Clinical trial NCT03289858
Conditions: Hip Fractures
Sponsor: University of Massachusetts, Worcester
Start date: 2017-09-01; Completion date: 2019-01-22
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, randomized study looking at the effect that a long-acting local anesthetic has on pain control in patients having surgery for hip fractures. The investigators are conducting the study to see if that reduces the amount of pain medicine needed after surgery, and if it reduces other medical complications after surgery.

Detailed description:
Osteoporotic fragility fractures of the hip are common in the geriatric population, are increasing in frequency, and represent a growing social and economic burden. Pain control after surgical treatment is an area of growing interest, as improvement in post-injury pain is often an important indication for surgical treatment of hip fractures.

Typically a mainstay of post-operative pain control, the use of opiates has come under increasing scrutiny, as it has been shown to be associated with delirium, respiratory depression, and even may even lead to addiction or abuse in the medically frail geriatric population. These concerns have led to efforts to minimize the use of post-operative opiates in hip fracture patients. In that context, a treatment that could reduce the necessity of post-op narcotics while still improving pain control would be potentially valuable.

There has been growing interest in the use of long-acting local anesthetics for improving pain control in orthopaedics, particularly in the elective total joint arthroplasty population. Studies have shown that arthroplasty patients receiving long-acting local anesthetics have decreased opiate requirements, reduced length of stay, and lower costs. Although well-demonstrated in the elective arthroplasty population, the effects of long-acting local anesthetics have yet to be demonstrated in the hip fracture population. Given that these fractures frequently occur in medically frail patients with multiple comorbidities, in whom post-operative confusion and delirium are relatively common, there is the potential for treatments that decrease opiate requirements to demonstrate substantial medical and economic benefits.

Exparel (liposomal bupivacaine) and long-acting local anesthetics have been used extensively in hip replacement surgery and have not been shown to be associated with any increased risks. In the case of patients with displaced femoral neck fractures treated with arthroplasty, the surgical techniques are identical to those being used in this study. Exparel has also been used in trauma surgery as well as foot and ankle surgery without any increased described risks, although its use explicitly in hip fractures has not been published. However, the PI has trained in other medical centers where Exparel is routinely used in hip fracture patients without any identified increased risks or complications, but there is a paucity of data on this subject, which is the rationale for this study.

The investigators hypothesize that in patients with osteoporotic fragility fractures of the hip, patients receiving intraoperative long-acting local anesthetics will have decreased pain and decreased post-operative opiate requirements, leading to less delirium and decreased hospital resource utilization during their index hospitalization.

The goal is to conduct a multi-center prospective randomized control trial to determine if liposomal bupivacaine is superior to standard of care by addressing the below separate but related aims:

1. Determine the effectiveness of Exparel to reduce narcotic requirements and pain post operatively after hip fracture treatment. Excess narcotic use in the elderly population is associated with a host of complications often magnified by polypharmacy, including in hospital delirium, increased length of stay, nausea, constipation, urinary retention, respiratory depression and others. Decreasing narcotic usage in this group of patients following hip fracture can possibly reduce such complications. Patients will receive standard of care medical treatment and be randomized to intra-operative Exparel vs. placebo injections. Opioid requirements, complications, pain score, and length of stay will be assessed in the post-operative period. Hypothesis: The investigators hypothesize that total morphine requirements and pain scores will be decreased in this group following the administration of exparel in the geriatric hip fracture fracture population.
2. Determine the effectiveness of Exparel to reduce delirium in post-operative hip fracture patients. In hospital delirium in elderly patients is associated with poor outcomes, including prolonged length of stay, poor participation in rehabilitation, and falls. Use of a locally administered liposomal bupivacaine could decrease the need for additional medications for pain control in addition to decreased mental stress for patients in this unfamiliar situation, thus resulting in decreased episodes of delirium. The investigators will assess delirium utilizing Confusion Assessment Method (CAM) scores in the post-operative period at regularly scheduled intervals and compare average scores between the treatment / standard of care group. Hypothesis: The investigators hypothesize that total episodes of delirium will be decreased in the liposomal bupivacaine group.
3. Determine if Exparel is cost-effective in hip fracture patients. The costs associated with increased narcotic usage, prolonged stay, resources, and complications can be significant. The use of liposomal bupivacaine may lead to decreased resource utilization to care for hip fractures. The investigators will conduct an economic analysis evaluating total inpatient hospitalization costs including costs associated with length of stay, medication requirements, and resources associated with consultations and diagnostic evaluations. These costs will be compared against the cost of Exparel administration to evaluate the net cost effect of the intervention. Hypothesis: The investigators hypothesize that the net cost of inpatient care will be decreased when compared to standard of care.

Arms: arm 1: Exparel (liposomal bupivacaine) is FDA approved, with a labeled indication of "single-dose infiltration into the surgical site to produce postsurgical analgesia." arm 2: Saline Solution (Sodium Chloride)
Interventions: intervention 1: Exparel intervention 2: Sodium Chloride
Intervention descriptions: intervention 1: Subcutaneous injection at conclusion of surgical fixation of hip fracture intervention 2: Saline Injection

Protocol documents:
SAP_004.pdf: 
Official Title: Does the Use of Liposomal Bupivacaine Decrease Narcotic Requirements in Geriatric Hip 
Fractures? A Randomized, Double Blinded Control Trial  
 
NCT Number: NCT03289858 
 
Date of Document: August 27, 2017 
 
 


Statistical Analysis Plan for Randomized Controlled Trial for Exparel Hip Fracture (H00013594)  
Primary Outcome Variables: Total morphine equivalents in the post-operative period for 24, 48, and 72 
hours, CAM score and average Pain Visual Analog Scale  
Secondary Outcome Variables: Length of stay, discharge disposition, timing and participation with 
inpatient physical therapy, complications and 30 day readmission. 
Comparisons between continuous variables will be made using Students t-test, and categorical variables 
using the Chi-square statistic or Fischer’s Exact Test, based on incidence.  
Power analysis: Recent studies evaluating regional nerve blocks in hip fractures have shown an average 
morphine sulfate equivalent of 3.5 +/- 0.52 mg/d in the first 3 postoperative days. That same study 
showed a 33% reduction in morphine equivalents (3.5 mg/d vs 2.1 mg/d). Assuming a similar effect size, 
this study would require only 8 patients group to be powered to 80% with a significance level of 0.05. 
With a target recruitment goal of 50 patients, the study would be powered to detect differences as low 
as 0.42 mg/d (a 12% effect size) 

Prot_003.pdf: 
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Official Title: Does the use of Liposomal Bupivacaine Decrease Narcotic Requirements in 
Geriatric Hip Fractures? A Randomized, Double Blinded Control Trial 
 
NCT Number: NCT03289858 
 
Date of the Document: March 15, 2018 
 


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1. Title 
Does the use of Liposomal Bupivacaine Decrease Narcotic Requirements in Geriatric Hip Fractures? A 
Randomized, Double Blinded Control Trial 
 
2. IRB Review History 
N/A  
 
3. Objectives 
              Decreasing pain and narcotic requirements in the elderly population following hip fracture could 
be associated with improved outcomes and the prevention of complications. Our goal is to conduct a 
multi-center prospective randomized control trial to determine if liposomal bupivicane is superior to 
standard of care by addressing the below separate but related aims: 
 
1. 
Determine the effectiveness of Exparel to reduce narcotic requirements and pain post 
operatively after hip fracture treatment.  Excess narcotic use in the elderly population is associated with 
a host of complications often magnified by polypharmacy, including in hospital delirium, increased length 
of stay, nausea, constipation, urinary retention, respiratory depression and others.  Decreasing narcotic 
usage in this group of patients following hip fracture can possibly reduce such complications.  Patients will 
receive standard of care medical treatment and be randomized to intra-operative Exparel vs. placebo 
injections. Opioid requirements, complications, pain score, and length of stay will be assessed in the post-
operative period. 
• Hypothesis:  We hypothesize that total morphine requirements and pain scores will be decreased 
in this group following the administration of exparel in the geriatric hip fracture fracture population. 
 
2. 
Determine the effectiveness of Exparel to reduce delirium in post-operative hip fracture 
patients.  In hospital delirium in elderly patients is associated with poor outcomes, including prolonged 
length of stay, poor participation in rehabilitation, and falls.  Use of a locally administered liposomal 
bupivicane could decrease the need for additional medications for pain control in addition to decreased 
mental stress for patients in this unfamiliar situation, thus resulting in decreased episodes of delirium.  
We will assess delirium utilizing Confusion Assessment Method (CAM) scores in the post-operative period 
at regularly scheduled intervals and compare average scores between the treatment / standard of care 
group. 
• Hypothesis:  We hypothesize that total episodes of delirium will be decreased in the liposomal 
bupivicane group. 
 
3. 
Determine if Exparel is cost-effective in hip fracture patients.  The costs associated with 
increased narcotic usage, prolonged stay, resources, and complications can be significant.  The use of 
liposomal bupivacaine may lead to decreased resource utilization to care for hip fractures.  We will 
conduct an economic analysis evaluating total inpatient hospitalization costs including costs associated 
with length of stay, medication requirements, and resources associated with consultations and diagnostic 
evaluations. These costs will be compared against the cost of Exparel administration to evaluate the net 
cost effect of the intervention. 
• Hypothesis:  We hypothesize that the net cost of inpatient care will be decreased when compared 
to standard of care. 


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4. Background 
Osteoporotic fragility fractures of the hip are common in the geriatric population, are increasing 
in frequency, and represent a growing social and economic burden1,2. Pain control after surgical treatment 
is an area of growing interest3, as improvement in post-injury pain is often an important indication for 
surgical treatment of hip fractures4,5. 
               Typically a mainstay of post-operative pain control, the use of opiates has come under increasing 
scrutiny, as it has been shown to be associated with delirium, respiratory depression, and even may even 
lead to addiction or abuse in the medically frail geriatric population6. These concerns have led to efforts 
to minimize the use of post-operative opiates in hip fracture patients. In that context, a treatment that 
could reduce the necessity of post-op narcotics while still improving pain control would be potentially 
valuable. 
                There has been growing interest in the use of long-acting local anesthetics for improving pain 
control in orthopaedics7, particularly in the elective total joint arthroplasty population8. Studies have 
shown that arthroplasty patients receiving long-acting local anesthetics have decreased opiate 
requirements, reduced length of stay, and lower costs,8-12. Although well-demonstrated in the elective 
arthroplasty population, the effects of long-acting local anesthetics have yet to be demonstrated in the 
hip fracture population. Given that these fractures frequently occur in medically frail patients with 
multiple comorbidities13,14, in whom post-operative confusion and delirium are relatively common15,16, 
there is the potential for treatments that decrease opiate requirements to demonstrate substantial 
medical and economic benefits. 
Exparel (liposomal bupivacaine) and long-acting local anesthetics have been used extensively in 
hip replacement surgery and have not been shown to be associated with any increased risks17-23. In the 
case of patients with displaced femoral neck fractures treated with arthroplasty, the surgical techniques 
are identical to those being used in this study. Exparel has also been used in trauma surgery24 as well as 
foot and ankle surgery25 without any increased described risks, although its use explicitly in hip fractures 
has not been published. However, the PI has trained in other medical centers where Exparel is routinely 
used in hip fracture patients without any identified increased risks or complications, but there is a paucity 
of data on this subject, which is the rationale for this study.  
                We hypothesize that in patients with osteoporotic fragility fractures of the hip, patients receiving 
intraoperative long-acting local anesthetics will have decreased pain and decreased post-operative opiate 
requirements, leading to less delirium and decreased hospital resource utilization during their index 
hospitalization. 
 
5. Inclusion and Exclusion Criteria 
Inclusion Criteria 
• Age 55 or older 
• Sustaining either an OTA/AO type 31A or 31B fracture undergoing ORIF or hemiarthroplasty 
• Able to consent 
• Isolated injury 
 
Exclusion Criteria 
• OTA/AO 31B1 (Impacted/slightly displaced) 
• Baseline dementia or cognitive deficit 
• Inability to consent 


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• Chronic Opioid use 
• End stage liver disease with Model for End-Stage Liver Disease (MELD) greater than 20. 
• End stage renal disease as defined by patients requiring hemodialysis at least twice weekly 
• Polytrauma, defined as: 
o Concurrent upper or lower extremity fracture, pelvis fracture, spine fracture, rib fractures, or 
facial fractures 
o Blunt chest or abdominal trauma resulting in diagnosed organ injury 
o Head trauma resulting in intracranial bleed or diagnosed concussion 
• Allergy to amide-type local anesthetics 
• Prisoners (unlikely to be accessible for follow-up) 
 
6. Study-Wide Number of Subjects 
                 This is a multi-center study being conducted in conjunction with the University of Kentucky. The 
total recruitment goal is 60 patients, with a goal enrollment of 30 patients at University of Massachusetts, 
and 30 patients at University of Kentucky.  
 
Recent studies evaluating regional nerve blocks in hip fractures have shown an average morphine 
sulfate equivalent of 3.5 +/- 0.52 mg/d in the first 3 postoperative days26. That same study showed a 33% 
reduction in morphine equivalents (3.5 mg/d vs 2.1 mg/d). Assuming a similar effect size, this study would 
require only 8 patients group to be powered to 80% with a significance level of 0.05. With a target 
recruitment goal of 50 patients, the study would be powered to detect differences as low as 0.42 mg/d (a 
12% effect size). Assuming a 10-20% loss to follow-up, we aim to recruit a total of 60 patients studywide 
(i.e. 30 at each site). 
 
7. Study-Wide Recruitment Methods 
                 Recruitment methods will be the same at both University of Massachusetts and University of 
Kentucky. Refer to 24. Recruitment Methods for details of recruitment methods at University of 
Massachusetts. 
 
8. Study Timelines 
• Duration of an individual subject’s participation in the study 
An individual subject’s participation in the study begins at enrollment and ends after the 30 day post-
op follow-up period.  
• Duration anticipated to enroll all subjects 
From recent internal data review, we treat between 250-300 hip fractures annually at UMMMC. We 
anticipate 10-25% of patients will be both eligible and willing to enroll in the study, so to enroll 30 
patients should take 6-12 months. 
• Estimated date for the investigators to complete this study (complete primary analyses) 
Primary analysis should be completed once the final cohort of patients complete their 30 day study 
window, so we expect 13-14 months after initiation of enrollment. 
 


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9. Study Endpoints 
• 
Primary Outcome Variables: Total morphine equivalents in the post-operative period for 24, 48, and 
72 hours, CAM score and average Pain Visual Analog Scale 
• 
Secondary Outcome Variables:  Length of stay, discharge disposition, timing and participation with 
inpatient physical therapy, complications and 30 day readmission. 
 
10. Procedures Involved 
• 
Patient identification: Patients will be identified on morning intake rounds by the trauma team and 
the research staff who are present daily to screen and enroll patients. 
• 
Screening/Enrollment: The research staff will review the charts to identify patients meeting the 
inclusion/exclusion criteria. Patients will be approached for study participation and enrolled in the 
study prior to surgery. For potential participants, the research staff will interview the patients, confirm 
willingness to participate and inclusion/criteria. 
o We will utilize a Mini-COG (Screening for Cognitive Impairment in Older Adults)27.  A score of 
<4, which has been shown to have high sensitivity for dementia screening will define cognitive 
impairment and will preclude enrollment. 
o At time of enrollment, preoperative demographics will be recorded which will include age, 
sex, comorbidities, current use of anti-epileptic/anti-depressive medications for pain control, 
type of surgical approach, pre-ambulatory status and implant class. 
o After this review and screening, the patient will be given the opportunity to ask researchers 
questions about the study. It will be reiterated to all patients during preoperative discussions 
that their enrollment status in no way will affect their ability to get adequate post-operative 
pain control. 
• 
Randomization: Randomization will be done through the research pharmacy. Participants will 
undergo block randomization (block size: 10) through a computer-generated algorithm.  
• 
Treatment: Surgical treatment will be performed according to the attending surgeon and is 
independent of the study. At the conclusion of surgery, they will receive a subcutaneous injection of 
either Exparel placebo. Patients will receive operative treatment of the hip fracture per the 
operating surgeon.  At the conclusion of surgery, Exparel will be given in 20cc doses, diluted with 
40cc of normal saline to make 60cc of total injection volume. The injection solution contains a total 
of 266mg free base bupivacaine (equivalent of 300 mg bupivacaine HCl). The research pharmacy will 
prepare the injection solution to contain either Exparel or placebo solution. In intra-capsular 
arthroplasty cases, the solution will be injected circumferentially into the capsule, surrounding 
musculature, and subcutaneous layer. In cases with extra-capsular fractures treated with sliding hip 
screws or cephalomedullary nails, the solution will be administered in the deep tissue and muscles 
around the fascial incisions as well as in the subcutaneous layer. At the time of medicine or placebo 
administration, the operating room circulating nurse will create a log entry for Exparel 
administration in the medication administration record (MAR). This is the section of the medical 
record where all medications must be recorded, and will be consulted prior to delivery of any other 
local anesthetic agents, which will serve to limit the additional exposures and minimize the risk of 
toxicity. 
• 
Post-operative inpatient care: While admitted to the hospital, patients will receive medical care per 
routine, including a standardized post-operative pain control regimen. Post-operatively, all patients 
will receive a uniform pain control protocol consistent with the current standard of care. We have 
worked with our anesthesia team to create a consensus-driven protocol to ensure patients are 


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evaluated for pain and having pain treated in an appropriate and uniform manner. The written 
protocol is included at the conclusion of this document as Appendix A. We will collect the following 
data from inpatient hospitalization.  
o As a part of the research study regiment, delirium will be assessed using the Confusion 
Assessment Method (CAM)28, which will be administered 6 hours following surgery, post-
operative day 1, 2 and 3 between 8AM-12PM, when a provider is called to the bedside to 
evaluate the patient for confusion, and also by nursing staff at each nursing shift (Q12). 
o Adverse events will be monitored and recorded during hospitalization following standard of 
care regiment and later be used and accessed for data collection of the research study. The 
adverse events monitored and recorded will include: alteration of mental status, respiratory 
depression, wound complications, fixation-related complications.  
o The following information will be accessed via the electronic medical record after discharge: 
▪ 
Total morphine equivalents post-surgery, including and excluding recovery unit 
administration of narcotics in the immediate post-operative period. 
▪ 
Pain Visual Analog Score (VAS) score, which is obtained Q4 by nursing staff. 
▪ 
Timing and participation with physical therapy will be recorded looking at time until 
first therapy evaluation, and level of mobilization achieved 
▪ 
Length of stay, discharge disposition  
• 
Post-hospital follow-up: Follow up after discharge will be done according to each individual surgeon’s 
practice per their standard of care. It typically involves a follow up appointment at 2-4 weeks post-
operatively, with longer follow-up as needed based on the injury type, surgical fixation strategy, and 
the trajectory of recovery. In addition to data collected as indicated above, including total morphine 
equivalents post-op period, CAM score, average pain VAS, length of stay, discharge disposition, 
timing/participation with inpatient physical therapy and adverse complications, data concerning 30-
day patient readmission will be collected during the 30-day post-op period. 
 
11. Data and Specimen Banking 
No specimens will be obtained or retained for future study. The stored deidentified data from the 
study will be kept for a minimum of 6 years for records in the event follow-up studies are pursued and 
will remain protected and encrypted. Data will be permanently deleted following this time period. The 
banked data will be stored on a password-protected research drive corresponding to “orthotrauma 
(\\ummhcnas03)”. Upon conclusion of the study, the data will be stored in a password encrypted file that 
only the PI has access to. 
 
12. Data Management 
Following initial enrollment, each patient will be assigned a unique patient identifier. All electronic 
documentation containing total morphine equivalents, visual analogue scores and all other medical 
information will be associated with this unique patient identifier during analysis. All protected health 
information will be stored in a separate, password-protected research file that will not be accessed 
regularly. Following our secondary analysis, all personal health information will be removed from our 
electronic files and destroyed in accordance with patient privacy guidelines. 
Data obtained at UMMMC during the study will be recorded and stored using Redcap software 
that will be maintained at the hospital by the research staff. The University of Kentucky will be responsible 
for their own data infrastructure. Upon conclusion of the study, the University of Kentucky will share de-
identified data (with information relating to the study endpoints) with the University of Massachusetts 


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for final analysis. Final analysis will be conducted using Excel spreadsheets. All documents will be stored 
on a password-protected research drive and only research personnel will have access to its content.  Paper 
documents, including consent forms, will be stored in a locked cabinet in a secure research room. 
Each researcher on the project has passed the CITI exam on ethical conduct of research and has 
received training and supervision regarding patient confidentiality.  Only approved research personnel 
will administer consents and perform phone surveys. All efforts will be made to maintain the 
confidentiality of the patient reported data. Only study personnel listed in eIRB will have access to 
identified study data.  
Consistent with other research projects through the UMass Orthopedic Trauma Center, all other 
research-related files including but not limited to copies of consents and surveys will be stored on a 
password protected research drive or locked research cabinet. Research personnel also have allocated 
space with locked drawers for source document files and secure workspace apart from patient or public 
areas that is also locked. 
 
13. Provisions to Monitor the Data to Ensure the Safety of Subjects 
Subjects in this study will be exposed to minimal risk as both treatment arms are considered 
standard postsurgical care.  The patients are monitored continuously as inpatients post-operatively and 
any issues with medication effects, wound healing, or other medical complications will be logged as 
adverse events. Blinding will only be broken for unexpected complications potentially related to 
bupivacaine and the research study (e.g. wound complications, or cardiac issues possibly attributable to 
bupivacaine administration). The research team will meet monthly to monitor data collection and 
handling.  During this time, study staff will also review adverse events logs and pain scores. 
 
14. Withdrawal of Subjects  
We do not anticipate any situation in which a subject would be withdrawn from the study by the 
researchers should they wish to remain.  We anticipate analyzing the data via an intention to treat analysis 
and thus would include data from all subjects initially enrolled, even if they developed an intolerance or 
medical contraindication to continuing the study. 
However, a subject may choose to withdraw from the study on their own accord, at any time, for 
any reason. Contact information and instructions detailing how to withdraw from the study will be 
provided in the consent form and will involve contacting the principal investigator directly. If a subject 
chooses to withdraw, any and all data that was previously collected will be included in the analysis; 
however, we will cease any further data collection. All personal health information collected prior to a 
patient’s withdrawal from the study will be destroyed in accordance with patient privacy laws. In addition, 
any paper documents obtained will be destroyed in accordance with standard HIPPA guidelines. Upon 
being notified of a patient’s decision to withdraw from the study, researchers will no longer contact the 
patient via phone, administer in-office surveys, or access their medical information online.  
15. Risks to Subjects  
Surgical risks are described to the patient prior to surgery and are part of standard of care 
procedures for hip fracture surgery.  There are no additional surgical risks to patients who participate in 
this study. 
The medications used post-operatively are commonly used for treatment of pain following 
surgery and carry the same risks when taking these medications for postoperative  care. These represent 


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the standard of care for post-operative pain control, and are already part of our existing post-operative 
pain control pathway. 
Although the treatment arm in this study involves randomization to liposomal bupivacaine 
(Exparel), standard bupivacaine is routinely used peri-operatively in the treatment of hip fracture patients 
in our institution. The major risks associated with Exparel administration relate to the administration of 
bupivacaine in general (rather than its liposomal formulation). They include allergic reaction, and potential 
cardiovascular or central nervous system toxicity. Per the FDA labeling, risks that occur with greater than 
or equal to 10% frequency include nausea, constipation, and vomiting. 
There is also a risk of a breach of confidentiality. All research team members are appropriately 
trained and understand the importance of confidentiality. 
 
16. Potential Benefits to Subjects  
The addition of long-acting local anesthesia could potentially benefit patients by resulting in 
improved pain control, reduced opiate requirements, and a resultant decrease in medical complications. 
As noted above, nerve blocks in hip fractures have been associated with a 33% decrease in opiate use26, 
and regional anesthesia in ankle fractures has similarly been shown to decrease opiate use by over 60%29. 
In arthroplasty, long-acting local anesthesia has been shown as effective as regional anesthesia for pain 
control, and is associated with decreased narcotic use and even shortened length of stay17,19-21,30,31. It is 
possible that hip fracture patients could not only realize similar benefits, but could actually see increased 
benefit in terms of opiate-related complication reduction, given the increase medical frailty of this 
population6,13-16. 
 
17. Vulnerable Populations  
The osteoporotic hip fracture population is comprised almost exclusively of geriatric patients, 
which could be considered a vulnerable population. We will formally use the mini-COG as a screening tool 
to exclude patients with baseline cognitive impairment. Additionally, patients unable to consent for 
themselves will be excluded. As such, only cognitively intact patients will be included in the study. 
Whenever possible, we will also discuss involvement in the study with the patient’s family (provided the 
patient gives permission for us to discuss with them) to ensure that the decision to participate in the study 
is made with appropriate consideration and that the entire family is comfortable with involvement. 
 
18. Multi-Site Research  
This study is being conducted in conjunction with the University of Kentucky, which is a busy 
academic (level 1) trauma center with a similar hip fracture volume to UMMMC. Funding is divided evenly 
between both centers, and both have equivalent recruitment goals. The two principal investigators, Eric 
Swart and Paul E. Matuszewski, are close colleagues who remain in constant communication and will 
maintain coordination to ensure that:  
• 
All sites have the most current version of the protocol, consent document, and HIPAA authorization.  
• 
All required approvals are obtained at each site (including approval by the site’s IRB of record).  
• 
All modifications are communicated to sites and approved (including approval by the site’s IRB of 
record) before the modification is implemented.  
• 
All engaged participating sites safeguard data as required by local information security policies.  
• 
All local site investigators conduct the study appropriately.  


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• 
All non-compliance with the study protocol or applicable requirements is reported in accordance 
with local policy.  
• 
All sites are informed of problems, interim results, and the study closure.  
 
19. Community-Based Participatory Research  
Not applicable 
 
20. Sharing of Results with Subjects 
To maintain the double-blinded nature of the study, the both researchers and subjects will not be 
aware of which treatment group a subject has been randomly assigned to. At the conclusion of the study, 
following de-identification and data analysis, results of this data collection may be shared with patients 
who have participated in this research as it becomes available, if they request it verbally or in writing.  This 
will only occur after final data analysis, if a subject inquires. 
 
21. Setting  
Research subjects will be identified, recruited and followed post-operatively as inpatients at the 
University Campus of UMass Memorial Medical Center (UMMMC). They will be followed post-discharge 
at the Ambulatory Care Center (ACC). Data analysis will primarily occur in locked, private offices at in one 
of two secure research offices located at the University Campus. 
 
22. Resources Available  
UMass Memorial is the largest health system in central Massachusetts. It consists of three 
separate campuses, Hahnemann, Memorial, and University campus. The Orthopedics Department has 
locations on all three campuses that each provide a dedicated research space, which contain computers 
with access to password-protected research drives. 
The Principle Investigator (PI) will be responsible for overseeing the study and ensuring 
consistency throughout the project. The orthopedic PI will serve as the research coordinator and assist in 
data collection and analysis. Recruitment and consent will be performed by the PI or the research 
assistant. Each member of the research staff has passed the CITI exam on ethical conduct of research and 
have received training and supervision regarding patient confidentiality and study protocol. The PI will 
meet with all research staff periodically to review each role and ensure adequate training for the 
respective positions. Upon enrollment of each patient, the corresponding surgical team will be counseled 
concerning the details of the study and their role, prior to admitting the patient into the OR. 
The hospital research pharmacy has already been approached about this study and a protocol is 
in place to ensure appropriate randomization, blinding, and treatment occurs for the study-related 
portion (injection of Exparel vs. placebo at the conclusion of the operation).  
The PI and research assistant will be responsible for institutional /IRB communication as well as 
data review and assistance with follow-up patient coordination as needed. There are no anticipated 
adverse consequences associated with this study, however, the principal investigator and research 
assistant will both be available should any unexpected medical or psychological problems arise. The 
research subjects will be provided with appropriate contact information in the consent form and will be 
provided with the PIs contact information at the time of enrollment as well.    


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23. Prior Approvals  
Not applicable 
 
24. Recruitment Methods 
No formal external recruitment methods will be used for this study, as hip fracture patients are 
universally admitted to the hospital after injury while awaiting surgery. Patients will be identified, 
screened, and approached for enrollment in the study as noted above (see 8. Study Timeline). After review 
and screening, the patient will be given the opportunity to ask researchers questions about the study. It 
will be reiterated to all patients during preoperative discussions that their enrollment status in no way 
will affect their ability to get adequate post-operative pain control. There will be no financial 
compensation in return for participation in this study. 
 
25. Local Number of Subjects  
The local recruitment goal at University of Massachusetts is 25 patients (Refer to 6. Study-
Wide Number of Subjects) 
 
26. Confidentiality  
As part of our design, researchers will have access to patients’ names and phone numbers in order 
to collect the required data. Upon enrollment, each patient will also be assigned a unique identifier. All 
patient personal information will be stored in a master list that links the patient’s identifying information 
to their medical record number, which will be maintained in a separate, locked file that only approved 
research personnel will have access to. During the data collection period, researchers will not directly use 
this master list and, instead, will draw upon information from a separate that contains only the patient’s 
first name, phone number, and unique patient identifier 
 
All paper data collection documents are kept in locked file cabinets within locked offices that are 
accessible only to the project investigators and staff. All online databases are password protected to guard 
against unauthorized access and only approved research personnel will be granted access. 
 
27. Provisions to Protect the Privacy Interests of Subjects (HIPAA)  
All eligible subjects will identified by orthopedic trauma team and researchers during morning 
intake rounds.  After this point, only approved research personnel will have access to patients’ private 
health information. All research will be stored electronically on secure research drives or locked offices as 
described above. 
Only health information related to their orthopedic injury and surgery will be reviewed for the 
purposes of this study. Other unrelated personal health information will not be accessed or used in any 
way. All subjects will sign a HIPAA authorization form for use of any protected health information to be 
used for research purposes, as stated above. 
 


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28. Compensation for Research-Related Injury  
There 
will 
be 
no 
additional 
compensation 
for 
research 
related 
injury 
as 
all 
treatments/medications are approved for postoperative pain management. Patients would be treated for 
any complications of surgery including non-union or fractures that may be slow to heal using approved 
methods by their treating surgeon consistent with standard of care.  The patient would be responsible for 
all costs associated with this treatment. 
 
29. Economic Burden to Subjects  
Although considered standard of care and typically covered by insurance, the cost of the study 
medication (Exparel) will be paid for by an external grant. All other treatment costs are within the standard 
of care and the expenses will be paid for by the patient and their health insurance. There is no additional 
post-operative follow-up required for this study beyond the surgeon’s standard follow-up routine. There 
will be no financial compensation in return for participation in this study. 
 
30. Consent Process 
We will obtain consent in accordance with the guidelines from the HRP-802 INVESTIGATOR 
GUIDANCE: Informed Consent (http://www.umassmed.edu/ccts/irb/investigator-guidance/). The 
consenting process will take place in the University Campus of UMass Memorial Medical Center 
(UMMMC) as previously described. All research personnel administering consents will be provided with 
copies of the above inclusion and exclusion criteria to apply to potential study participants. All subjects 
have the option to withdraw from the study at any time point by contacting the principal investigator. 
Consent will only be obtained by approved research personnel who have passed the CITI exam for ethical 
conduct of research.  
Patients will be given ample time to review the contents of the consent in private. The patient will 
be approached about the study as soon as they are identified to give them adequate time to review the 
study information prior to surgery. A researcher will then be available to answer all questions regarding 
the patient’s participation in the study, including but not limited to all risks and benefits. The patient may 
refuse to participate at any time during the consenting process or over the course of the study. 
 
31. Process to Document Consent in Writing  
The consent will be documented in accordance with the guidelines detailed previously in the HRP-
803 INVESTIGATOR GUIDANCE: Documentation of Informed Consent. The patient will receive a copy of 
this consent for their personal records during the enrollment process. This consent has been largely 
modeled after the Template Consent Document (HRP-502) and provides answers to many anticipated 
questions. Each signed consent will be stored in a locked cabinet in a secure research office that only 
approved study personnel are able to access. 
 
32. Drugs or Devices  
Exparel (liposomal bupivacaine) is FDA approved, with a labeled indication of “single-dose 
infiltration into the surgical site to produce postsurgical analgesia”. As such, this study represents on-label 
use of the medication. Use of Exparel post-operatively in this patient population does not involve a novel 
route or dosage, and is not being used in a patient population that would increase the risks. Exparel is 


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routinely used during arthroplasty surgery at our healthcare system Memorial Hospital in a population 
with a similar (although not identical) age profile and medical comorbidity profile. Additionally, this 
medication was routinely used at other institutions that the PI has trained at in hip fracture patients 
without identified increased medical risks or complications. 
We will maintain coordination with the research pharmacy to store, handle and administer the 
drug, in accordance with the study procedure. The IDS will be responsible for drug preparation and 
accountability. Refer to 8. Study Timelines for details on the study procedure. Placebo will consist of 
normal saline. Exparel is not a clear/transparent solution, so per discussion with the IDS, blinding will be 
performed by delivery of the medication in an opaque syringe. 
Devices used for fixation of the hip fracture are determined by the attending surgeon based on 
the injury characteristics, and are independent of involvement in this study. 
 
33. References 
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fractures in the United States. JAMA. 2009; 302(14): 1573-9, 
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Bone Miner Res. 2007; 22(3): 465-75, 
3. 
Sanzone AG. Current Challenges in Pain Management in Hip Fracture Patients. J Orthop 
Trauma. 2016; 30 Suppl 1: S1-5, 
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Koval KJ, Zuckerman JD. Hip Fractures: I. Overview and Evaluation and Treatment of 
Femoral-Neck Fractures. J Am Acad Orthop Surg. 1994; 2(3): 141-149, 
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Koval KJ, Zuckerman JD. Hip Fractures: II. Evaluation and Treatment of Intertrochanteric 
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Chau DL, Walker V, Pai L, Cho LM. Opiates and elderly: use and side effects. Clin Interv 
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Chughtai M, Cherian JJ, Mistry JB, Elmallah RD, Bennett A, Mont MA. Liposomal 
Bupivacaine Suspension Can Reduce Lengths of Stay and Improve Discharge Status of 
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Surdam JW, Licini DJ, Baynes NT, Arce BR. The use of exparel (liposomal bupivacaine) to 
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Zuckerman JD. Hip fracture. N Engl J Med. 1996; 334(23): 1519-25, 
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Appendix A: Post-operative Pain Control Protocol 
• Preop management 
• Intra-op 
o Spinal vs. GETA per anesthesia and orthopaedic surgeon discussion with patient 
o Exparel vs placebo at conclusion of case 
• Post-op / floor: 
o Standard PACU / floor pain assessment protocol 
o No toradol 
o Standing Tylenol 650mg PO q6hrs 
o Pain > 4/10, one dose 2.5mg PO oxycodone 
o Pain > 8/10, one dose 5mg PO oxycodone 
o Breakthrough pain: additional oxycodone 5mg PO once 
o Rescue pain: Hydromorphone 0.1mg IV once