Clinical trial NCT03663283
Conditions: Arthropathy Shoulder
Sponsor: Mayo Clinic
Start date: 2018-10-29; Completion date: 2020-02-14
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to determine if peripheral nerve block with liposomal bupivacaine in combination with standard bupivacaine will prolong the duration of block, improve pain scores, and decrease opioid utilization in the post-operative period when compared to peripheral nerve block with standard bupivacaine alone.

Detailed description:
This is a prospective, single-blinded randomized clinical trial comparing outcomes in patients undergoing total shoulder arthroplasty (anatomic and reverse) who receive a peripheral nerve block with liposomal bupivacaine in combination with standard bupivacaine versus standard bupivacaine alone. Once consent is obtained, baseline characteristics will be recorded and patients will be randomized to intervention or control. Following surgery, patients will be followed until their 3-week post-operative visit. The primary outcome measure will be the mean difference in patient pain scores over the first 72 hours post-operatively between two groups. Secondary outcomes will include: (1) Total opioid consumption (as measured utilizing morphine intravenous equivalents) in first 72 hours and at 3 weeks (2) Patient perceived duration of block determined as the time patient perceives complete resolution of block (3) Patient satisfaction with pain control at 72 hours, 3 weeks post-operatively and patient reported outcome measures (SANE, SST, ASES, VR-12) at 3 weeks post-operatively.

Arms: arm 1: Administered utilizing ultrasound guidance by an anesthesiologist. Study patients will receive 10ml (133 mg) of liposomal bupivacaine mixed with 7.5ml of 0.5% plain bupivacaine and 7.5ml of 0.25% bupivacaine. Further, 8 mg (2 ml) IV dexamethasone will be administered concomitantly at the time of the block. arm 2: Peripheral nerve blocks will be performed with ultrasound guidance by an anesthesiologist. Standard bupivacaine hydrochloride will be utilized. 25 ml of 0.5% bupivacaine for peripheral nerve block will be utilized. Further, 8 mg (2 ml) IV dexamethasone will be administered concomitantly at the time of the block.
Interventions: intervention 1: Liposomal Bupivacaine intervention 2: Bupivacaine Hydrochloride
Intervention descriptions: intervention 1: Interscalene Nerve Blocks intervention 2: Interscalene Nerve Blocks

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Liposomal Bupivacaine 
Interscalene Nerve Block in 
Shoulder Arthroplasty: A Single 
Blinded 
Prospective Randomized 
Control Trial 
 
 NCT03663283 
 
6/10/2018 


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Liposomal Bupivacaine Interscalene Nerve Block in Shoulder Arthroplasty: A Single Blinded 
Prospective Randomized Control Trial      
 
 
Principle investigator: Dr. Steven Hattrup   
 
Co-investigators: 
 
  
 
Statistician: 
 
 
Protocol Number (IRBe): 18-005366 
 
 
Initial version: 5/20/2018 Version (1.0)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
1.1 
BACKGROUND ..................................................................................................... 4 
1.2 
DOSE RATIONALE................................................................................................. 4 
1.3 
RISKS AND BENEFITS ............................................................................................ 5 
2 
STUDY OBJECTIVES ............................................................................................. 5 
3 
STUDY DESIGN ...................................................................................................... 5 
3.1 
GENERAL DESCRIPTION ........................................................................................ 5 
3.2 
NUMBER OF SUBJECTS .......................................................................................... 6 
3.3 
DURATION OF PARTICIPATION ................................................................................ 6 
3.4 
PRIMARY SAFETY ENDPOINTS ................................................................................ 7 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL............................. 7 
4.1 
INCLUSION CRITERIA ............................................................................................ 7 
4.2 
EXCLUSION CRITERIA ........................................................................................... 7 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ........................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ........................................................................ 8 
5 
STUDY DRUG ......................................................................................................... 8 
5.1 
DESCRIPTION ....................................................................................................... 8 
5.2 
TREATMENT REGIMEN .......................................................................................... 8 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ..................................... 9 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................. 9 
5.5 
PRIOR AND CONCOMITANT THERAPY ...................................................................... 9 
5.6 
MASKING/BLINDING OF STUDY ............................................................................ 10 
6 
STUDY PROCEDURES ......................................................................................... 10 
6.1 
VISIT 1 .............................................................................................................. 10 
6.2 
SURGICAL STAY ................................................................................................. 10 
6.3 
TIME FROM DISCHARGE TO FIRST POST-OPERATIVE VISIT.......................................... 11 
6.4 
FIRST POST-OPERATIVE VISIT (3-WEEKS POST-OP) .................................................. 11 
6.5 
ALL TIME POINTS ............................................................................................... 11 
7 
STATISTICAL PLAN ............................................................................................ 12 
7.1 
SAMPLE SIZE DETERMINATION............................................................................. 12 
7.2 
STATISTICAL METHODS ...................................................................................... 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................... 13 
8 
SAFETY AND ADVERSE EVENTS ....................................................................... 13 
9 
DATA HANDLING AND RECORD KEEPING ...................................................... 14 
9.1 
CONFIDENTIALITY .............................................................................................. 14 
9.2 
SOURCE DOCUMENTS ......................................................................................... 14 
9.3 
CASE REPORT FORMS ......................................................................................... 15 
9.4 
RECORDS RETENTION ......................................................................................... 15 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................. 15 


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10.1 
STUDY MONITORING PLAN .................................................................................. 15 
10.2 
AUDITING AND INSPECTING ................................................................................. 15 
11 
ETHICAL CONSIDERATIONS ......................................................................... 16 
12 
STUDY FINANCES ............................................................................................ 16 
12.1 
FUNDING SOURCE .............................................................................................. 16 
13 
PUBLICATION PLAN ........................................................................................ 16 
14 
REFERENCES ................................................................................................... 17 
 
 
 
 
 
LIST OF ABBREVIATIONS 
AE 
ASES 
Adverse Event/Adverse Experience 
American Shoulder Elbow Society 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
 
INB 
Interscalene Nerve Block 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
PROMs 
Principal Investigator 
Patient Reported Outcome Measures 
 
 
SANE 
Single Assessment Numeric Evaluation 
SST 
 
 
 
  Simple Shoulder Test 
VR-12  
 
 
  Veteran RAND 12 Item Health Survey 


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Introduction 
 
This document is a protocol for a human research study which will be evaluating the effect 
of liposomal bupivacaine INB on post-operative pain and narcotic consumption in patients 
undergoing primary total shoulder arthroplasty. This study will be carried out in accordance with 
the applicable United States government regulations and Mayo Clinic research policies and 
procedures.  
1.1 
Background 
 
The “Opioid Crisis” has been characterized by a significant rise in the prevalence of 
opioid dependence and drug related deaths.  Not only has this placed a substantial strain on the 
health care economy, but resultant government legislation has led to greater restrictions on 
narcotic prescriptions. Consequently, there has been increasing interest in the development of 
multi-modal pain control regiments, particularly, in the post-operative period.  
 
Furthermore, in those patients undergoing orthopedic surgery, adequate pain control is highly 
important1. Patients with poor post-operative pain management in the first 48 hours have an 
approximate 50 percent chance of achieving long-term satisfactory pain relief2.  Inadequate pain 
management has been shown to not only increase hospital length of stay, but increase the risk of 
thromboembolic events, pulmonary complications2-4, and chronic pain.  Regional analgesia 
through the use of local anesthetic agents is a commonly employed strategy for pain 
management. In shoulder surgery, specifically, peripheral nerve block with long acting local 
anesthetic is a well-established technique for pain control. Typical agents including bupivacaine 
and ropivacaine, in general, provide a block duration of 12 to 24 hours. 
 In 2011, liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, San Diego, USA) was 
approved by the US Food and Drug Administration (FDA) for use as a local anesthetic for 
surgical site infiltration. Liposomal bupivacaine is composed of a phospholipid bilayer that 
encapsulates bupivacaine, extending drug delivery for up to 72 hours and potentially extending 
periods of regional analgesia.  Early studies evaluating liposomal bupivacaine noted lower 
subjective pain scores, increased time to first opiate medication, and decreased opiate 
requirements when compared to placebo5,6.   
 
Liposomal bupivacaine was FDA-approved for use in interscalene nerve blocks (INB) in the 
setting of shoulder surgery on April 6, 2018. Despite approval, there is limited data comparing 
liposomal bupivacaine to traditional agents in this population. The objective of this study is to 
determine if peripheral nerve block with liposomal bupivacaine in combination with standard 
bupivacaine will prolong the duration of block, improve pain scores, and decrease opioid 
utilization in the post-operative period when compared to peripheral nerve block with standard 
bupivacaine alone. 
 
1.2 
Dose Rationale  
 
The FDA approved dosing of liposomal bupivacaine for peripheral nerve block will be utilized 
(maximum dose of 133 mg). FDA approved dosing ratio of liposomal bupivacaine to 


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bupivacaine HCl will be utilized, which recommends mg dose of bupivacaine HCl to liposomal 
not to exceed 1:2.   
 
1.3 
Risks and Benefits 
 
The most significant risks associated with this study are directly related to surgery itself.  
 
Risks associated with the nerve block: Block failure, nerve injury, hematoma, infection, and 
pneumothorax 
 
Serious risks associated with bupivacaine-containing products, while extremely rare, include: 
1. Central nervous system reactions: persistent anesthesia and paresthesias, excitation 
and/or depression 
2. Cardiovascular reactions: dysrhythmias, death  
3. Allergic reactions: anaphylaxis, angioedema.   
Patients who are at highest risk of these complications including patients with severe liver and 
respiratory disease will be excluded from this study.   
 
Potential benefits from participation in the study include improved post-operative outcomes: 
diminished post-operative pain, and decreased opioid consumption.  
 
2 Study Objectives 
 
The primary outcome measure will be: 
1. Mean difference in patient pain scores over the first 72 hours post-operatively between 
two groups 
  
Secondary outcomes will include: 
1. Total opioid consumption (as measured utilizing morphine intravenous equivalents) in 
first 72 hours and at 3 weeks 
2. Patient perceived duration of block determined as the time patient perceives complete 
resolution of block 
3. Patient satisfaction with pain control at 72 hours, 3 weeks post-operatively and patient 
reported outcome measures (SANE, SST, ASES, VR-12) at 3 weeks post-operatively   
 
3 Study Design 
3.1 
General Description 
 
This will be a prospective, single-blinded randomized clinical trial comparing outcomes in 
patients undergoing total shoulder arthroplasty (anatomic and reverse) who receive a peripheral 


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nerve block with liposomal bupivacaine in combination with standard bupivacaine versus 
standard bupivacaine alone. Subjects will be screened in the outpatient clinic upon initial patient 
election to proceed with shoulder replacement surgery. Interested and qualified patients meeting 
all inclusion criteria will be offered the opportunity to participate in this study. Once consent is 
obtained, baseline characteristics will be recorded and patients will be randomized to 
intervention or control. Following surgery, patients will be followed until their 3-week post-
operative visit.   
 
3.2 
Number of Subjects 
This study will require a sample size of 50 subjects per group in order to achieve 80% power. 
The target enrollment will be 110 total subjects in order to combat an expected attrition of 10%. 
3.3 
Duration of Participation 
The duration of time that patients can expect to be directly involved in the study is 3-
weeks; i.e. initial surgery up until the first post-operative visit at 3-weeks.  
 
 
 
 
Screeningattimeofinitialpre-opvisit1
Baselinedemographicinformation,VAS,ASES,SST,
SANE,VR-12collected
InpatientMetricsMeasured(24hrs)
1)
Timeuntilblockcessation
2)
ShoulderpainscoresQ4hr
3)
Totalopioidutilization(Morphineequivalents)
Control
UltrasoundguidedINBwith25mlof0.5%standard
bupivacaine
1Patientinitiallyelectstoproceedwithshoulderreplacement
Randomizedattimeof2nd pre-opvisit (i e.justpriorto
surgery)(n=110)
Metricsmeasuredatfirstpost-opvisit
1)
Totalopioidutilizationsincesurgery
2)
Satisfactionscores,VAS,ASES,SST,SANE,VR-12
Intervention
UltrasoundguidedINBwith10ml(133mg)ofliposomal
bupivacainemixedwith7.5mlof0 5%plainbupivacaine
and7.5mlof0 25%bupivacaine
Metricsmeasuredfromdischargetofirstpost-opvisit
1)
Shoulderpainscoresq12hruntilPOD3
2)
TotaldailyopioidutilizationuntilPOD3
3)
SatisfactionscoresPOD3
Surgery
Anatomic versus Reverse Total Shoulder Arthroplasty


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3.4 
Primary Safety Endpoints 
All patients will be continuously monitored for local anesthetic toxicity or other reaction to 
liposomal bupivacaine for the entire surgical scope of care.  During surgery, standard ASA 
monitors will be in place. In the PACU, vital signs will be obtained every 15 minutes with 
continuous telemetry and pulse ox, with a minimum 2:1 RN monitoring. Continuous surveillance 
will be exercised for medication reaction or local anesthetic toxicity including but not limited to: 
tinnitus, perioral numbness, mental status changes, cardiac arrhythmia, respiratory compromise, 
rash, or hives.  20% intralipid for treatment of toxicity will be available at all times. In addition, 
patients will be monitored for signs of pneumothorax related to the peripheral nerve block 
including but not limited to: dyspnea, oxygen desaturation, or hemodynamic instability. At 
discharge, patients will be educated regarding signs and symptoms for local anesthetic toxicity 
and instructions to call the on-call physician with mild symptoms and present to the ED if 
moderate or severe symptoms. 
 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
- 
All adult patients (>18 years of age)  
- 
Patients undergoing standard or reverse total shoulder arthroplasty for the primary 
diagnoses of glenohumeral arthritis or cuff tear arthropathy  
- 
Cognitively intact with the ability to give informed consent as outlined by our 
institutional review board. 
- 
Patients must be capable of participating in the post-operative electronic survey and / or 
able to maintain a written diary of events  
4.2 
Exclusion Criteria 
- 
Non-elective cases 
- 
Infection, tumor, trauma   
- 
Weight < 50 kg 
- 
Patients with any contraindications to regional anesthesia including allergy or 
hypersensitivity to amide-type local anesthetics  
- 
Patients with allergy to any component of medication regimen e.g. amide-type local 
anesthetics, oxycodone, hydromorphone, fentanyl  
- 
Chronic pain patients with history of chronic opioid use (defined as 20 mg morphine 
equivalent / day for greater than 30 days pre-operatively 
- 
Concurrent painful physical condition that may require analgesic treatment that is not 
related to the shoulder surgery (chronic peripheral neuropathy, radiculopathy, or other 
neurologic disorder)  
- 
Severe hepatic disease defined by clinical evidence of liver disease with abnormal liver 
function tests. 
- 
Pregnancy 


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- 
Respiratory disease that contraindicates interscalene nerve block (elevated contralateral 
hemidiaphragm, contralateral pneumonectomy, or severe COPD with FEV1 < 50% 
predicted, and 02 dependence) 
4.3 
Subject Recruitment, Enrollment and Screening 
All patients >18 years of age who present to either the PI’s (SJH) or Co-Investigator’s 
(JTT) clinical practices for elective anatomic or reverse total shoulder arthroplasty for the 
primary diagnoses of glenohumeral arthritis or cuff tear arthropathy and meet the inclusion 
criteria will be invited to participate in the study. 
4.4 
Early Withdrawal of Subjects 
Should patient wish to withdraw from the study due to any major adverse events i.e. from 
the surgery, intervention, or the inpatient stay, he or she may do so without any penalty and we 
will monitor and treat any adverse event.  
 
If patient decides he or she would like to withdraw from the study for any reason 
whatsoever, he or she may do so without any penalty even after data collection has begun. 
5 Study Drug  
5.1 
Description 
Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, San Diego, USA) was approved by the 
US Food and Drug Administration (FDA) for use as a local anesthetic for surgical site 
infiltration. Liposomal bupivacaine is composed of a phospholipid bilayer that encapsulates 
bupivacaine, extending drug delivery for up to 72 hours and potentially extending periods of 
regional analgesia. It is administered in a liquid form. On April 6th, 2018 Exparel was FDA-
approved for use in INB to produce postsurgical regional anesthesia.  
 
In this study, liposomal bupivacaine will be utilized in peripheral nerve block for the purposes of 
postsurgical regional anesthesia in patients undergoing shoulder arthroplasty.   
 
5.2 
Treatment Regimen 
Liposomal Bupivacaine Group: 
 
 
In this group, all INBs will be administered utilizing ultrasound guidance by an attending 
anesthesiologist experienced in the technique, or experienced anesthesiology resident with direct 
attending supervision and assistance. Study patients will receive 10ml (133 mg) of liposomal 
bupivacaine mixed with 7.5ml of 0.5% plain bupivacaine and 7.5ml of 0.25% bupivacaine. 
Further, 8 mg (2 ml) IV dexamethasone will be administered concomitantly at the time of the 
block  
 
Control Group: 
 
In this group, all peripheral nerve blocks will be performed with ultrasound guidance by 
an attending anesthesiologist experienced in the technique, or experienced anesthesiology 


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resident with direct attending supervision and assistance. Standard bupivacaine will be utilized. 
25 ml of 0.5% bupivacaine for peripheral nerve block will be utilized. Further, 8 mg (2 ml) IV 
dexamethasone will be administered concomitantly at the time of the block.   
5.3 
Method for Assigning Subjects to Treatment Groups 
 
Our 110 participants will be equally randomized to one of two treatment arms using a 
randomized block strategy with varying block sizes7. The randomization list will be created in 
SAS v9.4 (SAS Institute; Cary, NC) and will be uploaded into the REDCap randomization 
module.  
 
The pharmacy team, the study coordinator, and the statistician will have access to the 
randomization module with the pharmacy team serving as the primary randomizers and the study 
coordinator and statistician serving as back-ups. Only the statistician will have knowledge of 
how the randomization list was built and will be the only one that has seen it. 
5.4 
Preparation and Administration of Study Drug 
The pharmacist will prepare, and dispense the medication sequentially. Medication 
syringes will be blinded utilizing black tape. Patients will then undergo peripheral nerve block 
under ultra sound guidance and receive either the study group medication or the control group 
medication.  
5.5 
Prior and Concomitant Therapy 
All patients will receive no more than 4 mg of midazolam for sedation at the time of the 
block. All patients will undergo general endotracheal anesthesia using propofol, fentanyl, 
rocuronium or succinylcholine, sevoflurane in air-oxygen, and ondansetron.  Fentanyl will be 
limited to 250 micrograms intraoperatively.  Reversal of muscle relaxant will be with either 
neostigmine and glycopyrollate or suggamadex. Block success will be assessed pre-operatively 
with shoulder abductor weakness and re-assessed on arrival to PACU.  Patients will receive a 
standardized post-operative pain management regimen for 24 hours from PACU arrival.   
 
On the post-operative floor the pain regimen will be standardized according to 
department protocol as follows:  
 
 Acetaminophen 1000mg Q8 hours scheduled 
 Tramadol 50mg Q6 hours PRN pain scale 4-6 with repeat dose 
 Tramadol 100mg Q6 hours PRN pain scale 7-10 with repeat dose 
 Oxycodone 5mg Q4 hours PRN pain scale 4-6 with repeat dose for pain not controlled 
with tramadol 
 Oxycodone 10mg Q4 hours PRN pain scale 7-10 for pain not controlled with tramadol 
 IV Fentanyl 25 mcg Q2hr PRN pain scale 7-10 with repeat dose for pain not controlled 
with above 
 
 


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Discharge medications will include one of the following options: 
 
1. Oxycodone 5 or 10 mg Q4 hrs PRN for moderate (5-6) to severe (7-10) pain  
2. Oxycodone-acetaminophen 5/325 or 10/325 Q4 hrs PRN for moderate (5-6) to severe (7-
10) pain, not to exceed 8/day 
3. Hydrocodone-acetaminophen 5/325 or 10/325 Q4 hrs PRN for moderate (5-6) to severe 
(7-10) pain, not to exceed 8/day 
4. Tramadol 50 mg or 100 mg Q6 hrs PRN for moderate (5-6) to severe (7-10) pain, not to 
exceed 6/day 
5. Tylenol 1000 mg q6hr PRN pain moderate to severe pain, total dose not to exceed 4000 
mg/day 
5.6 
Masking/Blinding of Study  
Patients, care team in recovery, study team members collecting and recording data, and 
statisticians will be blinded to randomization assignment. The administering anesthesiologist and 
pharmacy will be unblinded. All patients will be documented in EMR as receiving liposomal 
bupivacaine to ensure the blind is maintained and to ensure that safety features in the EMR for 
all patients receiving liposomal bupivacaine are activated. Further, all additional standard 
precautionary measures (e.g. wrist band) will be similarly implemented for both patient groups.  
6 Study Procedures 
6.1 
Visit 1 
This will be the initial visit when patient elects to undergo total shoulder replacement 
surgery. Patients who meet inclusion criteria will be given the opportunity to be enrolled in the 
study if they so choose.  A brief survey will be performed by the research assistant to determine 
if any exclusion criteria are met. Should they elect to partake, they will be consented and 
assigned to specific treatment groups. Patient pain scales (VAS) and patient reported outcome 
measures (ASES, SST, SANE, VR-12) will be measured at the pre-operative visit. All patient 
demographic information and medical history will be obtained as is routine during the pre-
operative visit.  
6.2 
Surgical Stay 
Patient reported pain will be measured utilizing visual analogue scales – VAS at 4 hour 
intervals during the duration of their inpatient hospitalization following surgery. Further, time 
until cessation of the nerve blockade as quantified as time to patient reported cessation of the 
nerve blockade, and time until first opioid rescue will be noted. Patients and nursing staff will be 
educated on how to accurately quantify time to patient reported cessation of the nerve blockade 
as follows: pain scores of 3 or greater at surgical site will be considered as time of cessation of 
nerve block. 
Furthermore, all narcotic utilization during the hospitalization will be recorded. All 
values will be presented as morphine equivalents8.  
Operative time, laterality of surgery, length of stay, and disposition at discharge from the 
hospital will additionally be collected. 


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6.3 
Time from discharge to first post-operative visit 
At discharge, pain scores will be measured utilizing electronically managed surveys that 
will be e-mailed to each patient on a twice daily basis (upon waking the AM and just prior to 
bedtime) after discharge for the first 72 hours following surgery. Finally, patient satisfaction 
scores (Likert scores) will be emailed to the subjects at 72 hours.    
Total opioid consumption will similarly be measured based off of electronically managed 
surveys or a written diary on a daily basis following discharge for the first 72 hours. All values 
will be presented as morphine equivalents. 
6.4 
First Post-operative Visit (3-weeks post-op) 
During the first follow-up visit, total opioid consumption during their post-operative 
course will be measured, and pain scales and satisfaction scores will be obtained including 
ASES, SST, SANE, VR-12. Total opioid consumption will be quantified by the number of 
narcotic prescription pills remaining. Opioid consumption will be standardized to morphine 
equivalents. All diaries will be collected at this time.  
6.5 
All Time Points 
If patient non-compliance with electronic surveys is identified, the study coordinator will  
attempt to contact non-compliant patient to either encourage him/her to either complete the 
surveys, or to directly obtain respective data points from them.  Further, patients who are given 
diaries will receive daily reminder phone calls from the study coordinator in the 72 hours 
following discharge. 
Complications will be recorded. These include cardiac arrest, acute respiratory failure, 
venous thromboembolism event, ileus, SSI, deep infections, urinary tract infection, nerve injury, 
pneumothorax.   
 
Schedule of Events 
 
 
Study Activity 
Pre-op Visit  
Surgical Stay 
Time from discharge to first post-
op visit 
Post-op Visit 
Study Agent Administration 
 
X 
 
 
Informed consent 
X 
 
 
 
Randomization 
 
Xa 
 
 
Demographics  
X 
 
 
 
History / Physical Exam 
X 
 
 
 
Concurrent Meds 
X 
 
 
 
Pain Scores 
X 
X 
X 
X 
PROMsb 
 X 
 
 
X 
Satisfaction Scoresc 
 
 
 X 
X 
Opioid Use 
 
X 
 X 
X 
Adverse Event 
Evaluation 
 
X 
X 
 
 a: In pre-op, will be performed by pharmacy 
 b: ASES, SANE, SST, VR-12 scores 
 c: Obtained at 72 hrs post-op and at 1st post-op visit  
 
 


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7 Statistical Plan 
7.1 
Sample Size Determination 
Using an equal-variance t-test with a multiplicity-adjusted alpha of 0.0167 (0.05/3), we 
need 55 subjects per group in order to achieve 80% power to detect a true effect size of 0.66 or 
larger. The total sample size of 110 includes 10 additional patients to protect against an estimated 
attrition rate of 10%. The effect size was estimated using an established MCID of 29 for VAS 
pain scales and a standard deviation of 3.  
  
7.2 
Statistical Methods 
Descriptive Statistics 
 
Univariate descriptive statistics for categorical variables will include frequency and percent and 
for numerical variables will include mean, standard deviation, median, and range (minimum 
value, maximum value). Univariate tests of these variables with the treatment variable will be 
performed with either the Chi-Square test or two sample t-test in order to identify potential 
confounders. 
 
Handling of Missing Data 
Initial descriptive statistics will be performed to quantify univariate missingness and distribution 
of variables. Observed values that appear to be extreme will be verified with the research staff 
for accuracy. If extreme values do not appear to exhibit undue influence on the statistical 
methods they will be kept in the analysis. Otherwise they will be removed. Extreme values found 
to be erroneous will be corrected. 
 
Missing values for outcomes (e.g. VAS, opioid consumption, etc) will be imputed using the last 
observation carried forward method. Since we expect downward trends in these observations as 
time from procedure increases, this method will provide a conservative between-treatment 
estimate of the effect (assuming the observations are missing at random and are roughly missing 
with equal frequency within each treatment group). 
 
These results will be compared to the results of a linear mixed-model which doesn’t require that 
every patient has data for every measure at every point in time. Instead, it all information 
recorded and only excludes those time points at which data is missing. For example, if a patient 
is missing data at 48 hours, then the linear mixed-model will only include the data at 24 hours 
and 72 hours. In contrast, the last observation carried forward method would use the observed 
value from 24 hours for the 48 hour value and then all three time points will be included. 
In both cases, the baseline values for VAS and opioid consumption must be known for the 
patient to be included in the analysis. 
 
Multiplicity 
There is only one primary hypothesis so we will not adjust for multiplicity at the highest level. 
However, if the linear mixed-model shows that the time by treatment interaction term is 
statistically significant and we perform post-hoc pairwise comparisons, the Tukey-Kramer 


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method will be used to adjust for multiple comparisons. There are several secondary aims that 
we consider exploratory analyses and as such will not adjust for multiple comparisons. 
 
Primary Hypothesis: The average post-op pain score, adjusted for baseline pain scores, over the 
72 hours post-op will be significantly lower in the liposomal bupivacaine group. 
 
The difference in post-operative numeric pain scores between the treatment groups over time 
will be analyzed using a linear mixed-model with an interaction term for time and treatment and 
will adjust for the baseline (pre-op) scores. 
 
Secondary Hypothesis 1: The average post-op satisfaction score over the 72 hours post-op will 
be significantly lower in the liposomal bupivacaine group. 
 
The difference in post-operative numeric satisfaction scores between the treatment groups over 
time will be analyzed using a linear mixed-model with an interaction term for time and 
treatment. 
 
Secondary Hypothesis 2: Time to block cessation will be longer in the liposomal bupivacaine 
group than the standard bupivacaine group. 
 
The difference in time to block cessation will be analyzed between treatment groups using a two 
sample t-test if necessary model assumptions are met or the Wilcoxon Rank-Sum test if 
assumptions are not met. 
 
Secondary Hypothesis 3: Total opioid consumption will be significantly lower in the liposomal 
bupivacaine group. 
 
The distribution of total opioid consumption for the two groups will be compared using a 
multiple linear regression model with a term to adjust for baseline opioid consumption. 
 
Interim Analysis 
Our study does not entail any sequential or adaptive trial designs and as such requires no interim 
analyses. 
 
7.3 
Subject Population(s) for Analysis 
Only patients who are randomized into the study and have necessary baseline values for primary 
and secondary outcomes will be included in the analyses.  
8 Safety and Adverse Events 
 
8.1 Adverse Events: 
The investigator/study team will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 


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An adverse event is defined as an untoward or undesirable experience associated with the use of 
a medical product (i.e. drug, device, biologic) in a patient or research subject. All adverse events 
that are considered related to the direct use of liposomal bupivacaine will be defined, collected, 
and reported. 
The principal investigator will be responsible for determining whether an event is related to the 
direct use of liposomal bupivacaine. An AE will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the 
standard of care procedure or in the package insert for liposomal bupivacaine. 
All study-related AEs will be followed until stabilization or resolution. 
8.2 Adverse Event Reporting Period: 
For this study, the study treatment follow-up period is defined as 7-10 days after the procedure 
when they are contacted by the study team.  
 
8.3 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   Medical monitoring will include a regular assessment of the number and type 
of serious adverse events. 
9 Data Handling and Record Keeping 
9.1 
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.  
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. 
 
9.2 
Source Documents 
The study coordinator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject.  Source documents 
are defined as documentation of the observations and activities of a clinical study.  Source 
documents may include, but are not limited to, study progress notes, e-mail, correspondence, 
subject quality of life surveys, subject diaries, computer printouts, laboratory data, and recorded 
data from automated instruments.  All source documents for this study will be maintained by the 


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investigator in accordance with ICH GCP and applicable regional or national regulations.  The 
official signed informed consent form (ICF) for each subject will be maintained as a source 
document, and a copy provided to the subject. 
 
When paper source documents are used, ICH GCP and applicable regional or national 
regulations documentation guidelines will be followed.  For example, incorrect entries should be 
crossed out with a single pen stroke.  Corrections must be made adjacent to the item to be 
altered, initialed and dated with the reason for the correction if necessary by the investigator or 
designee.  Overwriting of data or use of a liquid correction is not allowed.   
 
Designated study personnel will enter data from source documents corresponding to a subject’s 
visit into the protocol specific redcap database.  Subjects will not be identified by name in the 
study database, but will be identified by a subject number. 
 
9.3 
Case Report Forms 
Subject data will be entered into a RedCap database.  Each field in the RedCap database will be 
filled out completely by the investigator or designee as stated in the Delegation of Authority Log.  
All data entry in RedCap will have corresponding source documentation filed in the subject 
study record.   
9.4 
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. 
 
The sponsor-investigator will retain the specified records and reports for as outlined in the Mayo 
Clinic Research Policy Manual –“Retention of and Access to Research Data Policy” 
 
All data will be stored in a locked office and will be maintained for at least 5 years after the 
completion of the project. Any data containing patient personal information will be destroyed 
once the study is complete and final report written.   
10 Study Monitoring, Auditing, and Inspecting 
10.1 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. 
 
10.2 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 


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will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 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. 
 
This study will not include any vulnerable subjects. 
12 Study Finances 
12.1 Funding Source 
 
This study will be independently funded by the respective departments.  Additional, a Mayo 
Small Grant application is currently in submission.  
13 Publication Plan 
 
The primary responsibility for publication of the results of this study will be held by the PI 
(SJH). Approval must first be obtained from the PI prior to any dissemination of study results to 
any third parties.   
 
 
 
 
 
 
 


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14 References 
 
 
1. Hamilton DF, Lane J V, Gaston P, et al. What determines patient satisfaction with surgery? 
A prospective cohort study of 4709 patients following total joint replacement. BMJ Open. 
2013;3(4). doi:10.1136/bmjopen-2012-002525. 
 
2. Wells N, Pasero C, Mccaffery M. Chapter 17 . Improving the Quality of Care Through Pain 
Assessment and Management. Patient Saf Qual An Evidence-Based Handb Nurses Vol 1. 
2004.  
 
3. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice 
guidelines for acute pain management in the perioperative setting: an updated report by the 
American Society of Anesthesiologists Task Force on Acute Pain Management. 
Anesthesiology. 2012;116(2):248-273. doi:10.1097/ALN.0b013e31823c1030. 
 
4. Wu CL, Naqibuddin M, Rowlingson AJ, Lietman SA, Jermyn RM, Fleisher LA. The effect 
of pain on health-related quality of life in the immediate postoperative period. Anesth Analg. 
2003;97(4):1078-1085, table of contents. 
 
5. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of depofoam?? 
bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. 
2011;28(9):776-788. doi:10.1007/s12325-011-0052-y. 
 
6. Gorfine SR, Onel E, Patou G, Krivokapic Z V. Bupivacaine extended-release liposome 
injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a 
multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 
2011;54(12):1552-1559. doi:10.1097/DCR.0b013e318232d4c1. 
 
7. Efird J. Blocked randomization with randomly selected block sizes. Int J Environ Res Public 
Health. 2011;8:15–20. doi: 10.3390/ijerph8010015  
 
8. Opioid 
Oral 
Moprhine 
Milligram 
Equivalent 
(MME) 
Conversion 
Factors. 
https://www.cms.gov/Medicare/Prescription-Drug-
Coverage/PrescriptionDrugCovContra/Downloads/Opioid-Morphine-EQ-Conversion-
Factors-Aug-2017.pdf. Accessed July 11, 2018.  
 
9. Katz NP, Paillard FC, Ekman E. Determining the clinical importance of treatment benefits 
for interventions for painful orthopedic conditions. J Orthop Surg Res 2015;10:24.  


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