Clinical trial NCT05005260
Conditions: Pain, Postoperative Brachial Plexus Block
Keywords: Interscalene nerve block total shoulder arthroplasty pain management OBAS QoR-15
Sponsor: Mayo Clinic
Start date: 2021-10-14; Completion date: 2023-03-18
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to assess analgesia efficacy between liposomal bupivacaine single injection interscalene blockade vs. continuous interscalene nerve block for patients undergoing primary total shoulder arthroplasty.

Detailed description:

Arms: arm 1: Subjects will receive a preoperative single-injection interscalene nerve block with long-acting numbing medicine, liposomal bupivacaine arm 2: Subjects will receive a preoperative interscalene nerve block with a continuous catheter device which provides local anesthetic, bupivacaine, for up to 3 days.
Interventions: intervention 1: Bupivacaine HCl intervention 2: Liposomal bupivacaine + Bupivacaine Hcl 0.5% Inj
Intervention descriptions: intervention 1: Subjects randomized to the continuous interscalene nerve block group will receive a loading dose of 15-20 mL bupivacaine HCl 0.5% followed by a continuous catheter infusion of bupivacaine 0.2% at 8 mL per hour for 72 hours. intervention 2: Subjects will receive a one-time interscalene nerve block injection of 5 mL of bupivacaine 0.5% (25 mg) admixed with 10 mL of liposomal bupivacaine (133 mg).

Protocol documents:
Prot_SAP_000.pdf: 
LB-ISB vs C-ISB 
Page 1 of 33 
 
Prospective, randomized clinical trial comparing analgesic efficacy of liposomal 
bupivacaine single-injection interscalene blockade to continuous interscalene blockade for 
patients undergoing primary total shoulder arthroplasty 
 
 
 
 
 
Regulatory Sponsor: 
Jason K. Panchamia, DO 
Department of Anesthesiology 
Mayo Clinic – Rochester Campus  
507-284-9698 
Study Product: 
Liposomal Bupivacaine (Exparel®) 
Protocol Number: (IRBe) 
21-000908 
ClinicialTrials.gov 
NCT05005260 
 
 
 
 
Version 
Date 
1.0 
07/02/2021 
 
 
 
 
 
 


LB-ISB vs C-ISB 
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Table of Contents 
1 
Introduction ........................................................................................................................................... 6 
1.1 
Background ................................................................................................................................... 6 
1.2 
Investigational Agent .................................................................................................................... 7 
1.3 
Clinical Data to Date ..................................................................................................................... 7 
1.4 
Dose Rationale and Risk/Benefits ................................................................................................. 8 
2 
Study Objectives ................................................................................................................................... 9 
2.1 
Primary Objective ......................................................................................................................... 9 
2.2 
Secondary Objective ..................................................................................................................... 9 
3 
Study Design ......................................................................................................................................... 9 
3.1 
General Design .............................................................................................................................. 9 
3.2 
Primary Outcome ........................................................................................................................ 12 
3.3 
Secondary Outcomes .................................................................................................................. 12 
4 
Subject Selection Enrollment and Withdrawal ................................................................................... 13 
4.1 
Inclusion Criteria ........................................................................................................................ 13 
4.2 
Exclusion Criteria ....................................................................................................................... 14 
4.3 
Early Withdrawal of Subjects ..................................................................................................... 15 
4.3.1 
When and How to Withdraw Subjects ................................................................................ 15 
4.3.2 
Data Collection and Follow-up for Withdrawn Subjects .................................................... 15 
5 
Study Procedures ................................................................................................................................ 16 
5.1 
Pre-op Plan .................................................................................................................................. 16 
5.2 
Dosing ......................................................................................................................................... 16 
5.3 
Assessment .................................................................................................................................. 17 
5.4 
Intra-op Plan ................................................................................................................................ 17 
5.5 
Postoperative Management ......................................................................................................... 17 
6 
Safety Endpoints ................................................................................................................................. 18 
7 
Study Drug .......................................................................................................................................... 19 
7.1 
Description .................................................................................................................................. 19 
7.2 
Treatment Regimen ..................................................................................................................... 19 
7.3 
Method for Assigning Subjects to Treatment Groups ................................................................. 19 
7.4 
Preparation and Administration of Study Drug .......................................................................... 19 
7.5 
Subject Compliance Monitoring ................................................................................................. 19 


LB-ISB vs C-ISB 
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7.6 
Prior and Concomitant Therapy .................................................................................................. 20 
7.7 
Packaging .................................................................................................................................... 20 
7.8 
Masking/Blinding of Study ......................................................................................................... 20 
7.9 
Receiving, Storage, Dispensing and Return ................................................................................ 20 
8 
Statistical Plan ..................................................................................................................................... 20 
8.1 
Sample Size Determination ......................................................................................................... 20 
8.2 
Statistical Methods ...................................................................................................................... 20 
8.3 
Descriptive Statistics ................................................................................................................... 20 
8.4 
Handling of Missing Data ........................................................................................................... 20 
8.5 
Subject Population(s) for Analysis ............................................................................................. 21 
9 
Safety and Adverse Events ................................................................................................................. 21 
9.1 
Definitions ................................................................................................................................... 21 
9.2 
Recording of Adverse Events ..................................................................................................... 23 
9.3 
Reporting of Serious Adverse Events and Unanticipated Problems ........................................... 24 
9.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB ................................................... 24 
9.4 
Unmasking/Unblinding Procedures ............................................................................................ 25 
9.5 
Stopping Rules ............................................................................................................................ 25 
9.6 
Medical Monitoring .................................................................................................................... 26 
10 
Data Handling and Record Keeping ............................................................................................... 26 
10.1 
Confidentiality ............................................................................................................................ 26 
10.2 
Source Documents ...................................................................................................................... 27 
10.3 
Records Retention ....................................................................................................................... 27 
11 
Study Monitoring, Auditing, and Inspecting................................................................................... 28 
11.1 
Study Monitoring Plan ................................................................................................................ 28 
11.2 
Auditing and Inspecting .............................................................................................................. 28 
12 
Ethical Considerations .................................................................................................................... 29 
13 
Study Finances ................................................................................................................................ 29 
13.1 
Funding Source ........................................................................................................................... 29 
14 
Publication Plan .............................................................................................................................. 29 
 
 
 


LB-ISB vs C-ISB 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ASA 
American Society of Anesthesiologists 
ASES 
American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form 
C-ISB 
Continuous Interscalene Nerve Block 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IRB 
Institutional Review Board 
LANSS 
Leeds Assessment of Neuropathic Symptoms and Signs 
LAST 
Local Anesthetic Systemic Toxicity 
LB-SISB Liposomal Bupivacaine Single injection interscalene blockade 
NRS 
Numeric Rating Scale 
OBAS 
Overall Benefit of Analgesic Score 
OME 
Oral Morphine Equivalents  
PACU 
Post-anesthesia Care Unit 
PHI 
Protected Health Information 
PI 
Principal Investigator 
POD 
Postoperative Day 
QoR-15 
Quality of Recovery 15-item short form patient survey 
RASS 
Richmond Agitation-Sedation Scale 
SAE 
Serious Adverse Event/Serious Adverse Experience 
TDABC 
Time-Driven Activity-Based Costing 
TSA 
Total Shoulder Arthroplasty 
 
 
 
 
 
 
 
 


LB-ISB vs C-ISB 
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Title 
Prospective, randomized clinical trial comparing analgesic efficacy of liposomal 
bupivacaine single-injection interscalene blockade to continuous interscalene blockade for 
patients undergoing primary total shoulder arthroplasty 
Running Title 
LB-SISB vs CISB 
Protocol Number 
21-000908 
Phase 
Phase IV 
Methodology 
Single center, unblinded, randomized control trial with two intervention arms 
Overall Study 
Duration 
14 Months (time when data collected for last patient) 
Subject 
Participation 
Duration 
Up to 7 days post-operatively  
Single or Multi-
Site  
Single-Site 
Objectives 
Primary objective is to assess analgesia efficacy between liposomal bupivacaine single 
injection interscalene blockade vs. continuous interscalene nerve block for patients 
undergoing primary total shoulder arthroplasty.  Secondary objectives include pain scores 
and opioid consumption at pre-defined time intervals, peripheral nerve block 
complications, length of hospital stay, and postoperative follow-up for up to 7 days after 
surgery depending on follow-up availability. 
Number of 
Subjects 
88 patients will be randomized to one of two interventions: liposomal bupivacaine single 
injection interscalene blockade or continuous interscalene nerve block. 
Diagnosis and 
Main Inclusion 
Criteria 
Patients presenting for unilateral primary total shoulder arthroplasty (includes anatomic 
and reverse total shoulder arthroplasty), who can provide consent, older than 18 years of 
age, and have American Society of Anesthesiologists (ASA) physiological status I-III. 
Study Product, 
Dose, Route, 
Regimen 
Liposomal bupivacaine (Exparel®).  Patients will receive a one-time interscalene nerve 
block injection of 5 mL of bupivacaine 0.5% (25 mg) admixed with 10 mL of liposomal 
bupivacaine (133 mg). 
Duration of 
Administration 
One-time injection 
Reference therapy 
Continuous interscalene nerve block through an indwelling nerve catheter utilizing 
standard bupivacaine hydrochloride 
Statistical 
Methodology 
Randomization of each patient to a study arm will occur in a 1:1 allocation utilizing 
randomization schedule which will be created by the Division of Biomedical Statistics and 
Informatics.   Subgroup analysis will be performed evaluating reverse total shoulder 
arthroplasty vs anatomic total shoulder arthroplasty, and patients who received allocated 
treatment per planned protocol 
 
 


LB-ISB vs C-ISB 
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1 
Introduction 
 
This document is a clinical research protocol.  The described study will be conducted in 
compliance with the protocol, Good Clinical Practices standards and associated Federal 
regulations, and all applicable institutional research requirements.   
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
 
Use of study medications within this study is not intended to be reported to the U.S. Food & 
Drug Administration (FDA) in support of a new indication for use or to support any other 
significant change in the labeling for the drug.  Additionally, use of study medications within this 
study is not intended to support a significant change in the advertising for the product. 
 
1.1 
Background 
 
Uncontrolled postoperative pain can be associated with significant deleterious consequences, 
including elevated stress response, decrease quality of life, increase in morbidity and mortality, 
and persistent post-surgical pain.1 Total shoulder arthroplasty (TSA) is considered to be a major 
surgical procedure resulting in severe postoperative pain, especially in the first 48 hours after 
surgery.2 In our recently published randomized clinical trial3 (IRB 15-009646; Mayo Clinic, 
Rochester, MN, USA), we reported that within a multimodal analgesic protocol, the continuous 
interscalene blockade (ISB) through an indwelling nerve catheter provides superior analgesia 
compared to single-injection interscalene blockade and local infiltration analgesia in the 
immediate postoperative period after primary TSA.3  Despite this, a few drawbacks to the 
continuous ISB include technical difficulty of catheter placement, increased procedure time, 
catheter dislodgement, leakage at the site of insertion, and developing an infrastructure to 
support the catheter.   
Since our publication, liposomal bupivacaine, an extended-release bupivacaine formulation 
(currently marketed as Exparel®; Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) had 
been approved by the FDA for use in single-injection ISB.4  Limited data has shown liposomal 
bupivacaine single-injection ISB to provide enhanced and prolonged analgesia compared to 
placebo and standard bupivacaine HCl single-injection ISB with a similar safety profile.5,6  There 
is a paucity of data comparing continuous-ISB (C-ISB) to liposomal bupivacaine single-injection 
ISB (LB-ISB) in a head-to-head clinical trial.  Furthermore, the cost-effectiveness of either 
technique remains unknown in the context of the overall episode of care. 


LB-ISB vs C-ISB 
Page 7 of 33 
 
The primary aim of this study is to evaluate the analgesia efficacy between liposomal 
bupivacaine single injection interscalene blockade (LB-ISB) vs. continuous interscalene nerve 
block (C-ISB) for patients undergoing primary total shoulder arthroplasty.    
1.2 
Investigational Agent 
 
Liposomal bupivacaine was approved by FDA in 2011 for surgical site infiltration and in 2018 
for use in interscalene brachial plexus nerve blocks for postoperative pain control.4  Liposomal 
bupivacaine consists of vesicles of bupivacaine loaded in the aqueous chambers using 
DepoFoam® technology (Pacira Pharmaceuticals Inc, San Diego, CA).4  These vesicular 
liposomes will dissolve slowly and release bupivacaine over time, providing a longer analgesic 
effect than standard bupivacaine HCl. Chahar et al. provides a detailed review regarding 
liposomal bupivacaine’s pharmacokinetics and molecular structure.7 Given the slow release of 
bupivacaine utilizing this unique DepoFoam® technology, analgesic effects can last up to 72 
hours after a single injection into the surgical site.4,8 
Liposomal bupivacaine (Exparel®) is supplied in one vial, containing either 133 mg or 266 mg 
(1.3%; 13.3 mg/mL) of bupivacaine suspended in multivesicular liposomes in normal saline.   
Bupivacaine HCl is an amide local anesthetic which inactivates voltage gated sodium channels. 
In nerves, this results in loss of action potential and signal conduction along the nerve fiber 
leading to sensory and/or motor blockade. Bupivacaine is a long-acting local anesthetic indicated 
for multiple routes of administration including local infiltration and peripheral nerve blocks.9 
1.3 
Clinical Data to Date 
 
Clinical Efficacy 
Most studies evaluating liposomal bupivacaine are limited to administration via surgical site 
infiltration; these clinical trials demonstrate prolong analgesia and decrease opioid consumption 
when compared to placebo in patients undergoing various surgical procedures.6,10,11  In contrast, 
analgesic outcomes were inconsistent when liposomal bupivacaine was compared to bupivacaine 
HCl for surgical site infiltration in total knee and hip surgery.12-14  Similarly, clinical trials 
evaluating interscalene nerve block with bupivacaine HCl compared to liposomal bupivacaine 
surgical site infiltration have shown variable analgesic outcomes.15-17 
Current data pertaining to the administration of liposomal bupivacaine via interscalene nerve 
blocks are sparse.  Patel et al. reported significantly improved pain scores and reduced opioid 
consumption up to 72 hours postoperatively after comparing LB-ISB (utilized 133 mg of 
liposomal bupivacaine) to placebo ISB (using normal saline).6  Vandepitte et al. compared LB-
ISB to ISB with standard bupivacaine HCl in patients undergoing major shoulder surgery.5  In 
the LB-ISB group, the authors admixed 5 mL of 0.25% bupivacaine HCl with 133 mg of 


LB-ISB vs C-ISB 
Page 8 of 33 
 
liposomal bupivacaine, while the control group received 15 mL of 0.25% standard bupivacaine 
HCl.  The LB-ISB group had a moderate reduction in worst pain score in the first postoperative 
week compared to the control group (generalized estimating equation [GEE] estimated marginal 
mean values, 3.6 ± 0.3 vs 5.3 ± 0.4 points on the Numeric Rating Scale, difference, 1.6 ± 0.5; 
95% CI, 0.8–2.5).   
 
Recently, a retrospective investigation evaluating LB-ISB vs C-ISB reported improved pain 
scores for LB-ISB on postoperative day (POD) 0 and 1, with similar opioid consumption and 
better cost efficiency compared to C-ISB.18   In the LB-ISB group, the authors prepared an 
injectate mixture composed of 10 mL of 0.5% bupivacaine HCl with 133 mg of liposomal 
bupivacaine.   There were no complications noted in either group.    
 
Safety 
In a meta-analysis, the safety profile of liposomal bupivacaine was similar to bupivacaine HCl.  
The most common side effects in the liposomal bupivacaine group (800 patients) were nausea 
(3.3%) and constipation (2.0%).  Cardiac complications were tachycardia (4%), and bradycardia 
(2%), which did not require treatment and were similar to bupivacaine HCl group.  One death 
was reported in the 800 patients that received liposomal bupivacaine, and one in the bupivacaine 
HCl group; both drugs were not deemed to be causative agents.19   
Ilfeld et al. evaluated the safety of liposomal bupivacaine in peripheral nerve blocks (ankle, 
femoral nerve, and intercostal nerve block patients), and reported the most common adverse 
events to be mild in severity.20   These symptoms included nausea, pyrexia, constipation, 
vomiting, and pruritus. The incidence of central nervous system and cardiac adverse events were 
similar between liposomal bupivacaine, bupivacaine HCl, and placebo groups.  The authors 
concluded that liposomal bupivacaine shares a similar safety profile to bupivacaine HCl and 
normal saline. 
Patel et al. compared the interscalene neve block with liposomal bupivacaine to normal saline 
and reported a similar incidence of adverse events between both groups.6  Most of the adverse 
events were considered mild in severity (nausea was the most reported adverse event).  The 
authors performed pharmacokinetic assessments in patients receiving 166 mg and 266 mg of 
liposomal bupivacaine via interscalene block and reported peak concentrations occurring at 48 
hours, with the mean peak concentrations (209 and 461 ng/mL, respectively) remaining below 
the thresholds for local anesthetic associated cardio- and neuro toxicity (2,000–4,000 ng/mL).   
Similarly, in a clinical trial comparing LB-ISB to ISB with standard bupivacaine HCl, there were 
no increased risk of complications in the LB-ISB group (RR, 1.6; 95% CI, 0.9–2.7).5  Budge et 
al. reported no complications in their retrospective investigation comparing LB-ISB to C-ISB.18 
User Experience 


LB-ISB vs C-ISB 
Page 9 of 33 
 
At our institution, liposomal bupivacaine has been used by our surgical colleagues for a variety 
of procedures (breast, hip, shoulder, knee, abdominal) without any reported side effects 
attributed to the medication.  Furthermore, we have used liposomal bupivacaine for interscalene 
nerve block on numerous patients after FDA approval without any adverse events.      
1.4 
Dose Rationale and Risk/Benefits 
 
C-ISB group 
Patients will receive a loading dose of 15-20 mL bupivacaine HCl 0.5% followed by a 
continuous catheter infusion of bupivacaine 0.2% at 8 mL per hour for 72 hours.  We have used 
this dose for many years in our practice, and we have successfully employed this in our previous 
randomized clinical trial.3 Further, this dose is commonly employed in studies involving 
interscalene blocks.21  These doses conform to the manufacturer recommended single and daily 
dose maximum administration and reliably provides postoperative analgesia.9 
LB-ISB 
Patients will receive 5 mL of Bupivacaine HCl 0.5% (25 mg) mixed with 10 mL of liposomal 
bupivacaine (133 mg).  This mixture is in accordance with manufacturer prescribing guidelines: 
max recommended dose of liposomal bupivacaine for interscalene nerve blocks is 133 mg and 
mixing dose ratio of standard bupivacaine HCl to liposomal bupivacaine of 1:2 or less (25 mg / 
133 mg).4  Liposomal bupivacaine exhibits a bimodal plasma concentration profile, where an 
initial peak occurs at 1 hour and a second peak occurs between 12 to 36 hours.8  Therefore, 
adding standard bupivacaine HCl to liposomal bupivacaine will bridge the analgesic gap in the 
first few hours after the nerve block is performed.  A similar administration mixture for 
interscalene blocks was used by Vandepitte et al.5 
2 
Study Objectives 
2.1 
Primary Objective 
To evaluate the analgesia efficacy in the first 24 hours postoperative period between liposomal 
bupivacaine single injection interscalene blockade and continuous interscalene nerve block via 
numeric rating pain score and opioid consumption for patients undergoing primary total shoulder 
arthroplasty.    
2.2 
Secondary Objective 
To evaluate the following: the analgesia efficacy between both groups up to 7 days 
postoperatively using numeric rating pain score assessment and opioid consumption, adverse 
events, duration of hospital stay, surgical recovery via quality of recovery questionnaire, and 
cost-benefit analysis via time-driven activity-based costing model.   


LB-ISB vs C-ISB 
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Please refer to Section 3.2 and 3.3 for detailed outcome measures.   
3 
Study Design 
3.1 
General Design 
Single center, unblinded, randomized control trial with two intervention arms assessing acute 
pain management.  These two arms include: 1) liposomal bupivacaine single-shot interscalene 
blockade (LB-ISB group) and 2) continuous interscalene nerve block (C-ISB group) 
The study will be registered with www.ClinicalTrials.gov 
After approval by Mayo Clinic IRB, we will work closely with the department of orthopedics at 
Mayo Clinic Hospital, Methodist Campus to enroll patients into the study.  Potential subjects will 
consist of patients who present for elective primary TSA meeting the inclusion and exclusion 
criteria (Section 4.1 and 4.2).  Subjects will be approached by study staff for recruitment in 
person and informed consent will be obtained during the preoperative clinic visit.  Prior to 
surgery, subjects will be randomized to either one of the two study groups using dynamic 
allocation in a computer application developed by personnel in the Division of Biomedical 
Statistics and Informatics (Section 7.3).  Subjects unable to give consent themselves will not be 
approached for participation.  No remuneration will be provided.  All efforts will be made to 
enroll participants regardless of ethnic heritage. No passive recruitment methods (newspapers, 
advertisements, or flyers) will be used.   
Eighty-eight patients are required for this clinical trial.  After baseline values are established, 
data will prospectively be collected during the peri-operative period up to 7 days post-
operatively (patient will have follow-up via office visit or telephone call) for the purpose of this 
study.  Data will be collected utilizing the institution’s electronic medical record system and be 
transferred to an electronic research database (e.g. Excel, REDCap). Figure 1 and Table 1 
summarizes the data that will be collected during this study. 
 
 
 
 
 
 
 


LB-ISB vs C-ISB 
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Table 1.  Summary of data collection 
*Patients may be contacted up to postoperative day 7 to collect data depending on availability of patient 
and study staff during follow-up encounters. 
 
 
Pre-
operative 
Peri- & Post-operative 
Study Activity 
Pre-op 
POD 0 (day of 
surgery) 
POD 
1 - 4 
Informed Consent 
x 
Inclusion/Exclusion Criteria 
x 
Pain Scores 
(numeric rating scale) 
x 
x 
x 
Patient and Surgical Data Collections 
x 
x 
 
OBAS 
 
 
X 
QoR-15 Patient Survey  
x 
 
x 
Opioid Consumption  
x 
x 
Length of Hospital Stay 
x 
Adverse Events Monitoring 
 
x 
x 
Peripheral Nerve Block - catheter related 
complications 
 
x 
x 
Follow up via telephone call or office visit 
 
x 
X* 


LB-ISB vs C-ISB 
Page 12 of 33 
 
 
 
 
 
Study Recruitment 
Inclusion/exclusion criteria 
Discuss Study 
Consent 
 
74 Patients 
Randomize on Day of Surgery 
Dynamic Allocation 
 
1:1 LB-ISB vs. C-ISB 
LB-ISB  
37 patients 
 
C-ISB  
37 patients 
 
Shoulder Surgery  
Postoperative Period 
Up to POD 7 
(dependent on follow-
up availability) 
Capture:  
-
Pain Scores 
-
Opioid Consumption 
-
Length of Hospital Stay 
-
Adverse Events 
-
Quality of recovery Score 
-
Overall Benefit of Analgesic Score 
-
TDABC 
Office Visit 
Pre-OP 
Intra-OP 
Post-OP 
Figure 1.  Diagram of patient flow from recruitment to outpatient follow-up 


LB-ISB vs C-ISB 
Page 13 of 33 
 
3.2 
Primary Outcome 
To investigate the hypothesis that within our current multimodal analgesia total joint protocol, C-
ISB provides superior analgesia via NRS pain intensity scores (difference ≥ 1.5) and opioid 
consumption (difference ≥ 20 mg oral morphine equivalents) on POD 1 compared to LB-ISB 
following primary total shoulder arthroplasty.   
3.3 
Secondary Outcomes 
1. Pain intensity (NRS) assessments prior to surgery, post-anesthesia care unit (PACU), every 4 
to 6 hours beginning on arrival to patient room (to the closet time interval), and hospital 
discharge up to POD 7.     
2. Opioid consumption in daily oral morphine equivalents (OME) – preoperative, 
intraoperative, PACU stay, beginning on arrival to patient room up to POD 7. 
a) Patients will be asked to record their daily intake of opioids and pain scores at pre-
defined intervals. A research team member will follow-up with study patients to 
document the patient’s pain score and opioid consumption values for the previous day 
as well as administer the quality of recovery 15-item questionnaire.   
3. Moderate to severe complications during regional anesthesia block placement (inadvertent 
epidural or subarachnoid injection, local anesthetic systemic toxicity*, and pneumothorax). 
* Local anesthetic systemic toxicity is suspected if a patient has acute onset of central 
nervous system changes (tinnitus, metallic taste in mouth, perioral numbness) or 
cardiovascular changes (bradycardia, hypotension, EKG changes). 
4. Peripheral nerve block catheter-related complications including presence of site infection 
(tenderness to palpation, erythema, swelling, drainage of pus), hematoma, and local 
anesthetic systemic toxicity.  
5. Inadvertent catheter dislodgement 
6. Duration of hospital stay (number of days), in addition to reason for hospital length of stay > 
1 night (i.e., social work/disposition, inadequate pain control, nausea/vomiting, other) 
7. Postoperative follow-up 
a. Telephone encounter or office visit to collect NRS pain scores at rest, opioid 
consumption, questionnaire, and adverse events.  Data will be collected for 
postoperative days 0 to 4; however, patients may be contacted up to postoperative day 
7 to collect this information if patients or study staff are unavailable.   
8. Questionnaire Forms 
a) QoR-15 
i. Quality of Recovery (QoR) 15-item short form patient survey is a validated, 
reliable, and feasible scoring system evaluating 5 dimensions of health: 
psychological support, comfort, emotions, physical independence, and 
pain.22,23 
ii. Collected preoperatively and POD 1 to 4 via office visit or telephone call. 
b) Overall benefit of Analgesic Score (OBAS)  
i. Validated tool measuring patient’s experience with their postoperative pain 
regimen.24  This simple 7 question (Q1 to Q7) scoring system entails a 
combination of pain intensity, adverse opioid events, and patient satisfaction.  
The total OBAS score is calculated via ‘sum items Q1 through Q6 and add [4 
– score from Q7].’  This score consists of a 29-point scale ranging from 0 


LB-ISB vs C-ISB 
Page 14 of 33 
 
(best) to 28 (worst); therefore, lower OBAS scores indicate more analgesic 
benefit.  This will be administered to patients prior to hospital discharge. 
9. Cost-benefit analysis  
a) Examining the cost of each analgesic modality within the overall episode of 
orthopedic surgical care using the time-driven activity-based costing (TDABC) 
model, which provides a more accurate representation of true costs by estimating the 
quantity of time and the cost per unit of time of each resource from preoperative visits 
to hospital discharge25,26   
10. Additional outcome measures for future investigation 
a)   American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form 
i. ASES questionnaire will be collected pre-operatively, 3-month, and at 1 year 
postoperatively via office visit or telephone call.  Collected data will be used 
in a follow-up study.27 
b)   Patient-Reported Outcomes Measurement Information System (PROMIS®) 
i. Already an established and standard questionnaire being collected for all 
orthopedic surgical patients. 
 
4 
Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
1. Adult patients with an American Society of Anesthesiologists (ASA) physiological status 
I-III 
2. Patients presenting for unilateral primary total shoulder arthroplasty (includes anatomic 
and reverse total shoulder arthroplasty). 
3. Patients 18 years of age and older 
4. Able to provide informed consent for him or herself  
4.2 
Exclusion Criteria 
1. Chronic pain syndromes  
2. Chronic opioid use (>1 month) with OME >5 mg/day OR acute opioid use (< 1 month) 
with OME > 30 mg/day. 
3. Body mass index (BMI) > 45 kg/m2 
4. Severe drug allergy* to medications used in this study, including non-steroidal anti-
inflammatory drugs (i.e. celecoxib) and local anesthetics.   
• *defined as an immune reaction resulting in shortness of breath, hives, anaphylaxis, 
wheezing, and fever 
5. Personal or family history of malignant hyperthermia.  
6. Major systemic medical problems such as: 
• Pre-existing severe renal disorder defined as glomerular filtration rate (GFR) <50 
units/m2 (if labs are available), currently on dialysis, or highly suspected based on 
history.   


LB-ISB vs C-ISB 
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• Severe hepatic disorder defined as current or past diagnosis of acute/subacute 
necrosis of liver, acute hepatic failure, chronic liver disease, cirrhosis (primary 
biliary cirrhosis), chronic hepatitis/toxic hepatitis, liver abscess, hepatic coma, 
hepatorenal syndrome, other disorders of liver 
• Pre-existing medical history of moderate to severe pulmonary disease requiring 
medical therapy (obstructive and/or restrictive), use of home oxygen, preoperative 
baseline oxygen saturation < 93% on room air.   
• History of contralateral hemidiaphragm dysfunction (e.g., paralysis) or phrenic 
nerve injury. 
7. Contraindication to a regional anesthesia technique (e.g., preexisting neuropathy+ in the 
operative extremity, coagulopathy, sepsis, infection at site of injection, uncooperative, 
and refusal).  
• 
+ pre-existing neuropathy includes sensory and/or motor deficits due to nerve 
insult of surgical extremity, radicular symptoms of surgical extremity, history of 
unresolved brachial plexus injury/brachial plexopathy, and tumors of the brachial 
plexus.  Patients with nerve compression distal to site of surgery, such as history 
of carpal tunnel syndrome or cubital tunnel syndrome, are NOT considered 
contraindications to regional anesthesia. 
8. Known to be currently pregnant or actively breastfeeding++ 
• 
++ All surgical patients are currently screened using a standardized Pregnancy 
Assessment tool (http://mayoweb.mayo.edu/sp-forms/mc8800-mc8899/mc8801-
161.pdf) 
9.  Impaired cognition (e.g. Alzheimer’s disease, moderate to severe dementia, 
encephalopathy)    
10. Non-English speaking 
 
4.3 Early Withdrawal of Subjects 
 
4.3.1 When and How to Withdraw Subjects 
 
If the patient is unable to comply with the study protocol or they wish to withdraw from the 
study their participation in the study will be terminated. Furthermore, if the placement of the 
peripheral nerve blocks cannot be performed, if an unanticipated reoperation is performed 
(during the same hospital stay), if an unanticipated complication unrelated to the study (e.g. 
pulmonary embolism, myocardial ischemia) where patients are unable to participate in study 
protocol, or if the patient remains intubated and sedated postoperatively for greater than one day, 
the patient will be terminated from the study. If the interscalene nerve block catheter becomes 
occluded or is pulled out prematurely, patients will remain in the study as our primary analysis 
will be performed based on the intention to treat. 
 
In order to account for 10% dropout, which includes patients terminated from the study, a total 
sample-size of N = 88 (44 per group) is proposed. Follow-up will not be performed for patients 
terminated from the study. 
 


LB-ISB vs C-ISB 
Page 16 of 33 
 
If the patient chooses not to participate, he or she will be provided the current perioperative care 
plan in place by the surgeon which will include various pain management options regardless of 
participation. 
 
4.3.2 Data Collection and Follow-up for Withdrawn Subjects 
 
Patients who voluntarily withdraw from the study, are terminated due to unforeseen 
circumstances such as reoperation, or if intubated and sedated postoperatively for greater than 
one day, will have their data collected in the peri-operative and follow-up periods up to the point 
of termination. Our primary analysis will be performed based on the intention to treat. A 
subgroup analysis will also be performed on patients who received the allocated treatment as per 
the planned protocol. 
 
The safety profile for liposomal bupivacaine has been assessed in previous studies as mentioned 
in Section 1.3, and the primary outcome for this study involves assessing its analgesic efficacy 
compared to other standard methods of regional anesthesia acute pain management techniques 
for patients undergoing total shoulder arthroplasty. Survival data for liposomal bupivacaine will 
not be assessed in this study; thus, we will plan to exclude data after a patient’s 
termination/withdrawal date. 
 
If the patient chooses not to participate, he or she will be provided the current perioperative care 
plan in place by the surgeon and will include various pain management options regardless of 
participation. 
 
5 
Study Procedures 
5.1 
Pre-op Plan 
All patients will undergo a standardized multimodal analgesia total joint pathway (See attached 
document).   Preoperatively, patients will be sedated, under the discretion of the anesthesiologist, 
with intravenous midazolam (1-4 mg) and fentanyl (50-200 mcg) for alleviation of anxiety and 
pain.  Additional sedatives at the discretion of the anesthesia team.  The interscalene nerve block 
will be performed under continuous live ultrasound guidance, obtaining visualization of the roots 
(C5-C6 is ideal) or trunks (Superior Trunk is ideal) of the brachial plexus in between the anterior 
and middle scalene muscles as described by Chan.28  An in-plane or out-of-plane approach to 
needle advancement under live ultrasound guidance will be at the discretion of the 
anesthesiologist.  In cases with poor ultrasound imaging, a combined nerve stimulator and 
ultrasound guidance technique is acceptable.  Appropriate needle placement will be verified by 
injecting normal saline 0.9% and visualizing spread within the interscalene groove at the level of 
the roots/trunks of the brachial plexus.  Local anesthetic may also be used for hydrodissection to 
navigate needle placement into the correct position.  The proceduralist should attempt to use less 
than 10 mL of normal saline 0.9% to identify correct placement of peripheral nerve block.   


LB-ISB vs C-ISB 
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For patients randomized to C-ISB group, a continuous catheter device (Perifix ® Catheter, 
B.Braun, Bethlehem, PA, USA) will be placed within the interscalene groove at the level of the 
roots/trunks of the brachial plexus.  After delivery of the catheter, verification of the catheter 
within the interscalene groove will be assessed by again evaluating spread of normal saline 0.9% 
or local anesthetic within the interscalene groove.   
 
5.2 
Dosing 
The local anesthetic solutions used for each block are displayed in Figure 2. The initial loading 
dose for the continuous ISB group will be administered through the nerve catheter.   The 
ambulatory nerve catheter system (On-Q CB004, Avanos Medical, INC., Alpharetta, GA) will be 
connected to the nerve catheter and the infusion rate will be initiated at 8 mL/hr.  Infusion rate 
changes will be at the discretion of the operating room anesthesiologist and, subsequently, the 
acute pain service.  Patients discharged with the ambulatory nerve catheter system will be 
managed using our institutional protocol which includes patient/family instructions, daily follow-
up, and a dedicated team to cover concerns or questions 24 hours, 7 days a week 
(http://intranet.mayo.edu/charlie/anesthesiology-perioperative-medicine-rst/anesthesia-
home/divisions/ce-anesthesia/continuous-nerve-catheters-pilot/#tabs-16274-0-0).   
 
Treatment Arm 
Local Anesthetic 
Total Volume of 
Preoperative 
Bolus 
Infusion 
 
Liposomal 
Bupivacaine 
Interscalene Nerve 
Block (LB - SISB) 
 
 
5 mL of Bupivacaine 
0.5% mixed with 10 mL 
of liposomal bupivacaine 
(133 mg)* 
15 mL 
N/A 
Continuous 
Interscalene Nerve 
Block (CISB) 
Bupivacaine 0.5% with 
1:200,000 Epinephrine 
(premixed solution) 
15-20 mL 
On-Q Select-A-Flow 
CB004 pump with 
continuous infusion of 
bupivacaine 0.2% at 8 mL 
per hour for 72 hours 


LB-ISB vs C-ISB 
Page 18 of 33 
 
Figure 2.  Treatment Arms.   
* In accordance with manufacturer prescribing guidelines: max dose of liposomal bupivacaine 
of 133 mg and mixing ratio of standard bupivacaine HCl to liposomal bupivacaine of less than 
1:2 (25 mg / 133 mg) 
5.3 
Assessment 
Patients in both groups will undergo sensory testing to evaluate block success.  Sensory testing is 
as follows, sensation to cold over the deltoid muscle (0= absent or diminished, 1 = at baseline).  
Motor block will be assessed by deltoid contraction (0= absent or diminished, 1 = at baseline).  
Block will be assessed at least 25 minutes after the placement of the block, if pre-surgical time 
permits, or postoperatively in the recovery room, or patients’ room on POD 0.  This assessment 
will be charted in the electronic anesthesia medical record when it has been completed. 
5.4 
Intra-op Plan 
Intraoperative anesthetic management entails general endotracheal anesthesia with standard 
American Society of Anesthesiologists monitoring.  All patients will receive 8 mg of intravenous 
(IV) dexamethasone. Intraoperative opioids, antiemetic prophylaxis, and additional 
intraoperative monitoring (e.g., arterial line) are at the discretion of the attending 
anesthesiologist. 
5.5 
Postoperative Management 
Postoperatively, all study patients will follow a standardized multimodal analgesia total joint 
pathway (see attached document). Medical care will be co-managed by both the orthopedic 
surgery team and anesthesia acute pain service, which is comprised of a regional 
anesthesiologist, anesthesia resident, and trained nursing staff. This service provides 24-hour in-
hospital coverage with daily patient rounding to act on potential concerns associated with 
continuous local anesthetic infusion. 
multimodal 
protocol TSA 122720
TSA Study Post-op 
standardized meds.p 
 
6 
Safety Endpoints 
 
These methods are already established procedures in the practice of perioperative pain control 
for a total shoulder arthroplasty.  There is minimal risk of placing a peripheral nerve block.  
Those risks include infection, bleeding, and/or nerve damage.  Patients will be monitored during 
the perioperative period for any adverse events.  During regional anesthesia block placement, 


LB-ISB vs C-ISB 
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trained sedation nurses or anesthesia personnel (staff physicians, residents, or nurse anesthetists) 
will be monitoring patients.  Patients will be monitored throughout the procedure utilizing the 
American Society of Anesthesiologists (ASA) standard monitors*, aspirating for blood or 
cerebral spinal fluid prior to administration of local anesthetic solution in divided doses, frequent 
assessment of the patient’s well-being via verbal communication, and always having emergency 
medications and airway equipment readily available.  Performing this regional block (ISB) is 
considered standard in our practice to provide optimal postoperative analgesia. 
* blood pressure (non-invasive blood pressure cuff cycling every 3 to 5 minutes or 
continuous arterial blood pressure monitoring placed due to clinical judgment of 
covering anesthesiologist), 5 lead EKG, continuous pulse-oximetry, and continuous 
monitoring from operating room anesthesia personnel (if the procedure is performed in 
the operating room) or frequent assessments by nurses who are trained to care for 
patients receiving regional anesthesia blocks (if procedure is performed in block room) 
Patients that are not discharged the same day after surgery will be admitted to the regular nursing 
floors.  Vital signs (heart rate, oxygen saturation, and blood pressure) will be captured every 4 to 
6 hours or more frequently if the clinical situation dictates in all postoperative orthopedic 
patients.     
Patients admitted to the hospital will be followed daily by the acute pain service and surgical 
team.  Patients discharged with a continuous interscalene nerve block will be followed by the 
acute pain service team.  All study patients, regardless of treatment arm and hospital status 
(inpatient vs outpatient), will be followed by study personnel.   Adverse events and/or 
complications will be monitored, which includes but not limited to, local anesthetic systemic 
toxicity, neurologic complications, hematoma, bleeding, infection, and wound problems.  Nerve 
damage and assessment is part of the follow-up regarding this study and will be followed closely.  
In the event an infection was to occur, the PI would be notified, protocol would be followed, and 
investigators of the study would review the incident.   
The principal investigator or a designated co-investigator of the study will be notified if a patient 
in the study requires an unanticipated ICU admission.   
7 
Study Drug  
7.1 
Description 
Liposomal bupivacaine (Exparel®) is supplied in one vial, containing either 133 mg or 266 mg 
(1.3%; 13.3 mg/mL) of bupivacaine suspended in multivesicular liposomes in normal saline.  It 
is regularly stocked in our pharmacy and automated dispensing medication system (Pyxis 
Medstation) found in the operating rooms and procedure rooms due to its frequent use for 
postoperative pain control. 


LB-ISB vs C-ISB 
Page 20 of 33 
 
7.2 
Treatment Regimen 
Patients randomized to LB-ISB will receive a preoperative single-injection interscalene block for 
pain management following primary total shoulder arthroplasty. The solution administered will 
contain 5 mL of bupivacaine 0.5% (25 mg) along with 10 mL of liposomal bupivacaine (133 
mg), which conforms to manufacture recommended guidelines.4  
7.3 
Method for Assigning Subjects to Treatment Groups 
Subjects that are consented and enrolled will be randomized into one of the two study groups: 
liposomal bupivacaine single injection interscalene blockade or continuous interscalene nerve 
block. In order to ensure balance on the demographic characteristics of the patients in the two 
study groups, the subjects will be stratified on sex and age group (≥65 vs. <65),  Within each 
stratum, subjects will be assigned to either of the two study groups using dynamic allocation in a 
computer application developed by personnel in the Division of Biomedical Statistics and 
Informatics. Using dynamic allocation will ensure that the subject allocation will remain 
balanced on the stratification factors and the study group assignment throughout the entire 
subject accrual phase.  This computer-based randomization system will be available only within 
the Mayo firewall on the intranet and will be username and password protected and accessible 
only to the study personnel. 
7.4 
Preparation and Administration of Study Drug 
At the time of the peripheral nerve block procedure, liposomal bupivacaine will be dispensed 
from the Pyxis Medstation and the 0.5% bupivacaine HCl solution will be obtained from the 
anesthesia stock room.  Both solutions are sterile; therefore, they will be poured in a sterile 
fashion into the wells located in a sterile peripheral nerve block tray.  The proceduralist will then 
mix 10 cc of liposomal bupivacaine (133 mg) with 5 cc of 0.5% bupivacaine (25 mg) into the 
same syringe for administration during the procedure.  For specific injection technique, please 
refer to section 5.1.   
7.5 
Subject Compliance Monitoring 
Patients receiving treatment will be enrolled in a prospective database.  No other treatment is 
necessary, except the peripheral nerve block before their scheduled procedure. 
7.6 
Prior and Concomitant Therapy 
Patients may receive therapy for any conceivable condition, while enrolled in this trial, if they 
meet the inclusion criteria (section 4.1).  Since this clinical trial is assessing analgesia efficacy 
between two intervention arms, rescue analgesics will be available to all patients for uncontrolled 
pain as this is a standard practice at our institution.   
7.7 
Packaging 
Please refer to section 7.1. 


LB-ISB vs C-ISB 
Page 21 of 33 
 
7.8 
Masking/Blinding of Study  
This prospective randomized control trial will be unblinded.  We acknowledge that an unblinded 
study design carries research limitations.  We understand that there may be no way for us to 
prevent participants from being treated differently if the study is unblinded.  They may have a 
different experience dependent upon the intervention biasing their observed outcome; however, 
blinding would remove the benefit a single-injection peripheral nerve block which entails the lack 
of catheter management.  However, we hope to discover the best overall clinical pathway for 
management of TSA for our patient population. 
7.9 
Receiving, Storage, Dispensing and Return 
Liposomal Bupivacaine is already being used throughout the enterprise, and its storage, 
handling, transport, and disposal will not change. 
8 
Statistical Plan 
8.1 
Sample Size Determination 
Sample size calculations were performed based on the outcomes of pain (NRS) and opioid 
consumption (OME) measured at 24 hours after surgery. Using data from Panchamia et al3 , the 
standard deviations of NRS pain and opioid consumption were estimated to be 2.4 points and 
23.6 mg OME for the single injection inter-scalene block group and 2.3 points and 25.1 mg 
OME for the continuous interscalene block group, respectively.  Assuming that similar 
variability will be observed in the proposed study, a sample of 40 subjects in each arm (n=80 
total) will provide 80% power to detect a difference of at least 1.5 points in NRS pain and 20 mg 
OME measured at 24 hours post-surgery.  In order to protect against a potential drop-out rate of 
10%, a total of 88 subjects will be enrolled. Calculations were based on a two-sample t-test, with 
alpha=0.05, two-sided test.  
8.2 
Statistical Methods 
The primary outcomes will be pain, as measured by NRS pain intensity scores, and opioid 
consumption, as measured by milligrams of OME, recorded at 24 hours after surgery. Secondary 
outcomes will include OBAS, intraoperative and postoperative complications, NRS pain scores, 
length of hospital stay, and QoR-15 score.  The outcomes of pain, opioid consumption, OBAS, 
and QoR-15 score will be compared between the LB-ISB group and the C-ISB group using two-
sample t-tests; if the data are not sufficiently normally distributed, non-parametric Wilcoxon 
rank sum tests will be used. Since this is a prospective, randomized trial, subjects in the two 
groups are expected to be similar with respect to their baseline characteristics; therefore, no 
formal comparisons of baseline data will be performed. However, if it is determined that 
adjustments need to be made, this will be done using a general linear models framework.  Length 
of stay is likely to be skewed, and thus will be analyzed using the non-parametric Wilcoxon rank 
sum test.  Intraoperative and in-hospital post-operative complications will be analyzed using chi-
square tests and logistic regression. The primary analysis will be based on the intent-to-treat 


LB-ISB vs C-ISB 
Page 22 of 33 
 
approach, in which subjects will be analyzed in the groups they were randomized to, regardless 
of the treatment actually received.  If appropriate, additional secondary analyses may be 
undertaken to perform the comparisons on the subjects who completed the study per-protocol, 
and on an as-treated basis. 
8.3 
Descriptive Statistics 
The data will be summarized using standard descriptive statistics, including means and standard 
deviations for continuous data, and counts and percentages for categorical data. Baseline 
characteristics will be reported separately for each of the two study groups. Summary data will 
be reported both in the text and in tabular format.   
8.4 
Handling of Missing Data 
All Subjects enrolled according to the entry criteria will be eligible for evaluation, regardless of 
the sequence of treatment that ensues, and the primary analysis will be conducted as an intent-to-
treat analysis.  Management of dropouts and missing data will depend on their frequency and the 
nature of the outcome measure.  Analysis of the distribution of subjects with data and those 
without data in each study group will be reviewed for impact to assess potential 
bias.  Adjustments for missing data will be performed only if deemed necessary and will be 
described completely.  Outlier values will be evaluated for their validity, and all data will be 
included unless judged to be invalid.     
8.5 
Subject Population(s) for Analysis 
Our primary analysis will be performed based on the intention-to-treat.  Therefore, any subject 
randomized into the study and undergoing the planned surgical procedure, regardless of whether 
they received a liposomal bupivacaine single injection interscalene blockade or a continuous 
interscalene nerve block, will be included in the primary analysis in the group they were 
randomized to.  If appropriate, additional subgroup analyses may be performed on patients who 
received the allocated treatment as per the planned protocol, and on an as-treated basis.   
 
9 
Safety and Adverse Events 
9.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 


LB-ISB vs C-ISB 
Page 23 of 33 
 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, data and safety monitoring board (DSMB) reports, interim findings, product 
labeling change) that in the opinion of the local investigator may adversely affect the 
rights, safety, or welfare of the subjects or others, or substantially compromise the 
research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Non-UPIRTSO 
 
A reportable event that does not meet the Mayo Clinic IRB's definition of a UPIRTSO. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include: 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant birth defect/anomaly 
 
And/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  


LB-ISB vs C-ISB 
Page 24 of 33 
 
 
Adverse Event Reporting Period 
For this study, the study treatment follow-up period is defined as up to 4 days following the last 
administration of study treatment. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
may be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  Throughout the study, any new clinically significant findings/abnormalities that meet 
the definition of an adverse event must also be recorded and documented as an adverse event.  
 
Adverse Event Causality 
We understand the importance pharmacovigilance, and the significance of establishing a 
relationship between study drug and adverse events.  Causality assessment or algorithms are 
available to assist with evaluating the likelihood or relationship between study drug and adverse 
event.  We will utilize the WHO-UMC causality assessment system to assess adverse event 
causality.29 
 
Post-study Adverse Event 
Unresolved adverse events related to the study medication/procedure will be followed by the 
PI/Co-PI’s until the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 


LB-ISB vs C-ISB 
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this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
• Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: Hospitalization or prolonged 
hospitalization for diagnostic or elective surgical procedures for a preexisting condition.  
Surgery should not be reported as an outcome of an adverse event if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful. 
 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
9.2 
Recording of Adverse Events 
The study team will seek information on adverse events by specific questioning and, as 
appropriate, by examination.  This will occur on daily follow up inpatient encounters as well as 
telephone or office visit encounters up to 7 days post-procedure.  Information on all adverse 
events will be recorded in the electronic medical record and in the appropriate adverse event 
worksheet.  Related signs, symptoms, and abnormal diagnostic, laboratory or procedure results 
will be recorded as well.  PI/Co-PI’s will be notified of the adverse events. 
The clinical course of each adverse event will be followed until resolution, stabilization, or until 
it has been determined that the study treatment or participation is not the probable cause.  Serious 
adverse events that are still ongoing at the end of the study period will be followed, as stated 
above.  Any serious adverse event that occurs after the study period and is considered related to 
the study treatment or study participation will be recorded and reported. 
9.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriate action necessary 
to protect the study participant and then complete the Study Adverse Event Worksheet and log.  
The sponsor-investigator will evaluate the event and determine the necessary follow-up and 
reporting required.  Serious adverse events will be evaluated and reported per institutional policy 
and regulatory requirements.   
A safety committee, consisting of anesthesiologists not involved in the study, will be established 
prior to subject recruitment.  This group will review any serious adverse events and evaluate for 
causality.   
9.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
 
Information collected on the adverse event worksheet (and entered in the research database):  


LB-ISB vs C-ISB 
Page 26 of 33 
 
• Subject’s name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or intervention):  
• If the adverse event was expected:  
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution:  
 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
9.4 
Unmasking/Unblinding Procedures 
 
This study is an unblinded study.   
 
9.5 
Stopping Rules  
 
Adverse events and serious adverse events, as defined in Section 9.1 of this protocol, will be 
monitored by the study team for patient safety.  Known serious adverse events associated with 
interscalene nerve blocks include local anesthetic systemic toxicity (LAST)*, inadvertent 
epidural or subarachnoid injection, and pneumothorax.   Additionally, patients will be monitored 
throughout the procedure utilizing standard ASA monitors, aspirating for heme or cerebral spinal 
fluid prior to administration of local anesthetic solution in divided doses, frequent assessment of 
the patient’s well-being via verbal communication, and always having emergency medications 
and airway equipment readily available.  Performing this regional block is considered standard in 
our practice and these methods are already established procedures in the practice of perioperative 
pain control for a total shoulder arthroplasty.3,30,31  
* Local anesthetic systemic toxicity is suspected if a patient has acute onset of central 
nervous system changes (tinnitus, metallic taste in mouth, perioral numbness) or 
cardiovascular changes (bradycardia, hypotension, EKG changes). 
LAST is a known serious adverse event with any local anesthetic administration.  Preventive 
measures include high degree of suspicion, vital sign monitoring (blood pressure, EKG, oxygen 
saturation), using an appropriate dose of local anesthetic, injecting local anesthetic in divided 
dose, aspirating prior to injection of medication looking for heme, being prepared to treat a 


LB-ISB vs C-ISB 
Page 27 of 33 
 
LAST event immediately (checklist, external defibrillator, resuscitate medications, emergency 
airway equipment), and having lipid emulsion therapy readily available (standard of care).32  
Similar to our current clinical practice, this protocol entails numerous methods to monitor and 
prevent LAST in accordance with the American Society of Regional Anesthesiology and Pain 
Medicine recommended guidelines for LAST.33  We acknowledge that despite the rarity of these 
serious adverse events, the potential still exists.   
Study stopping criteria includes: 
a) The study will stop if 5% of subjects in either group experience inadvertent epidural or 
subarachnoid injection, and pneumothorax.  
b) The study will stop if 5% of subjects in either group experience LAST. 
c) The study will stop if 5% of subjects in any group experience an unanticipated serious 
adverse event (as defined in section 9.1 of this protocol). 
 
If the study is stopped for any of the reasons listed above, a root cause analysis will be performed 
to determine cause of adverse event and relationship to study protocol.  The study team will 
formulate an appropriate plan of action to ensure patient safety. Such a plan may include, but is 
not limited to, protocol modifications, immediate termination of accrual, and adjustments in 
management of previously enrolled participants continuing to undergo study interventions. 
 
9.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 11 “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
10 Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  


LB-ISB vs C-ISB 
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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents and data records 
include hospital records, clinical and office charts, laboratory notes case report forms, and 
recorded data from automated instruments 
 
Data Management 
A study case report form (CRF)/data collection form will be established and utilized by the study 
team to record outcome measures.  The data will then be transferred to an electronic research 
database (EXCEL).   Data from the electronic research database will be utilized for primary and 
secondary analysis.   
 
Data Security and Confidentiality 
All patient information will be de-identified and kept in secure locations where only authorized 
study personnel can have access. All computers are password protected and secured behind 
institution firewall.  Case report forms will be maintained, in a secure location within the 
institution campus.  
 
Data Quality Assurance 
All data will be entered by appropriately trained personnel.  This is a single-site study.   Data will 
be collected manually and electronically abstracted using our electronic medical record and our 
OR database/ICU database.  Data collected will be manually entered into the RedCap system for 
electronic data storage and analysis. Every 1 in 50 records will be cross-referenced for accuracy. 
 
Data Clarification Process 
Incomplete, or erroneous data will be corrected by analyzing the patient’s electronic record. 


LB-ISB vs C-ISB 
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10.3 Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents.  Records will be 
maintained according to regulatory and institutional requirements.   
In order to constitute evidence with respect to product safety or regulatory or legal compliance, 
the Investigator agrees to retain study-related documents in a location that is secure and to which 
access can be gained if required.  The following documents must be archived: the Investigator’s 
File containing all required GCP documents, including signed Informed Consent Forms and 
subject-related materials, and CRFs.   
With respect to coding case report forms and subject identification code list, as described in 
section 7.3, patients will be randomized using a randomization schedule.  Using this 
randomization schedule, an EXCEL spreadsheet application will be created which will include 
sequentially assigned subject-ID numbers and corresponding treatment assignments.  All case 
report forms utilize this subject-ID numbers.  Case report forms are maintained in a de-identified 
manner by including subject ID, subject’s initials, and dates of pertinent study involvement.    
The sponsor-investigator will retain the specified records and reports as outlined in the Mayo 
Clinic Research Policy Manual – “Retention of and Access to Research Data Policy” 
http://mayocontent.mayo.edu/research-policy/MSS_669717   
 
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance reviewer 
is given access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 


LB-ISB vs C-ISB 
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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
12 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
13 Study Finances 
13.1 Funding Source 
 
Funding will be obtained internally through the institution from the Department of Orthopedic 
Surgery at Mayo Clinic Hospital, Methodist Campus.  The funds will be used to support the use 
of a statistician to analyze data.  
 
14 Publication Plan 
 
After trial closure, data will be analyzed, and a manuscript will be submitted to the appropriate 
journal, after consensus among all the investigators.  No funding agency is involved with this 
study.   
 
The study will be registered with www.ClinicalTrials.gov 
 
 


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