Clinical trial NCT02762071
Conditions: Osteoarthritis Arthropathy Shoulder Pain Closed Fracture Proximal Humerus, Four Part
Sponsor: Johns Hopkins University
Start date: 2016-04-01; Completion date: 2019-04-15
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will compare interscalene nerve block versus liposomal bupivacaine (Exparel) for pain control after total shoulder replacements. Each method will be assessed in terms of post operative pain scores, pain medication consumption, length of stay, complications (nerve injuries, hematomas, cardiac/respiratory events) and rate of readmission due to pain. The aims of this study will be achieved through a randomized controlled trial and cost-effectiveness analysis.

Detailed description:
After the decision to proceed with shoulder replacement surgery, patients will be asked to participate in this randomized trial. Consent will be completed after explanation of each treatment group and the data to be collected. Patients will be randomized into one of the two treatment groups by simple randomization into one of two groups: Group 1 will receive interscalene nerve block and group 2 will receive liposomal bupivacaine for postoperative analgesia. Randomization will be stratified by site.

The surgeon at each site will be trained prior to enrollment on the correct way to perform Exparel injections intraoperatively. Patients in the interscalene nerve block group will be given a single shot block in the preoperative area by a fellowship-trained anesthesiologist.

The primary outcome is pain score on a visual analog scale (VAS) at 24 hours postoperatively. VAS pain scores range from 0 (no pain) to 10 (unbearable pain). Secondary outcomes are postoperative VAS pain scores at 6, 12, 18, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 96 hours; VAS pain score at the first postoperative visit ; intraoperative opioid consumption; postoperative opioid consumption at days 1, 2, 3, and 4; total opioid consumption at day 1 (intraoperative + postoperative day 1); duration of stay in the post-anesthesia care unit (PACU); duration of hospital stay; and VAS score for satisfaction with pain control in the hospital and at home, assessed at participants' first postoperative visit. VAS satisfaction scores range from 0 (not satisfied) to 10 (completely satisfied).

Arms: arm 1: Patients in this group will receive an interscalene nerve block containing the local anesthetic ropivacaine prior to surgery. The nerve block will be administered by a fellowship-trained anesthesiologist. arm 2: Patients in this group will receive a periarticular injection containing liposomal bupivacaine during surgery. The injection will be administered by the surgeon.
Interventions: intervention 1: Liposomal bupivacaine intervention 2: Interscalene Nerve Block
Intervention descriptions: intervention 1: Patients in this group will receive a periarticular injection containing liposomal bupivacaine during surgery. The injection will be administered by the surgeon. intervention 2: Patients in this group will receive an interscalene nerve block containing the local anesthetic ropivacaine prior to surgery. The nerve block will be administered by a fellowship-trained anesthesiologist.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
Liposomal Bupivacaine vs. Interscalene Nerve Block 
for Pain Control After Total Shoulder Arthroplasty: 
A Randomized Clinical Trial 
 
 
Date: 03/23/2016 
 
                             ClinicalTrials.gov Identifier: NCT02762071 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
JHM IRB - eForm A – Protocol 
 


 
 
• 
Use the section headings to write the JHM IRB eForm A, inserting the appropriate 
material in each. If a section is not applicable, leave heading in and insert N/A. 
• 
When submitting JHM IRB eForm A (new or revised), enter the date submitted to the 
field at the top of JHM IRB eForm A. 
 
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1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research. 
 
The incidence of shoulder replacements is quickly rising with the growing elderly 
population and new technologies, such as the reverse shoulder replacement.1-2 At this 
time, there are 53,000 shoulder replacements performed annually according to the 
Agency for Healthcare Research and Quality. The interscalene (IS) brachial plexus nerve 
block is considered the gold standard for shoulder anesthesia. While complications for IS 
nerve blocks are rare, they include chronic neurologic complications and substantial 
respiratory, cardiovascular, and central nervous system events.3 Femoral nerve blocks 
used in total knee arthroplasty are associated with complications such as insomnia, 
antalgic ambulation, and difficulty with rehabilitation, and increased incidence of falls.7,9   
 
A new approach to postoperative analgesia is the periarticular injection method, by 
which the surgeon administers local infiltration analgesia without the help of an 
anesthesiologist. Recent literature has shown that the liposomal bupivacaine (Exparel ®) 
injection provides better pain control, shortens hospital stays, and decreases costs for 
total knee and hip arthroplasties compared to the gold standard nerve block methods. 4-
12 Broome et. al found that total knee arthroplasty patients who had a liposomal 
bupivacaine injection saved an average of $600 compared to those who received a 
femoral nerve block.4 This translated to a savings of approximately one million dollars 
per year at their hospital alone. Eliminating the costs associated with interscalene nerve 
block administration in shoulder replacements could allow for significant cost-savings to 
our healthcare system. 
 
Currently, no published literature exists directly comparing liposomal bupivacaine and 
interscalene (IS) nerve blocks in shoulder replacements. This study would provide a 
direct comparison of available postoperative analgesia techniques for shoulder 
arthroplasty. The results of this work will demonstrate whether the liposomal 
bupivacaine injection technique results in the same postoperative pain compared to the 
typical interscalene nerve block method.  
 
 
2. 
Objectives (include all primary and secondary objectives) 
 
Aim #1: Determine clinical outcomes as they relate to pain control of the interscalene 
nerve block vs. liposomal bupivacaine injection in patients undergoing total shoulder 
arthroplasty.  


 
This will be evaluated using the Visual Analog Scale (VAS) pain score and pain 
medication data and side effects from opioids (nausea/vomiting, GI distress, itching, etc) 
from inpatient medical records and through daily follow-up questionnaires after 
patients are discharged until 96 hours after surgery. Data will be collected at routine 
clinical follow up appointments after surgery.  
 
Aim #2:  Determine the length of stay of liposomal bupivacaine compared to 
interscalene nerve block in patients undergoing total shoulder arthroplasty and 
calculate costs associated with any differentials. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with 
procedures, drug or device, and any other relevant information to justify the research) 
 
We conducted a retrospective cohort analysis of 58 shoulder arthroplasties performed 
by a single surgeon. Patients who underwent total, reverse, and hemiarthroplasties 
were included. The control group included patients who received interscalene nerve 
blocks for postoperative pain control. The experimental group included patients who 
received periarticular liposomal bupivacaine injections. Baseline demographic data 
included age, sex, body mass index (BMI), and American Society of Anesthesiologists’ 
(ASA) classification of physical health. We measured length of stay (LOS), pain 
medication administration, numeric rating scale (NRS) pain scores at four time intervals 
postoperatively (0.5 hours, 8-14 hours, 18-24 hours, 27-36 hours). Statistical analysis 
was performed.  
 
There were 21 patients in the IS nerve block group and 37 patients in the liposomal 
bupivacaine group who met all inclusion criteria. Baseline demographic data for age 
(p=0.53), sex (p=0.71), BMI (p=0.09), and ASA (p=0.33) did not differ between groups. 
The primary outcome measure, NRS pain score, showed no significant differences 
between groups at 0–1 hours after surgery (P = .99) or 8–14 hours after surgery (P = 
.208). At 18–24 hours after surgery, the liposomal bupivacaine group had a lower mean 
NRS score than the ISNB group (P = .001). This was statistically significant when taking 
repeated measures of variance into account (Fig. 1). Mean NRS score was also lower for 
the liposomal bupivacaine group at 27–36 hours after surgery (P = .029). This was not 
statistically significant when repeated measures of variance were considered (Table II). 
 
There was no difference in the amount of intravenous acetaminophen given during the 
hospital stay between groups. There was no statistically significant difference in opioid 
consumption on postoperative day 1 in the hospital (P = .59). However, there were 
significant differences between groups on postoperative days 2 and 3 (Fig. 2). On 
postoperative day 2, the ISNB group required significantly more opioids (112 mg) than 
the liposomal bupivacaine group (37 mg) (P = .001). The ISNB group also required 
significantly more opioids (25 mg) on postoperative day 3 than the liposomal 
bupivacaine group (5 mg) (P = .002). 
 
Sixteen of 37 patients in the liposomal bupivacaine group and 2 of 21 in the ISNB group 
(Table III) were discharged on the day after surgery. The mean LOS was 46±20 hours for 
the liposomal bupivacaine group and 57 hours±14 hours for the ISNB group (P = .012). 


 
There were no major cardiac or respiratory events in either group. No long-term 
paresthesias or neuropathies were noted. There were no readmissions for either group. 
 
Liposomal bupivacaine injections may provide better pain control 18-24 hours after 
surgery and shorten hospital stays after shoulder arthroplasty compared to interscalene 
nerve blocks as a means of postoperative pain control. Based on these results, larger 
analytic studies including randomized trials should be performed to explore the 
potential benefits of liposomal bupivacaine injections for pain control after shoulder 
arthroplasty. 
 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Study Design: After the decision to proceed with shoulder replacement surgery, patients 
will be asked to participate in this prospective randomized clinical trial.  
 
 
Study Groups:  
• 
Group 1 will receive interscalene nerve block.  
• 
Group 2 will receive liposomal bupivacaine with local bupivacaine for 
postoperative analgesia.  
 
Study Procedures: 
1. Before Surgery: The Informed Consent process will be completed prior to any data 
collection. Consent will be completed after explanation of each treatment group and the 
data to be collected. The following baseline data will be collection prior to surgery: 
• 
Demographics (including age, sex, BMI, work status, living environment) 
• 
Medical and Surgical History 
• 
ASA Physical Status Classification 
• 
Charlson Comorbidity Index Score 
• 
Pain History and Medications 
• 
VAS pain score 
 
2. Randomization: Subjects will be randomized prior to surgery into one of the two 
perioperative analgesia groups. Randomization will be stratified by gender.  
 
3. Surgery/Inpatient Stay:  
• 
Group 1: Patients in the interscalene nerve block group will be given a single 
shot block in the preoperative area by a fellowship-trained anesthesiologist. The 
shot will contain a local anesthetic like 5% Ropivacaine (5 mg/1 mL) with a 44 
millimeter 22 gauge needle with the patient in the supine position. 
• 
Group 2: The surgeon at each site will be trained prior to enrollment on the 
correct way to perform Exparel injections intraoperatively. The surgeon will give 
patients in the liposomal bupivacaine group the periarticular injection 


containing 266 mg of the drug in 40 mL injectable saline in the operating room; 
local 0.5% bupivacaine-epinephrine will also be used not to exceed dose limits. 
• 
Surgical/Inpatient Data Collection: 
o Pre-op procedure time 
o Surgical time 
o PACU time 
o Admission/Discharge time and date 
o Estimated blood loss 
o Procedures performed 
o Inpatient pain medications administered  
o Patient VAS scores every 6 hours after surgery 
 
 
4. After Discharge: 
• 
Patients will record the following information after discharge up until 96 
hours from their surgery: 
o VAS scores every 6 hours 
o Pain medication consumption (dosages, times) 
o Opioid-related side effects  
o Level of satisfaction with pain management  
• 
Study staff may conduct reminder phone calls to ensure patients complete 
outpatient data collection. The outcome assessor will be blinded to the 
treatment group. 
• 
Patients will record their VAS pain scores again at their 1st postop 
appointment, which typically occurs 10-18 days after surgery. 
 
Sample Size:  There will be 60 patients in each group, for a total study population of n = 
120.  
 
Study Locations: This will be a multi-center study. The sample size will enroll 120 (to 
account for 15% drop out rate) patients total, with approximately 30 patients enrolled 
at each site. The other participating sites are as follows: 
 
Dr. Michael Khazzam 
Sports Medicine and Shoulder Service 
University of Texas, Southwestern Medical Center 
1801 Inwood Rd, 1st Floor 
Dallas, TX 75390 
 
 
Dr. Peter Johnston 
MedStar St. Mary’s Hospital 
25500 Point Lookout Rd 
Leonardtown, MD 20650 
 
Dr. Kelly Kilcoyne 
William Beaumont Army Medical Center 
5005 N. Piedras St 
El Paso, TX 79920 


 
Aim #2: Determine the length of stay of liposomal bupivacaine compared to 
interscalene nerve block in patients undergoing total shoulder arthroplasty and 
calculate costs associated with any differentials. 
 
 
b. Study duration and number of study visits required of research participants. 
 
Patients will be enrolled in this study for 2 weeks after their surgical date. This time 
frame will include their hospital stay and include their time at home after discharge 
up until 96 hours after their surgery, and their 2-week postop appointment data. If 
patients are not scheduled for their postop appointment within 10-18 days after 
surgery (which is standard clinical practice), the study team will call the patient to 
obtain their pain score and medication data. Patient names will be stored in a 
password-protected database for 30 days after discharge to calculate 30-day 
readmission rates. 
  
Routine patient follow up is typically at 3, 6, and 12 months for the first year. Pain 
data and patient reported outcomes are collected at these visits as routine clinical 
care. Patients routinely complete the ASES and EQ-5D questionnaires at their 12 
month follow up appointment. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Patients will be masked by performing the ISNB under sedation. They will not be 
completely blinded to their treatment group due to the fact that the Exparel group 
will not get a needle puncture at the site of the typical ISNB location in the neck 
since Exparel is injected intraoperatively in the surgical field while the patient is 
completely under general anesthesia. While the patient and surgeon cannot be 
blinded for this study, the outcome assessor will be masked to prevent bias in the 
data collection process.  
 
d. Justification of why participants will not receive routine care or will have current 
therapy stopped. 
 
N/A 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
N/A 
 
f. Definition of treatment failure or participant removal criteria. 
 
Treatment is a one-time intervention for the nerve block. The assessment of their 
VAS pain score is routine clinical practice.  
 
g. Description of what happens to participants receiving therapy when study ends or if 
a participant’s participation in the study ends prematurely. 


 
In these cases, routine clinical care will continue based on the patient’s needs.  
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
Adults age 20-100 years old with degenerative changes of the shoulder joint 
(documented by radiographs) in patients planning total joint replacement with Dr. Uma 
Srikumaran (PI of this study) at Johns Hopkins Shoulder Service (Columbia, Odenton 
Clinic sites; HCGH/Bayview/JHH operative sites), with Dr. Michael Khazzam at the 
University of Texas Sports Medicine and Shoulder Service, with Dr. Peter Johnston at 
MedStar St. Mary’s Hospital Shoulder Service, and with Dr. Kelly Kilcoyne at William 
Beaumont Army Medical Center will be included. Patients who require revision 
surgeries, hemiarthroplasties, or who have chronic pain issues will be included. 
 
 
Exclusion Criteria:  
Patients with an allergy to liposomal bupivacaine will be excluded. Patients with 
contraindications to the interscalene nerve block (preexisting neurologic defects, local 
anesthetic allergy, coagulopathy, contralateral phrenic nerve dysfunction, severe 
chronic obstructive pulmonary disease) will be excluded as these patients could not be 
randomized.  
 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Drug and dosing used are the same as in the prior retrospective study. 
 
b. Justification and safety information if FDA approved drugs will be administered for 
non-FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
 
N/A 
 
c. Justification and safety information if non-FDA approved drugs without an IND will 
be administered.  
 
N/A 
 
7. 
Study Statistics 
a. Primary outcome variable. 
 
• 
VAS pain score at 24 hours postop.  
 
b. Secondary outcome variables. 
 
• 
VAS scores at all other data points, 


• 
Pain medication consumption (narcotics, NSAIDs, Tylenol) 
• 
Opioid-induced side effects (nausea, vomiting, constipation) 
• 
Length of hospital stay 
• 
30 day readmission rate. 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
A power analysis was performed to determine the sample size needed determine 
noninferiority between groups with respect to VAS pain score. The minimal clinically 
important difference of VAS is 1.4 cm13. The number was found to be 42 patients in 
each group, for a total n = 84. To ensure we reach this number, each of the 4 sites 
will aim to enroll 30 patients, to account for drop out. 
 
The age of the two treatment groups will be compared using t-test.  Sex distribution 
and the ASA scores of the groups will be compared using a chi-squared test and a 
Fisher exact test, respectively.  
 
The median and interquartile range of the VAS scores at each of the time points 
measured will be tabulated by treatment group, and at each time point the 
difference between groups will be tested using non-parametric rank sum tests.  
 
We will test the longitudinal trajectory of VAS scores over time, taking into account 
repeated measurements in the same patients using linear mixed model analysis. 
Treatment group, time period as a categorical variable, and the interaction between 
treatment and time period will be included as fixed effects, and patient ID will be 
included as the random effect. An initial omnibus test will be performed for all 
treatment and treatment by time interaction effects. If significant, the treatment by 
time interaction will be tested subsequently for each of the measurement periods. 
 
The association of day of discharge (as a categorical variable) with treatment will be 
tested using the Fisher exact test. 
 
d. Early stopping rules. 
 
We will monitor operative and post-operative complications including implant 
failures, nerve injuries, hematomas, and infections. We do not anticipate issues with 
these complications, as both techniques are in routine use in our current clinical 
practice. We did not find any differences in the complication rates in our 
retrospective cohort analysis.  
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
b. Steps taken to minimize the risks. 
c. Plan for reporting unanticipated problems or study deviations. 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
e. Financial risks to the participants. 
 


No additional risk associated with study for the participant, as study procedures are standard 
clinical care. There is a remote risk to the study subjects if there is a breach in confidentiality. All 
data will be collected and entered into a REDCap database. Data will be extracted from REDCap 
at the time of analysis.  
 
To manage this, we will incorporate the following standard procedures: 
1) Patient identifiers key to database will be kept on each site in password protected 
excel document. 
2) We will maintain the data in accordance with University and IRB standards.  Data 
will be kept on password protected university servers, and any printed material will 
be kept in a locked file cabinet.  
3) Only investigators associated with the study will have access to the data 
 
 
The reporting of unanticipated problems or study deviations will be reported to the JHM IRB 
pursuant to Hopkins IRB policies. 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
There is no direct benefit to the participant in the study. This study could help determine if one 
pain control technique is superior to the other. This could result in higher quality care for 
patients who undergo total shoulder arthroplasty in the future. It could result in savings for the 
healthcare system if one technique is found to be cost-effective.  
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, 
proposed bonus, and any proposed reductions or penalties for not completing 
the protocol. 
 
Patients will not be compensated for their participation in this study. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and 
identify who will pay for them. 
 
The costs of study procedures will be covered by the participant’s health insurance because 
these procedures are  both used for routine care. 
 
 
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Day JS, Lau E, Ong KL, Williams GR, Ramsey ML, Kurtz SM. (2010). Prevalence and 
projections of total shoulder and elbow arthroplasty in the United States to 2015.  
Journal of Shoulder and Elbow Surgery, 8, 1115-1120. 


3. 
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4. 
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following total knee arthroplasty: A case control study of intra articular injection versus 
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5. 
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Springer, B. D. (2014). Transition from nerve blocks to periarticular injections and 
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8. 
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and continuous femoral block. Acta Orthopaedica, 82, 441-447.  
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Ganapathy, S. (2012). Wound/intra-articular infiltration or peripheral nerve blocks for 
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Guild, G. N., Galindo, R. P., Marino, J., Cushner, F. D., & Scuderi, G. R. (2015). 
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and injection technique. Orthopedic Clinics of North America, 46, 1-8. 
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Tashjian RZ, Deloach J, Porucznik CA, Powell AP. Minimal clinically important differences 
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