normally have if you choose not to participate. 
The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the study. The 
person in charge of this study is Dr. Doug Jaffe. If you have questions, suggestions, or concerns regarding 
this study or you want to withdraw from the study his/her contact information is: 
 
If you have any questions, suggestions or concerns about your rights as a volunteer in this research, 
contact the Institutional Review Board at 
 or the Research Subject Advocate at 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055981
Meeting Date Approved 4/5/2022          
Version Valid Until: 4/4/2023


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INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific knowledge that 
may help other people in the future. You are being asked to take part in this study because you are having 
shoulder surgery. Your participation is voluntary. Please take your time in making your decision as to 
whether or not you wish to participate. Ask your study doctor or the study staff to explain any words or 
information contained in this informed consent document that you do not understand. You may also 
discuss the study with your friends and family.
If you do not wish to be involved in this study, you will still be able to receive a regional nerve block. 
WHY IS THIS STUDY BEING DONE?
A common way to reduce pain associated with shoulder surgery is to numb the nerves that go to the 
shoulder and the arm by doing a procedure called a nerve block. This numbness can last from a few hours 
to a few days, depending on the type of medication used in the nerve block. The medication is injected 
through a small needle in your neck, using an ultrasound machine to guide the needle. 
The purpose of this research study is to compare two modalities of medications used for nerve blocks, to 
see if they provide the same amount of pain relief after surgery. There is currently no standard of care for 
which medications are used in these types of nerve blocks, and patients often receive different types of 
medications. 
Bupivacaine is a medicine that blocks pain from being transmitted by the nerves in your arm. When used 
in a nerve block, it typically gives pain relief up to 6-12 hours after surgery. Medications called 
‘adjuvants’ can be added to bupivacaine to make it last longer. Studies have shown that the addition of 
epinephrine, clonidine, buprenorphine, and dexamethasone to bupivacaine can make it last much longer, 
possibly up to 72 hours. Liposomal bupivacaine, or “Exparel”, is a type of medicine that has been 
approved by the FDA for use in these nerve blocks. Liposomal bupivacaine is a slow-release form of 
bupivacaine that is believed to provide pain relief for up to 36-48 hours after surgery.  
The dosages of medications that you will receive are either 133mg liposomal bupivacaine with 25mg 
plain bupivacaine OR 50mg plain bupivacaine with adjunct medicines: 32mcg clonidine, 50mcg 
epinephrine, 2mg dexamethasone and 150mcg buprenorphine. 
Our goal is to see if regular bupivacaine with adjuvant medications works better, worse, or the same, as 
liposomal bupivacaine in relieving pain after shoulder surgery.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
80 people at 2 research sites (Wake Forest Baptist Health and Wake Forest- Davie Medical Center) will 
take part in this study.
WHAT IS INVOLVED IN THE STUDY?
On the day of your surgery, you will meet with one of the study coordinators to review this consent form. 
If you agree to participate, you will be randomized into one of the study groups described above. 
Randomization means that you are put into a group by chance. It is like flipping a coin. You will have an 
equal chance of receiving either liposomal bupivacaine or plain bupivacaine with added medications in 
your nerve block. You will not know which one you received. The surgeon will not know which 
medication you received, and the study coordinators will not know which medication you received. The 
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anesthesiologist who performs the nerve block will know which medication you received, but he will not 
tell you nor anyone else. 
An anesthesiologist will perform your nerve block using an ultrasound machine to guide a needle onto the 
space next to your nerves, called the brachial plexus. The anesthesiologist will inject the medication 
around the nerves, and your shoulder and arm will go numb after a few minutes. You will be taken to the 
operating room for surgery, where you will be given additional medications for pain and sedation. You 
will be followed by research personnel upon arrival to PACU and every 12 ours postoperatively after 
surgery both in the hospital and at home via a phone call.  Most of your arm will probably still be numb 
during this time, and the numbness will gradually wear off over the next few days. For 3 days after your 
surgery, you will be asked to rate your shoulder pain with movement every 12 hours, and medications you 
use for pain control will also be obtained.  If you are discharged from the hospital before 3 days after your 
surgery, a study coordinator will call you at home until 3 days after surgery has occurred in order to 
obtain your pain scores and pain medications.   
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for 4 days total, including the day of your surgery.  You can stop participating at 
any time. If you decide to stop participating in the study we encourage you to talk to the investigators or 
study staff first to inform them.
WHAT ARE THE RISKS OF THE STUDY?
Nerve blocks are overall very safe, however there is always some risks. The risks of this type of nerve 
block (interscalene nerve block) are: lasting irrigation to the nerves (rare), infection at the injection site, 
bleeding (rare), injury to the lung (rare), or allergic reaction (rare). The risk of these side effects is less 
than 1%. For patients with decreased lung function (like COPD or asthma), the risk of difficulty breathing 
is higher (very common), and these patients will be excluded from this study. These risks are the same 
regardless of the type of medication used in the nerve block. In addition, the medicines used for nerve 
blocks have their own small risks. Liposomal bupivacaine and plain bupivacaine have low risks (less than 
10%) of nausea, constipation, or vomiting. There are very rare risks (less than 1%) of changes in heart 
rhythms or seizures with these medications. Epinephrine has the low risk (less than 1%) of causing a fast 
heartbeat or high blood pressure. Clonidine has the low risk (less than 1%) of causing a slow heartbeat or 
low blood pressure. Buprenorphine has the very small risk (less than 1%) of causing drowsiness or 
causing slow breathing. Dexamethasone has the small risk (less than 1%) of causing increased blood 
sugar. All of these risks are very low, as these medicines will be injected around the nerves in your arm, 
rather than into your bloodstream. 
Your involvement in this study does not increase your risk of adverse effect any more than the risk of a 
regular nerve block. 
This study is comparing two approved methods for treating your condition. You will be randomly 
assigned to one of the two groups. It is possible that one treatment group may have a better response than 
the other. Therefore there is a risk that you may be assigned to a group that does not perform as well as its 
comparison.
Additionally, by entering this study you will not be eligible to have an interscalene catheter that is left in 
place after the surgery. These catheters can usually provide pain relief for 3-4 days, so there is the risk 
that you may not receive as many days of pain relief. 
In addition, there is always a slight risk of a breach of confidentiality.  We will do our best to protect your 
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confidential information.  There also may be other risks that we cannot predict. You should tell the 
research staff about all the medications, vitamins and supplements you take and any medical conditions 
you have. This may help avoid side effects, interactions and other risks.
Pregnant women are excluded from participation in this study. Because NO method of birth control is 
100% reliable, a pregnancy test is required at least 10 days from your last normal menstrual period, if you 
are a sexually active woman of childbearing potential.
SECURITY AND CONFIDENTIALITY: Taking part in this research study may involve 
providing information that you consider confidential or private.  Efforts, such as coding research records, 
keeping research records secure and allowing only authorized people to have access to research records, 
will be made to keep your information safe.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. You may or may not 
have longer pain relief after surgery.  We hope the information learned from this study will benefit other 
people in the future.
WHAT ARE THE COSTS?
All study costs, including any study medications (133mg liposomal bupivacaine with 25mg plain 
bupivacaine OR 50mg plain bupivacaine with adjunct medicines: 32mcg clonidine, 50mcg 
epinephrine, 2mg dexamethasone and 150mcg buprenorphine), and procedures related directly to 
the study, will be paid for by the study, which is funded with a departmental grant. Costs for your 
regular medical care, which are not related to this study, will be your own responsibility. You will 
be charged for the surgery, and administration fees, that would occur otherwise should you not be 
enrolled in study."
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all the 
choices you have. Instead of being in this study, you have these options:
-Receive interscalene nerve block with medications as decided by your anesthesiologist. Some 
options include liposomal bupivacaine, plain bupivacaine, mepivacaine, or another type of local 
anesthetic.  
-Receive an interscalene nerve block with a catheter left in place for 3-4 days. This would likely 
provide pain relief for at least 3 days. 
-Receive general anesthesia without a nerve block, if decided by your anesthesiologist. 
You could be treated with liposomal bupivacaine, plain bupivacaine, epinephrine, clonidine, 
dexamethasone, and buprenorphine even if you do not take part in the study.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published in 
scientific journals.  Your identity and/or your personal health information will not be disclosed unless it is 
authorized by you, required by law, or necessary to protect the safety of yourself or others.  There is 
always some risk that even de-identified information might be re-identified. 
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Participant information may be provided to Federal and other regulatory agencies as required.  The Food 
and Drug Administration (FDA), for example, may inspect research records and learn your identity if this 
study falls within its jurisdiction.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by funding from the Department of Anesthesiology at Wake Forest Baptist 
Health. The researchers do not hold a direct financial interest in the products being compared or a 
financial relationship to the manufacturers of the medications.  
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this study, 
Wake Forest University School of Medicine maintains limited research insurance coverage for the usual 
and customary medical fees for reasonable and necessary treatment of such injuries or illnesses. To the 
extent research insurance coverage is available under this policy the reasonable costs of these necessary 
medical services will be paid, up to a maximum of $25,000. Wake Forest University Baptist Medical 
Center holds the insurance policy for this coverage. It provides a maximum of $25,000 coverage for each 
claim and is limited to a total of $250,000 for all claims in any one year. The Wake Forest University 
School of Medicine, and the North Carolina Baptist Hospitals, Incorporated do not assume responsibility 
to pay for these medical services or to provide any other compensation for such injury or illness. 
Additional information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security number, and 
date of birth in order to pay for your care.  This is because the insurer is required by law to report any 
payments made to cover the care of any persons who are members of a government insurance plan to the 
Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For more 
information on medical treatment for research related injuries or to report a study related illness, adverse 
event, or injury you should call Dr. Doug Jaffe at 
.
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get from your 
medical records or other facilities about your health or behaviors is considered Protected Health 
Information. The information we will collect for this research study includes: Your medical history, your 
current medications, your surgical procedure, your age, height and weight, your pain scores after surgery, 
and your medication use after surgery. 
We will make every effort to keep your Protected Health Information private. We will store records of 
your Protected Health Information in a cabinet in a locked office or on a password protected computer. 
Your personal health information and information that identifies you (“your health information”) may be 
given to others during and after the study. This is for reasons such as to carry out the study, to determine 
the results of the study, to make sure the study is being done correctly, to provide required reports and to 
get approval for new products.  
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Some of the people, agencies and businesses that may receive and use your health information are the 
research sponsor; representatives of the sponsor assisting with the research; investigators at other sites 
who are assisting with the research; the Institutional Review Board; representatives of Wake Forest 
University Health Sciences and North Carolina Baptist Hospital; representatives from government 
agencies such as the Food and Drug Administration (FDA) or the Office of Human Research Protections 
(OHRP), the Department of Health and Human Services (DHHS) and similar agencies in other countries.  
Some of these people, agencies and businesses may further disclose your health information. If disclosed 
by them, your health information may no longer be covered by federal or state privacy regulations.  Your 
health information may be disclosed if required by law. Your health information may be used to create 
information that does not directly identify you. This information may be used by other researchers. You 
will not be directly identified in any publication or presentation that may result from this study unless 
there are photographs or recorded media which are identifiable.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least six years after the study is finished. At that time any 
research information not already in your medical record will either be destroyed or it will be de-
identified.  
You can tell Dr. Doug Jaffe, DO that you want to take away your permission to use and share your 
Protected Health Information at any time by sending a letter to this address:
Dr. Doug Jaffe, DO
However, if you take away permission to use your Protected Health Information you will not be able to be 
in the study any longer. We will stop collecting any more information about you, but any information we 
have already collected can still be used for the purposes of the research study.
By signing this form you give us permission to use your Protected Health Information for this 
study.  If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the research and 
any medications or devices you are being given as a participant may also be included in your medical 
record.  This part of the medical record will only be available to people who have authorized access to 
your medical record.  If you are not a patient at this Medical Center, a medical record will be created for 
you anyway to ensure that this important information is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will include a 
summary of the results.  You can search this website at any time. 
Medical procedure reports created as a result of your participation in the research study may be entered 
into the computer systems of Wake Forest University Health Sciences and North Carolina Baptist 
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Hospital.  These will be kept secure, with access to this information limited to individuals with proper 
authority, but who may not be directly involved with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study participants. 
Information about your participation in the study will be placed in the NCBH medical record, along with 
any routine medical test results that were obtained at NCBH as part of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the study at any 
time. Refusing to participate or leaving the study will not result in any penalty or loss of benefits to which 
you are entitled. If you decide to stop participating in the study we encourage you to talk to the 
investigators or study staff first to learn about any potential health or safety consequences. The 
investigators also have the right to stop your participation in the study at any time. This could be because 
it is in your best medical interest, your condition worsened, new information becomes available, you had 
an unexpected reaction, you failed to follow instructions, or because the entire study has been stopped.  
Information that identifies you may be removed from the data that is collected as part of this study and 
could be used for future research or shared with others without additional consent. 
You will be given any new information we become aware of that would affect your willingness to 
continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study investigator:
Daytime Hours: Dr. Doug Jaffe at 
. 
After Hours:  Regional Anesthesia Physician at 
 
 (enter your callback number followed by # key)
The Institutional Review Board (IRB) is a group of people who review the research to protect your rights. 
If you have a question about your rights as a research participant, or you would like to discuss problems 
or concerns, have questions or want to offer input, or you want to obtain additional information, you 
should contact the Chairman of the IRB at 
 or the Research Subject Advocate at 
 
You will be given a copy of this signed consent form and a copy will be placed in your medical record. 
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SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as described 
in this consent and authorization form.  If I have not already received a copy of the Privacy Notice, I may 
request one or one will be made available to me.  I have had a chance to ask questions about being in this 
study and have those questions answered.   By signing this consent and authorization form, I am not 
releasing or agreeing to release the investigator, the sponsor, the institution or its agents from liability for 
negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055981
Meeting Date Approved 4/5/2022          
Version Valid Until: 4/4/2023