Clinical trial NCT03587636
Conditions: Acute Pain
Sponsor: University of Minnesota
Start date: 2018-09-17; Completion date: 2021-03-17
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized prospective outcomes study comparing two groups of patients. One group will receive liposomal bupivacaine plus bupivacaine and the other will receive bupivacaine alone in interscalene blocks when undergoing total shoulder arthroplasty. The purpose of the study is to determine if LB plus bupivacaine provides superior pain control compared to bupivacaine alone when injected in an interscalene block for patients undergoing total shoulder arthroplasty surgery.

Detailed description:
Liposomal bupivacaine (LB) is a long acting local anesthetic. It is liposome encapsulated bupivacaine which allows for prolonged release of bupivacaine over a 72-hour period. Bupivacaine is a medium acting local anesthetic which provides between 6 and 24 hours of analgesia when used in a peripheral nerve block. Both medications are standard of care for use in interscalene blocks here at the U of MN.

LB has not been adequately studied in peripheral nerve blocks and has yet to be studied for use in interscalene blocks for Total Shoulder Arthroplasty (TSA) patients. It has been studied in Rotator Cuff Repairs (RCR) surgery and showed superior analgesia compared to bupivacaine.

The purpose of the study is to determine if LB plus bupivacaine provides superior pain control compared to bupivacaine alone when injected in an interscalene block for patients undergoing total shoulder arthroplasty surgery.

Arms: arm 1: 10 mL of liposome bupivacaine and 10 mL of 0.5% bupivacaine will be injected at the interscalene brachial plexus under ultrasound guidance arm 2: 20 mL of 0.5% bupivacaine will be injected at the interscalene brachial plexus under ultrasound guidance.
Interventions: intervention 1: liposome bupivacaine intervention 2: Bupivacaine
Intervention descriptions: intervention 1: interscalene block with liposomal bupivacaine plus bupivacaine intervention 2: interscalene block with bupivacaine

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 1 of 19 
Revised: 9/28/2017 
 
 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 2 of 19 
Revised: 9/28/2017 
PROTOCOL TITLE: 
Prospective Randomized controlled trial comparing liposomal bupivacaine to bupivacaine 
Interscalene blocks for total shoulder arthroplasty surgery 
PRINCIPAL INVESTIGATOR or FACULTY ADVISOR: 
Name James Flaherty 
Department of Anesthesiology 
Phone 612-624-9990 
Email Address jflahert@umn.edu 
STUDENT INVESTIGATOR: 
Name 
Current Academic Level (e.g., Medical Student, Resident) 
Department 
Telephone Number 
Email Address (must not be a personal email address) 
VERSION NUMBER/DATE: 
1 3/20/2018 
2 5/22/2018 
3 6/27/2018 
4 7/22/2019 
5 12/4/2019 
6 3/19/2020 
7 6/3/2020 
 
 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 3 of 19 
Revised: 9/28/2017 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
5/22/18 
Updated recruitment procedures 
No 
2 
6/27/18 
Edited for IRB response 
Yes 
3 
7/22/19 
Updated recruitment numbers 
No 
4 
12/4/2019 
Decreased discharge opioid amount 
Yes 
5 
3/19/2020 
Group size clarification 
Yes 
6 
6/3/2020 
e-consent addition 
No 
 
 
 
 
 
 
 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 4 of 19 
Revised: 9/28/2017 
Table of Contents 
 
1.0 
Objectives ................................................................................................................ 7 
2.0 
Background .............................................................................................................. 7 
3.0 
Study Endpoints/Events/Outcomes .......................................................................... 7 
4.0 
Study Interventions/Investigational Agent(s) .......................................................... 8 
5.0 
Procedures Involved................................................................................................. 8 
6.0 
Data and Specimen Banking .................................................................................. 11 
7.0 
Sharing of Results with Participants ...................................................................... 11 
8.0 
Study Population .................................................................................................... 12 
9.0 
Vulnerable Populations .......................................................................................... 12 
10.0 Local Number of Participants ................................................................................ 12 
11.0 Local Recruitment Methods ................................................................................... 12 
12.0 Withdrawal of Participants .................................................................................... 13 
13.0 Risks to Participants ............................................................................................... 13 
14.0 Potential Benefits to Participants ........................................................................... 15 
15.0 Statistical Considerations ....................................................................................... 15 
16.0 Confidentiality ....................................................................................................... 15 
17.0 Provisions to Monitor the Data to Ensure the Safety of Participants .................... 15 
18.0 Provisions to Protect the Privacy Interests of Participants .................................... 16 
19.0 Compensation for Research-Related Injury ........................................................... 17 
20.0 Consent Process ..................................................................................................... 17 
21.0 Setting .................................................................................................................... 18 
22.0 Multi-Site Research N/A........................................................................................ 18 
23.0 Resources Available............................................................................................... 18 
24.0 References .............................................................................................................. 19 
 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 5 of 19 
Revised: 9/28/2017 
ABBREVIATIONS/DEFINITIONS 
• 
LB/ liposomal bupivacaine 
• 
TSA/total shoulder arthroplasty 
• 
QOR/Quality of Recovery 
• 
RCR/rotator cuff repair 
• 
 
 
 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 6 of 19 
Revised: 9/28/2017 
STUDY SUMMARY 
 
Study Title 
Prospective Evaluation of Liposomal bupivacaine in 
Total Shoulder Surgery 
Study Design 
Prospective randomized double blind 
Primary Objective 
Total opioids in 72 hours 
Secondary Objective(s) 
Pain scores within 72 hours, QOR at 72 hours and 14 
days, Number of phone calls to surgeon, adverse events, 
time to discharge 
Research 
Intervention(s)/Investigational 
Agents 
Liposomal bupivacaine and bupivacaine vs bupivacaine 
Scientific Assessment 
HRPP facilitated scientific assessment 
IND/IDE # (if applicable) 
Study Medication has been approved for use in 
shoulder surgery April 6, 2018 
IND/IDE Holder 
Pacira Pharmaceuticals 
Investigational Drug Services 
# (if applicable) 
N/A 
Study Population 
Adult patients aged 18 and older who are undergoing 
total shoulder arthroplasty 
Local Sample Size (number of 
participants recruited locally) 
90 
 
 
 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 7 of 19 
Revised: 9/28/2017 
 
1.0 
Objectives 
Purpose: To determine if LB plus bupivacaine provides superior pain control 
compared to bupivacaine alone when injected in an interscalene block for patients 
undergoing total shoulder arthroplasty surgery.  
 
2.0 
Background 
Significance of Research Question/Purpose: Liposomal Bupivacaine (LB) has not 
been adequately studied in peripheral nerve blocks and has yet to be studied for 
use in interscalene blocks for Total Shoulder Arthroplasty (TSA) patients.  It has 
been studied in Rotator Cuff Repairs (RCR) surgery and showed superior 
analgesia compared to bupivacaine.   
Preliminary Data: It is our standard of care to use this medication in an 
interscalene block at the U of MN for patients undergoing TSA.  A retrospective 
study performed showed superior analgesia and less opioids in those having LB 
plus bupivacaine vs bupivacaine or ropivacaine only blocks.  
Existing Literature: Vandepitte et al showed that LB plus bupivacaine was 
superior to bupivacaine when used in interscalene nerve block for patients 
undergoing major shoulder surgery (both RCR and TSA).   
 
3.0 
Study Endpoints/Events/Outcomes 
Primary Endpoint/Event/Outcome: To determine if LB plus bupivacaine in an 
interscalene block results in less opioid use over 72 hours compared to 
bupivacaine only for TSA surgery.  
Secondary Endpoint(s)/Event(s)/Outcome(s):  
• To determine if LB plus bupivacaine in an interscalene block results in 
less pain over 72 hours as compared to bupivacaine only in an interscalene 
block for TSA surgery.  Assessed via total pain scores (Use of Visual 
Analog Scale) 
 
• To determine if LB plus bupivacaine in an interscalene block results in 
improved (Quality of Recovery) QOR at 72 hours and 14 days as 
compared to bupivacaine only in an interscalene block for TSA surgery.  
Assessed via QOR 15 patient survey.  
 
• To determine if LB plus bupivacaine in an interscalene block results in 
fewer phone calls to the surgeon within 72 hours as compared to 
bupivacaine only in an interscalene block for TSA surgery.   


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 8 of 19 
Revised: 9/28/2017 
 
• To determine if LB plus bupivacaine in an interscalene block hastens readiness 
for hospital discharge compared to bupivacaine only in an interscalene block for 
TSA surgery.  
 
4.0 
Study Interventions/Investigational Agent(s) 
Description: LB is a long acting local anesthetic.  It is liposome encapsulated 
bupivacaine which allows for prolonged release of bupivacaine over a 72-hour 
period.  Bupivacaine is a medium acting local anesthetic which provides between 
6 and 24 hours of analgesia when used in a peripheral nerve block.  Both 
medications are standard of care for use in interscalene blocks here at the U of 
MN. Acetaminophen is a medication used to treat pain, gabapentin is a 
gabapentinoid which is used to treat postoperative pain, and Celebrex is a 
selective COX-2 inhibitor also used to treat pain.   
Drug/Device Handling: The LB will be stored in a locked pyxis fridge in a box 
labeled Liposomal Bupivacaine.  The anesthesiologists in charge of regional 
anesthesia the day the procedure will be informed will write the order for 
dispensing the medication and the block per standard of care.  It will be retrieved 
by the PI and sub I’s for use in the interscalene blocks.  
Biosafety:  Per standard of care 
Stem Cells: N/A 
 
5.0 
Procedures Involved 
Study Design: Level I randomized prospective outcomes study comparing two 
groups of patients. Patients will be assigned either to Liposomal Bupivacaine plus 
bupivacaine for an interscalene block or they will receive bupivacaine for an 
interscalene block injection.  
Study Procedures: After consenting to the study (either in clinic or the PAC 
clinic) and completion of the preoperative process (per standard of care), a 
randomization scheme from a random number generator will be followed to 
ensure equal likelihood of group assignment. The patient will be placed in the 
supine position with the head of the bed elevated 30 degrees with standard ASA 
monitors applied.  Sedation will be provided with midazolam 0-2mg and propofol 
0-50 mg. The interscalene groove will be identified with the ultrasound. Using 
sterile technique, a 21g Nerve block needle will then be inserted and advanced 
under ultrasound guidance until it is in the interscalene groove.  Once in the 
interscalene groove, 20 mL of local anesthetic will be injected, with 10mL 
deposited at the top of the brachial plexus and 10mL at the bottom.  In the study 
group, 5 mL of each 0.5% bupivacaine and LB will be injected at each location.  


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 9 of 19 
Revised: 9/28/2017 
The control group with have 20mL of 0.5% bupivacaine divided between the 
injection sites. Patients would be required to take a dose of acetaminophen 975 
mg oral, gabapentin 300 mg oral, and Celebrex 400 mg oral prior to surgery (per 
standard of care). The patient will be monitored (vital signs, respiratory status and 
oxygen saturation) in the preoperative area until he/she is brought into the 
operating room for their procedure.  A working block prior to surgery will be 
confirmed via sensory testing of the shoulder.  
 
All patients will undergo a standard induction with propofol 1.5-3.0 mg/kg, 
lidocaine 60-100 mg, ondansetron 4 mg, dexamethasone 10 mg and ketamine 0.25 
mg/kg.  An LMA or ETT will be placed and an opioid sparing technique will 
occur.  Standardized maintenance will be a propofol infusion without 
neuromuscular blockers.  25-50 mcg of IV Fentanyl will be utilized for increases 
in heart rate greater than 20% or increases in systolic blood pressure above 
baseline.   
 
Once in the operating room the surgeon will use 10 mL of 0.25% bupivacaine for 
skin, subcutaneous, and intraarticular injection.  
 
When the operation is complete, the patient will be brought to the post-operative 
care unit (PACU).  The patient will receive IV fentanyl for a pain score of greater 
than 5 on the visual analog scale.  If more than 200 mcg of fentanyl is given and 
pain still remains above a 5 then IV hydromorphone will be used.  A dose of 5-10 
mg of oral oxycodone (or 2-4 mg of oral hydromorphone) will be given as soon as 
the patient is able to tolerate oral medication per standard protocol:  If their pain 
score is 4-6 (on the Visual Analog Scale) then 5mg oral oxycodone (2 mg 
hydromorphone) can be administered, if their pain is between 7 to 10 then 10 mg 
of oxycodone (or 4 mg of hydromorphone) can be administered.   The patient will 
either be discharged to a  hotel or brought to the ward where each day a member 
of the research team will evaluate (if in the hospital) or call (if discharged to 
hotel) the patient for signs of complications and ask the patient their maximum 
pain score, total opioids and non-opioid pain medication used, and length of stay.  
If patients have met criteria for discharge to home including pain <4/10, 
independence of intravenous analgesia, and medical stability for discharge but are 
awaiting placement, the time of discharge for the purposes of the study will be the 
day they have met such criteria as opposed to the actual time of discharge as this 
can vary depending on patient placement. 
 
Once the patient meets discharge criteria, they will be discharged home where 
each day they will fill out a pain diary.  Additionally, a member of the research 
team will call the patient for signs of complications and ask the patient their 
current pain score, total opioid pills taken and non-opioid pain medication taken 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 10 of 19 
Revised: 9/28/2017 
at 24, 48, and 72 hours postoperatively.  Additionally, they will perform a Quality 
of Recovery Score survey at 72 hours, and 14 days postoperatively.  
While in the hospital all patients will receive a standardized multimodal pain medication 
regimen.  Acetaminophen 975 mg q6 hours, ibuprofen 600mg q6 hours and prn 
oxycodone 5-10 mg q4 hours or 2-4 mg hydromorphone oral every 4 hours. All patients 
will be discharged with 30-40 pills of 5 mg oxycodone or 30-40 pills of hydromorphone 
2 mg with instructions to take 5-10 mg oxycodone for severe pain every 4 hours as 
needed or 2-4 mg every 4 hours hydromorphone as needed for severe pain. Patients will 
be instructed to start with the lower dose, but can repeat the dose if needed up to 10mg 
oxycodone or 4mg hydromorphone every 4 hours if needed.  
Assessments: Post-operatively patients will be evaluated at 2 and 6 hours post-
operatively by a blinded research staff.  This person will not be aware of the 
patient’s mode of analgesia. The patients will be contacted via in person 
assessment or via telephone at 24, 48, and 72 hours +/- 5 hours.  Patients will be 
asked to rate their pain on scale of 0-10.  The amount of opioids used by the 
patient will be recorded by study personnel as will any other adjuvant pain 
medication used. The time in phase 1 and phase 2 of PACU will be recorded. The 
patients will be asked at 72 hours post-injection if they would undergo an 
interscalene block with their medication again or if they would choose a different 
form of pain management (ex: higher doses of pain medications). Patients will fill 
out a Quality of Recovery Survey at 72 hours and 14 days, and be assessed for 
block related complications at this time. As part of the research, patients also will 
undergo diagnostic ultrasound of their diaphragm on POD 1.  All complications 
will be recorded including:  
• Failure of the block 
• Wound infections 
• Subsequent procedures 
• Complications related to placement of the interscalene block including 
nerve injury, prolonged sensory loss greater than three days, prolonged 
arm weakness greater than three days 
• Opioid related side effects of nausea and/or vomiting 
• Local anesthetic toxicity as evidenced by seizures or cardiovascular 
collapse without other reasonable etiology 
 
All data will be recorded on the Clinical Diagnostic Sheet and will then be given 
to the research coordinator for manual data entry.  Data collection will continue 
until POD #14.  At that time study participation will be terminated.  Should 
patients be re-admitted to the hospital in the next two weeks (Up to POD 30) for 
pain, a notation will be made in study records. 
 
An analysis of the total cost of analgesics will be tabulated at the conclusion of 
the study to determine the most cost effective treatment option as this will be 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 11 of 19 
Revised: 9/28/2017 
added into the cost of hospitalization including the number of days each patient 
spent in the hospital.   
 
Blinding Procedure:  A random number generator will be used to determine if 
the patient will have LB plus bupivacaine or bupivacaine for their interscalene 
block.  The primary investigator will access the number generator in the pre-op 
area immediately prior to block placement.  The website www.random.org will be 
used as the random number generator.   
 
The research assistant in this study will be blinded to the method of analgesia for 
the patient.  This person will not be responsible for any clinical testing and will 
record all data in the protected database daily.  They will not have any access to 
the patients’ clinical records or chart.  Any questions from the patient will be 
referred to the on-call resident or staff on call.   
 
Study Duration: We anticipate the study to take approximately 1 year from the 
date of enrollment of the first patient. Patients will be in the study for 14 days and 
then their chart monitored for up to 30 days post surgery. The data analysis should 
take one month after full enrollment of the study.  
Individually Identifiable Health Information: This study involves the use of 
individually identifiable health information. Please see attached HIPAA 
authorization form.  
Use of Radiation: N/A 
Use of Center for Magnetic Resonance Research: N/A 
 
6.0 
Data and Specimen Banking 
Storage and Access: All study data will be stored on excel spreadsheets stored in 
Box. Only the PI and members of the research team will have access to the data. 
Data: The data from this study will be collected both from Epic and directly from 
the patient. The data collected includes: demographic data, age, weight, ASA 
class, duration of surgery, length of stay in recovery room both phase 1 and 2, 
length of hospital stay, amount of opioids given intraoperatively and post-
operatively, non-opioid pain medication, pain score (0-10) at 2, 6, 24, 48, and 72 
hours, satisfaction with treatment, Quality of Recovery survey at 72 hours and 14 
days, and any adverse events.  
Release/Sharing: N/A 
 
7.0 
Sharing of Results with Participants 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 12 of 19 
Revised: 9/28/2017 
Results will not be shared with participants. 
 
8.0 
Study Population 
Inclusion Criteria: All adult patients aged greater than 18 years of age that are 
undergoing total or reverse total shoulder arthroplasty  
Exclusion Criteria: Patients with allergy to local anesthetics, daily use of opioids 
for more than 3 weeks prior to surgery, patient refusal and those who have opted 
out of research, patients with coagulopathy, non-english speaking patients, and 
those who do not have access to a telephone.  
Screening: Patients will be screened at their preoperative visit either in the 
surgeon’s office, pre assessment center, or preoperative area.   
 
9.0 
Vulnerable Populations 
Vulnerable Populations: No vulnerable populations will be included in the study. 
 
 
10.0 Local Number of Participants 
Local Number of Participants to be consented: 90 patients as we expect a drop out 
or loss to follow up of 20%. 
 
11.0 Local Recruitment Methods 
Recruitment Process: Patients will be recruited from the group of adult surgical 
patients at the University of Minnesota undergoing TSA and receiving an 
interscalene block. Patients will be approached at the preoperative assessment 
clinic at the Clinic and Surgery Center if possible by a research staff member to 
determine their interest in participation.  If they decide to be a participant they 
will be consented and given a copy of their consent form for their records and a 
consent will be scanned and placed into EPIC. If they need additional time to 
consider enrollment, they will be asked if we can reach out to them by phone the 
night before surgery or if we should revisit the study with them on the day of 
surgery.  If the patient is unable to be consented prior to day of surgery, the 
research staff will approach them in the preoperative surgical area.  These patients 
will have significant time to review the study with research staff as well as the 
physicians performing the procedure due to the fact they arrive several hours prior 
to their scheduled surgery.  All subjects will have enough time to ask questions 
about the study and the potential risks involved regardless of which venue they 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 13 of 19 
Revised: 9/28/2017 
are consented. Any patient that refuses to participate in the study at any time point 
will be placed on a secured list to avoid duplicate attempts to recruit them. 
Identification of Potential Participants: Patients will be identified by members of 
the treatment team in either the surgeon’s clinic, pre-assessment clinic, or 
preoperative area. Patients who have opted out of research will not be asked to 
participate in the study. Patients will be approached to consent for the study by a 
surgeon, anesthesiologist, or member of the research team. Patients who agree to 
participate in the study will sign both a study consent and HIPAA authorization 
allowing the use of specified information contained in medical records for 
research purposes.  
Recruitment Materials: N/A 
Payment: No payment will be provided to patients.   
 
12.0 Withdrawal of Participants 
Withdrawal Circumstances:.  Subjects who have consented prior to the day of 
surgery and for some reason choose not to participate will be withdrawn and a 
notation will be made in the study records and these people will be considered 
screen failures.  The surgeon may choose to withdraw the patient from the study 
prior to surgery for any medical reason or if they suffer a major life threatening  
adverse event.   
Withdrawal Procedures: If the patient is withdrawn from study prior to the 
procedure, they will be noted in study records as screen failures. If they undergo 
the procedure and they decide they no longer want to be a part of the study or 
withdrawn by the physician, they will be withdrawn and no further data will be 
collected.  This will also be noted in the study documentation. 
Termination Procedures:  If the study is terminated for any reason, or there is 
more than 5 % major adverse events the data that is already collected will be 
stored in a secure location only accessible to research personnel on this study. No 
further data will be collected if the study is terminated. 
 
13.0 Risks to Participants 
Foreseeable Risks: The study has the following risks:   
• 
infection (< 1%) 
• 
bleeding (< 1%) 
• 
nerve injury (< 1%) 
• 
cardiac arrhythmias (irregular heartbeat) (< 1%) 
• 
respiratory complications (<1 %) 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 14 of 19 
Revised: 9/28/2017 
These complications all fall within the standard risks of surgery and the 
performance of the interscalene injection. Any intervention being provided as a 
part of this study falls within the standard of care as both medication options are 
within the standard treatments for post-operative pain and are currently used as 
analgesic options at UMMC.  
 
EXPAREL contains bupivacaine. Serious side effects related to bupivacaine are 
not common, but may occur if too much is given or if it is accidentally injected 
into a blood vessel. When given incorrectly, side effects may involve the brain or 
the heart. 
 
The effects on the brain and central nervous system may include:  
• Restlessness (< 2%) 
• Anxiety (<2%) 
• Dizziness (<2%) 
• Tinnitus (ringing in the ears) (<2%) 
• Blurred vision (<2%) 
• Tremors (shaking) possibly proceeding to convulsions (<2%). 
 
The effects on the heart appear when too much bupivacaine is given or when 
bupivacaine is injected in a blood vessel by accident. These effects cause a 
decrease of the heart function, including low heart rate or abnormal heart rhythm, 
decreased blood flow, low blood pressure, and, in extreme cases, heart attack. 
(<2%) 
 
The numbing sensation caused by bupivacaine may be persistent, with slow, 
incomplete, or no recovery. Sometimes a tingling sensation may appear in the 
area treated with bupivacaine. When injected next to a large nerve, bupivacaine 
may cause weakness or paralysis. 
 
Allergic reactions are rare, but may include rash, itching and redness of the skin, 
sneezing, nausea, vomiting, dizziness, fainting, sweating, fever, and low blood 
pressure.  
 
Other side effects of liposomal bupivacaine when given into the wound include: 
• Nausea (22.6%) 
• Constipation (8.7%) 
• Vomiting (6%) 
• High temperature (5.5%) 
• Dizziness (<2%) 
• Swelling (<1%) 
• Low blood pressure (<2%) 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 15 of 19 
Revised: 9/28/2017 
• Anemia (<1%) 
• Itching (2.4%) 
• High heart rate (1.3%) 
• Headache (5%) 
Reproduction Risks:  
If the patient were pregnant we would not perform the study on them.  If they 
were to become pregnant there are no known risks to the patient. 
Risks to Others: N/A 
 
14.0 Potential Benefits to Participants 
Potential Benefits: The potential benefits of participating in this study include 
reduced pain following shoulder surgery and shortened hospital stay.   
15.0 Statistical Considerations 
Data Analysis Plan: We plan to collect our data using excel, which will be 
maintained in box.  When the study is completed and ready for statistical analysis 
the data will be shared with our staff statistician.  
Power Analysis: Following the pilot study of 30 patients, it was determined that 
40 additional patients (for a total of 70 patients, 35 per group) would need to be 
enrolled to reach 80% power.  
Statistical Analysis: This study will be analyzed by our staff biostatistician.  The 
data will be deidentified and shared with him in box.  The statistician will be 
provided the protocol so they are able to analyze for primary and secondary 
objectives. 
Data Integrity:  All patients will be assigned a unique patient identifier. The data 
that will be sent to the statistician will be deidentified.   
 
16.0 Confidentiality 
Data Security: All paper documents and consent forms will be stored in a locked 
cabinet in the anesthesia research office in B573 Mayo. All study data will be 
stored electronically in Box and only the PI and members of the research team 
will have access to the data.  
 
17.0 Provisions to Monitor the Data to Ensure the Safety of 
Participants 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
Page 16 of 19 
Revised: 9/28/2017 
Data Integrity Monitoring.  
The PI, co-investigators, and research assistants will all have access to the study 
data stored in the University’s Box storage system. All the research assistants 
have experience collecting pain scores and other relevant study information. The 
PI of the study will periodically review the study data to ensure accuracy and 
completeness of study data. 
Data Safety Monitoring: The Department of Anesthesiology has established a 
Data and Safety Monitoring Committee consisting of several staff 
anesthesiologists which include persons who are board certified as pain 
specialists. Data will be transmitted in box to persons on the board on a monthly 
basis for review.  If there are patterns of adverse events, the board will meet as 
needed and provide recommendations. 
All safety data will be collected on a case report form and transferred 
into an excel spread sheet that will be stored in box. Also, all phone 
call data will be collected on a case report form and transferred into 
excel in box.     
All data will be collected by research assistants on a daily basis.  
Subjects are monitored at several intervals on day of surgery and daily 
up to 72 hours.  If the patient is discharged prior to 72 hours they will 
Who will review the data. 
The data will be reviewed on a regular basis (weekly) by the PI and 
research staff.  If there are consistent complications noted a meeting 
will be convened by the DSMB for recommendations.  
The statistical tests for analyzing the safety data to determine whether 
harm is occurring. 
The statistician uses R or SAS for analysis.  Most likely  a regression 
analysis will be performed to see which event is most likely the 
contributor for the complications  Also a chi-square analysis can be 
performed.  All is very dependent on data variability. 
A fatal or serious adverse event that is attributable to either the 
delivery or the study medication itself. 
 
18.0 Provisions to Protect the Privacy Interests of Participants 
Protecting Privacy:  


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
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Patients will be asked if this is a good time to answer questions.  All patients will 
have the right to refuse to answer questions when called. All calls will be done in 
a secure office and the data is deidentified when entered.  It will be stored using a 
unique study identifier.   
 
Access to Participants: 
All patients are required to sign a consent that states their privacy of the data 
being collected.  In addition, they are required to sign a HIPAA consent that 
further describes the data being collected.  It also describes that all data is 
deidentified and stored in a secure database.  They will be informed that data is 
stored and reviewed in box which is HIPAA compliant and that only study 
personnel have accesss. 
 
19.0 Compensation for Research-Related Injury 
Compensation for Research-Related Injury:  
In the event that this research activity results in an injury, treatment will be 
available, including first aid, emergency treatment and follow-up care as needed. 
Care for such injuries will be billed in the ordinary manner, to the patient and/or 
insurance company.   
Contract Language: N/A 
 
20.0 Consent Process 
Consent Process (when consent will be obtained): Patients will be identified in the 
pre-operative time period by the surgeons and if possible will be consented by the 
research coordinator or research assistant. If patients have more questions and do 
not want to sign at their clinic will be asked if it is allowable for a study staff 
member to contact them prior to surgery via phone to clarify if they have any 
questions. On the day of surgery, if the patient has not already signed consent and 
is still interested in participating in the study they will be presented with consent 
and Health and Insurance Portability and Accountability Act (HIPAA) forms.  
The patient will review the forms with the surgeon, research staff, or 
anesthesiologist, with the REDCap e-consent process being preferentially used.  
Subjects will be reminded that participation is completely voluntary, and that they 
may stop participation at any time without question or penalty. The surgeon, 
research staff, or anesthesiologist will answer any questions that the subjects may 
have about the study. If the patient decides to participate, they will be asked to 
sign the consent and HIPAA forms. One copy will be saved for study records, and 
the subject will be provided with a copy of the forms for their own records.   


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
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Revised: 9/28/2017 
Waiver or Alteration of Consent Process: N/A 
Non-English Speaking Participants: N/A- No Non-English speaking patients will 
be enrolled in this study. 
Participants Who Are Not Yet Adults: N/A 
Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent: N/A 
Adults Unable to Consent: N/A 
 
21.0 Setting 
Research Sites: Patients will be consented in the surgeon’s clinic, pre assessment 
clinic, or preoperative area. The surgical procedures will take place at the M 
health Ambulatory Surgery Center or Fairview Riverside campus.   
International Research: N/A 
 
22.0 Multi-Site Research N/A 
 
23.0 Resources Available 
Resources Available:  
Research assistants are available to aid in consent and data acquisition. All 
research assistants will be familiar with the study protocol and have experience 
working with similar studies. 
 
We plan to enroll 70 subjects.  The plan is to screen 90 subjects to research this 
target population.  This center performs approximately 300 TSAs annually. 
We plan to conduct this study over 3 months.  Enrollment and data collection will 
be completed at this time.  Statistical Analysis will take approximately two 
months to complete. 
 
All procedures will be performed in the clinical facilities at the MHealth Clinics 
and Surgery Center and at the west and East Bank. Data storage and analysis will 
be done using desktop equipment which is available at the Research Office B573 
Mayo. 
 
 
In the event that this research activity results in an injury, treatment will be 
available, including first aid, emergency treatment and follow-up care as needed. 


PROTOCOL TITLE: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery 
 
 
VERSION DATE: 7 6/3/2020 
 
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Revised: 9/28/2017 
Care for such injuries will be billed in the ordinary manner, to the patient and/or 
insurance company.   
All study personnel will be adequately trained by the Principle Investigator on the 
study protocol and study conduct.  A log will be maintained to track which 
personnel are trained.  A delegation of authority log will also be maintained to 
track which personnel are responsible for specific duties. 
 
24.0 References 
1. 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;42:334-341.  
 

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Title of Research Study: Prospective Randomized controlled trial comparing liposomal 
bupivacaine to bupivacaine Interscalene blocks for total shoulder arthroplasty surgery
Investigator Team Contact Information: Dr. James Flaherty
For questions about the research study, research results, or other concerns, call the study team 
at: 
Investigator Name: Dr. James Flaherty
Investigator Departmental Affiliation: 
Anesthesiology
Phone Number: 612-624-9990
Email Address: jflahert@umn.edu
Study Staff: Jonah Pearson, Katherine 
Harmelink, Jessica Hatfield, Candace Nelson, 
Melissa Cohen, Ryan Eskuri
Phone Number: 612-625-7116
Email Address: cohen045@umn.edu
Supported By: This research is not supported by any company.  
Financial Interest Disclosure:  The primary investigator does not have any financial interest. 
Key Information About This Research Study
The following is a short summary to help you decide whether or not to be a part of this research study. 
More detailed information is listed later on in this form. 
What is research?
Doctors and investigators are committed to your care and safety. There are important differences 
between research and treatment plans:
●
The goal of research is to learn new things in order to help groups of people in the future. 
Investigators learn things by following the same plan with a number of participants, so they do 
not usually make changes to the plan for individual research participants. You, as an individual, 
may or may not be helped by volunteering for a research study.  
●
The goal of clinical care is to help you get better or to improve your quality of life. Doctors can 
make changes to your clinical care plan as needed.
Your doctor, who is also responsible for this research study, is interested in both your clinical care and 
the conduct of this research study. You have the right to discuss this study with another person who is 
not part of the research team before deciding whether to participate in the research.
Why am I being asked to take part in this research study?
You are being asked to take part in this research study because you are 
planning to receive an interscalene block as part of your surgical pain 
management plan. An interscalene block is an injection of numbing 
medication known as local anesthetic around the nerves that extend from 
your neck to your arm that allow you to feel sensation and pain of your 
arm.


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What should I know about a research study?
●
Someone will explain this research study to you.
●
Whether or not you take part is up to you.
●
You can choose not to take part.
●
You can agree to take part and later change your mind.
●
Your decision will not be held against you.
●
You can ask all the questions you want before you decide.
Why is this research being done?
The purpose of this study is to determine if liposomal bupivacaine plus bupivacaine compared to 
bupivacaine alone when given in an interscalene block provides better and longer pain control for total 
shoulder arthroplasty (TSA) surgery. Liposomal bupivacaine is a long acting anesthetic. It is liposome 
encapsulated bupivacaine which allows for prolonged release of bupivacaine over a 72-hour period. 
Bupivacaine is a medium acting local anesthetic, which provides between 6 and 24 hours of pain relief. 
Currently it is the standard of care to give either of these medications in an interscalene block at the 
University of Minnesota, however their effectiveness has not been adequately compared against one 
another in interscalene blocks for TSA patients. 
How long will the research last?
We expect that you will be in this research study for 14 days following TSA surgery. However, we will 
continue to monitor your chart for adverse events up to 30 days post-procedure.
What will I need to do to participate?
You will be asked to consent to be randomized to receive either liposomal bupivacaine plus bupivacaine 
or bupivacaine alone in an interscalene block. In addition, we would ask you to have your pain scores 
and pain medication use evaluated by a member of the research staff at 2, 6, 24, 48, and 72 hours post 
procedure. This will be done in person or via telephone call. At 72 hours and 14 days post-procedure, 
you will be asked to complete a Quality of Recovery Survey and asked if you would undergo an 
interscalene block with your medication again or if you would opt for a different form of pain 
management. At 72 hours and 14 days you will also be assessed for any block related complications.
More detailed information about the study procedures can be found under “What happens if I say yes, I 
want to be in this research?”
Is there any way that being in this study could be bad for me?
The foreseeable risks of the study are low and primarily relate to the nerve block and include things 
like infection, bleeding, nerve damage, and medication side effects. These risks are the standard risks 
of surgery and the interscalene injection. In addition there is always a risk of a data breach.
More detailed information about the risks of this study can be found under “What are the risks of being 
in this study?  Is there any way being in this study could be bad for me? (Detailed Risks)”
Will being in this study help me in any way?
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits include reduced pain following your procedure and shortened hospital stay. Other 
possible benefits include increased knowledge that may be applied to future patients.


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What happens if I do not want to be in this research?
You do not have to participate in this research. Choosing not to be in this study or to stop being in this 
study will not result in any penalty to you or loss of benefit to which you are entitled. This means that 
your choice not to be in this study will not negatively affect your right to any present or future medical 
care. If you choose not to participate you would not be randomized to receive one treatment over 
another. An interscalene block is the standard of care for patients undergoing this procedure and you 
would still receive an interscalene block regardless of your participation in this study. 
Detailed Information About This Research Study
The following is more detailed information about this study in addition to the information listed above.
How many people will be studied?
We expect up to 90 patients will be enrolled in this research study, with a goal of at least 35 per group.
What happens if I say “Yes, I want to be in this research”?
If you choose to take part in this research you will be randomized to receive an interscalene block with 
either liposomal bupivacaine plus bupivacaine or bupivacaine alone. The interscalene block is part of the 
standard of care and would be performed regardless of your participation in this study. The treatment 
you get will be chosen by chance, like flipping a coin. Neither you nor the study doctor will choose what 
treatment you get. You will have an equal chance of being given either treatment. You will not be told 
which treatment you are getting, however your study doctor will know.
You will receive standard oral pain medications once you are checked in for surgery. Following this, you 
will undergo the interscalene block with sedation provided to ensure your comfort. Your anesthetic care 
during surgery will not be affected by the block that you receive. You will receive a balanced general 
anesthetic which focuses on opioid sparing. While in the hospital you will receive a standardized pain 
medication regimen.  You will be discharged with oral pain medications for postoperative pain control. 
You will be provided with a pain diary to help you track your pain levels and medication use at home.
You will be evaluated at 2, 6, 24, 48, and 72 hours following your procedure by a member of the 
research staff for your pain scores using a 0-10 point scale, and for opioid and any other use of pain 
medications. This will be done in person or via telephone call. The research assistant will be blinded to 
which medication you have received. At 24 hours, an ultrasound will be taken of your diaphragm. At 72 
hours and at 14 days post-procedure you will be asked to complete a Quality of Recovery Survey and be 
assessed for any block related complications. Your chart will continue to be monitored up to 30 days 
post-procedure for any complications related to the procedure.
What are my responsibilities if I take part in this research?
You will be responsible for giving your pain scores and answering the questions of the Quality of 
Recovery survey to members of the research staff. 
What are the risks of being in this study?  Is there any way being in this study could be 
bad for me? (Detailed Risks)
The foreseeable risks of the study primarily relate to the nerve block and possible medication side 
effects. These complications all fall within the standard risks of surgery and the performance of the 
interscalene injection. Either intervention being provided as a part of this study falls within the standard 
of care as both medication options are within the standard treatments for post-operative pain and are 


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currently used as analgesic (pain management) options at the University of Minnesota Medical Center. 
In addition to these risks described further below, you risk having your day interrupted by the 
anesthesia team to ask about your pain control and side effects as well as having your record looked at 
to see medication use during your hospitalization. There is also some risk of a data breach involving the 
information we have about you.  We comply with the University’s security standards to secure your 
information and minimize risks, but there is always a possibility of a data breach.
 Risks from the nerve block are all estimated to be less than 1% and include infection, bleeding, nerve 
injury, cardiac arrhythmias (irregular heartbeat) and respiratory complications. 
Serious side effects related to bupivacaine are not common, but may occur if too much is given or if it is 
accidentally injected into a blood vessel. When given incorrectly, side effects may involve the brain or 
the heart. The effects on the brain and central nervous system may include restlessness, anxiety, 
tinnitus (ringing in the ears), blurred vision, and tremors (shaking) possibly proceeding to convulsions. 
The effects on the heart appear when too much bupivacaine is given or when bupivacaine is injected in 
a blood vessel by accident. These effects cause a decrease of the heart function, including low heart rate 
or abnormal heart rhythm, decreased blood flow, low blood pressure, and, in extreme cases, heart 
attack.
The numbing sensation caused by bupivacaine may be persistent, with slow, incomplete, or no recovery. 
Sometimes a tingling sensation may appear in the area treated with bupivacaine. When injected next to 
a large nerve, bupivacaine may cause weakness or paralysis.
Allergic reactions are rare, but may include rash, itching and redness of the skin, sneezing, nausea, 
vomiting, dizziness, fainting, sweating, fever, and low blood pressure. If you have these symptoms, 
please call your study doctor.
Other side effects related to liposomal bupivacaine can include nausea (22.6%), constipation (8.7%), 
vomiting (6%), high temperature (5.5%), headache (5%), itching (2.4%), dizziness (<2%), low blood 
pressure (<2%), high heart rate (1.3%), swelling (<1%), and anemia (<1%).
What do I need to know about reproductive health if I am in this study?  
The research may also hurt a pregnancy or fetus in ways that are unknown. These may be a minor 
inconvenience or may be so severe as to cause death.
Will it cost me anything to participate in this research study?
You and your insurance company will be charged for the health care services that you would ordinarily 
be responsible to pay. In some cases, insurance will not pay for services ordinarily covered because 
these services are performed in a research study. You should check with your insurance to see what 
services will be covered by your insurance and what you will be responsible to pay.
What happens to the information collected for the research?
Efforts will be made to limit the use and disclosure of your personal information, including research 
study and medical records, to people who have a need to review this information. We cannot promise 
complete confidentiality. Organizations that may inspect and copy your information include the 
Institutional Review Board (IRB), the committee that provides ethical and regulatory oversight of 
research, and other representatives of this institution, including those that have responsibilities for 
monitoring or ensuring compliance.
The sponsor, monitors, auditors, the IRB, the University of Minnesota Research Compliance Office and 


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other University compliance units, the US Office of Research Integrity (ORI), the US Office for the 
Protection of Human Research Protections (OHRP), the US Food and Drug Administration (FDA) may be 
granted direct access to your medical records to conduct and oversee the research. By signing this 
document you are authorizing this access. We may publish the results of this research. However, we will 
keep your name and other identifying information confidential.
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.
Will anyone besides the study team be at my consent meeting?  
You may be asked by the study team for your permission for an auditor to observe your consent 
meeting. Observing the consent meeting is one way that the University of Minnesota makes sure that 
your rights as a research participant are protected. The auditor is there to observe the consent meeting, 
which will be carried out by the people on the study team. The auditor will not document any personal 
(e.g. name, date of birth) or confidential information about you. The auditor will not observe your 
consent meeting without your permission ahead of time.
Whom do I contact if I have questions, concerns or feedback about my experience?
This research has been reviewed and approved by an IRB within the Human Research Protections 
Program (HRPP). To share feedback privately with the HRPP about your research experience, call the 
Research Participants’ Advocate Line at 612-625-1650 (Toll Free: 1-888-224-8636) or go to 
z.umn.edu/participants. You are encouraged to contact the HRPP if: 
●Your questions, concerns, or complaints are not being answered by the research team.
●You cannot reach the research team.
●You want to talk to someone besides the research team.
●You have questions about your rights as a research participant.
●You want to get information or provide input about this research.
Will I have a chance to provide feedback after the study is over? 
The HRPP may ask you to complete a survey that asks about your experience as a research participant. 
You do not have to complete the survey if you do not want to. If you do choose to complete the survey, 
your responses will be anonymous. 
If you are not asked to complete a survey, but you would like to share feedback, please contact the 
study team or the HRPP. See the “Investigator Contact Information” of this form for study team contact 
information and “Whom do I contact if I have questions, concerns or feedback about my experience?” of 
this form for HRPP contact information.
Can I be removed from the research?
The person in charge of the research study or the sponsor can remove you from the research study 
without your approval. We will tell you about any new information that may affect your health, welfare, 
or choice to stay in the research.
What happens if I am injured while participating in this research?
In the event that this research activity results in an injury, treatment will be available, including first aid, 
emergency treatment and follow-up care as needed.  Care for such injuries will be billed in the ordinary 
manner, to you or your insurance company. If you think that you have suffered a research related injury 


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let the study physicians know right away. 
Use of Identifiable Health Information
We are committed to respect your privacy and to keep your personal information confidential.  When 
choosing to take part in this study, you are giving us the permission to use your personal health 
information that includes health information in your medical records and information that can identify 
you. For example, personal health information may include your name, address, phone number or social 
security number. Those persons who get your health information may not be required by Federal 
privacy laws (such as the 1099 Rule) to protect it. Some of those persons may be able to share your 
information with others without your separate permission. Please read the HIPAA Authorization form 
that we have provided and discussed.
The de-identified results of this study may also be used for teaching, publications, or for presentation at 
scientific meetings.  
Your signature documents your permission to take part in this research.  You will be provided a copy of 
this signed document.
_______________________________________________      __________________
Signature of Participant                                                               Date
_______________________________________________
Printed Name of Participant
____________________________________________            __________________
Signature of Person Obtaining Consent                                     Date
______________________________________________________
Printed Name of Person Obtaining Consent