Effects of Liposomal Bupivacaine for Acute Pain in Hip and Femur Fractures: a Randomized, Active Comparator-controlled, Blinded Trial
Phase: PHASE2
Conditions: Femoral Fractures
Sponsor: Ian Elliott Brown

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 1 of 19 
Version date: 4-4-19 
 
 
1) Protocol Title 
Effects of liposomal bupivacaine for acute pain in hip and femur 
fractures:  a randomized, active comparator-controlled, blinded trial 
 
DoD Additional Requirement: 
This is an investigator initiated, single-center study funded by the United 
States Department of Defense Health Program. The UC Davis PI and 
research staff are aware of specific DoD requirements and confirm that all 
additional criteria for DoD research have been met.  
 
 
2) Author of Protocol 
 
 UC Davis Researcher 
 Researcher from other institution 
 Private Sponsor 
 Cooperative Group 
✓  Other: Volunteer Associate Clinical Professor 
 
3) IRB Review History 
This is our first revision to the initial submission to the IRB. 
 
4) Objectives 
This is an investigator-initiated, single-center, randomized, patient blinded, 
controlled trial. The purpose of this study is to compare the effect of a fascia 
iliaca compartment block (FICB) using 0.2% ropivacaine vs. liposomal 
bupivacaine in patients with femur and/or hip fractures admitted to the 
University of California Davis Medical Center (UCDMC). The primary 
endpoint will be the total opioid requirements during the 96 hour 
randomization period with secondary endpoints including total daily opioid 
requirements for days 1-4, duration of effect and objective pain scores using 
the numeric rating scale (NRS) during their hospital stay.   
 
Hypothesis: In patients with femur or hip fractures, a fascia iliaca 
compartment block using liposomal bupivacaine will result in less total 
opioid administration during the randomization period compared to a fascia 
iliaca compartment block using 0.2% ropivacaine.   
 
The long-term goal of this study is to provide pilot information to guide and 
design larger, multicenter trials which will evaluate the utility and cost-
effectiveness of long acting liposomal bupivacaine as an opioid-sparring 
analgesic strategy in injured trauma patients. Ultimately, it is hoped that this 
information can improve safe and effective narcotic sparing analgesia in the 
awake, combat casualty, as well as serve as primary steps towards 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 2 of 19 
Version date: 4-4-19 
 
 
evaluating broader considerations for liposomal analgesia to improve short- 
and long-term outcomes in these patients. 
  
5) Background 
Achieving adequate pain control in trauma patients proves challenging. 
Consequences of uncontrolled pain include immobility, respiratory 
compromise, exhaustion due to lack of sleep, disorientation, agitation, 
stress response, and post-traumatic stress disorder. The standard of care 
for analgesia in poly-trauma patients is the use of opioids administered via 
intravenous, epidural, or enteral routes with either intermittent dosing or as 
patient-controlled analgesia.  Though opioid agents can provide effective 
analgesia, they exhibit untoward effects that at times may be dose limiting. 
These adverse effects include hypotension, bradycardia, central nervous 
system depression, respiratory depression, somnolence, and nausea.  
Additional common side effects of opioid use include pruritus, dry mouth, 
urinary retention, vomiting, prolonged recovery of ileus, and constipation.  
Clinicians are becoming increasingly aware of additional consequences, 
such as, opioid tolerance necessitating increased doses, opioid induced 
hyperalgesia, and opioid dependence.  As such, increasing emphasis has 
been placed on a multimodal approach to the management of postoperative 
and post-traumatic pain.  This multimodal approach includes use of local 
and regional blocks using local anesthetics. 
 
The duration of standard local anesthetic formulations vary from 4-8 hours 
and administration can include single injections or continuous infusion 
catheters. Liposomal bupivacaine, Exparel®, has a prolonged duration of 
action of up to 96 hours.  Studies have verified its safety with a very low risk 
of dysrhythmias, local tissue reaction, effects on wound healing or nerve 
toxicity.  In the elective surgical setting, liposomal bupivacaine has been 
shown to have an opioid sparing effect, increased duration of analgesia, 
increased patient satisfaction, earlier discharge, and lower hospital cost.  
This formulation has not been studied in trauma patients and its novel use 
may impact practice in pain management of trauma patients. Patients may 
exhibit a lower opioid requirement with the use of the liposomal bupivacaine.  
In addition, this may reduce the incidence of untoward effects including 
respiratory depression, central nervous system depression, and 
gastrointestinal dysfunction, and subsequently speed recovery with 
improved mobilization and cooperation with physical therapy.   
To date, no studies have evaluated liposomal bupivacaine regional 
analgesia following extremity trauma.  This pilot study aims to assess the 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 3 of 19 
Version date: 4-4-19 
 
 
efficacy of long-acting liposomal bupivacaine compared to ropivacaine 0.2% 
in orthopedic trauma patients with acute pain following femur or hip fracture. 
 
6) Inclusion and Exclusion Criteria 
Inclusion criteria: 
1) age ≥18 years ≤ 70 years 
2) Patient’s s/p trauma, with confirmed femur and/or hip fractures with a 
planned admission to the hospital. 
3) Patient is ambulatory without assistance (e.g. walker, cane, caretaker) 
prior to incident.   
 
Exclusion Criteria: 
1) >10 hours since presentation to the emergency department 
2) History of seizure disorder, recent seizure or a document intra-cranial 
hemorrhage.  
3) Central or peripheral neurologic deficit on presentation 
4) Concern or compartment syndrome 
5) Associated additional long bone fractures 
6) End stage liver failure 
7) Renal failure requiring dialysis 
8) Pregnancy or breast feeding 
9) Prisoners 
10) Coagulopathy with INR >1.5 
11) Use of direct thrombin inhibitors (bivalirudin, argatroban, desirudin, 
dabigatran etexilate), or direct factor Xa inhibitors (rivaroxaban, 
apixaban, edoxaban) 
12) Suspected prolonged intubation within first 12 hours secondary to 
respiratory failure other than peri-procedurally  
13) Adults unable to consent 
14) Pediatric patients <18 years old 
15) Patients exhibiting signs of shock upon admission, HR >120 or SBP 
<100 mmHg.   
16) History of allergic reaction to local anesthetics 
17) Administration of any other local anesthetic in the 2 hours prior to the 
study enrollment. 
18) Distal femur fractures  
 
7) Number of Subjects 
17 patients per arm 
Total subjects: 34 
 
 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 4 of 19 
Version date: 4-4-19 
 
 
8) Recruitment Methods 
Subjects will be recruited from the UC Davis Trauma Center. Patients found 
to have femur and /or hip fractures admitted to UCDMC will be screened for 
eligibility.   
 
Waiver of HIPAA authorization for recruitment is requested for access to PHI 
during the screening to determine eligibility. 
 
Description of PHI that will be accessed. 
Information reviewed to assess eligibility will include: date of admission, date 
of birth, gender, mechanism of trauma injury (blunt/penetrating), x-rays, lab 
results, admission vital signs, home medications and the patient’s medical 
history.  
 
The use of PHI involves no more than minimal risk and granting of  
waiver will not adversely affect privacy of the patients.  
Access to medical records that contain patient’s personal information for the 
purpose of this study will be limited to the approved research personnel. 
These personnel already have knowledge of and access to identifiable 
medical information of current trauma patients as part of their daily job 
functions; hence, granting of this waiver will not adversely affect the privacy of 
the involved patients or the confidentiality of their information. EMR access to 
PHI is password-protected and no PHI will be reused or disclosed to any 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 5 of 19 
Version date: 4-4-19 
 
 
other person or entity, except as required by law. Data will be used solely for 
the purposes of determining study eligibility. 
 
The research could not practicably be conducted without a waiver or 
alteration. 
Without an initial review of the medical record for screening purposes, it 
would not be possible to identify potential subjects and confirm their 
applicability for study participation. 
 
The research could not practicably be conducted without access to and use of 
PHI.  
Since PHI is embedded in the medical record and since the screening 
process requires detailed information about trauma patients, access to 
medical records (viewing of PHI) is necessary. 
 
9) Compensation to the Subjects 
Subjects will not be compensated for this study. 
 
10) Study Timelines 
The duration of each subject’s participation is the length of their hospital 
stay.  
 
Duration anticipated to enroll all study subjects: 12 months. 
Data acquisition and analysis:  same 12 months 
Manuscript preparation: 6 months 
 Total time requirement: 1.5 years 
 
11) Study Endpoints 
 
Hypothesis:  In patients with femur or hip fractures, a fascia iliaca 
compartment block using liposomal bupivacaine will require less total opioid 
administration compared to a fascia iliaca block using 0.2% ropivacaine.   

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 6 of 19 
Version date: 4-4-19 
 
 
Primary Endpoint  
(1) Total opioid requirement during the 96 hour randomization period 
measured in milligram morphine equivalents.  
 
Secondary Endpoint 
(1) Percentage of time during the 96 hour randomization period that the 
objective pain score was above mild (defined as a numeric rating score 
>4).   
 
12) 
Procedures Involved 
  
 
 
The nature of the risks and benefits associated with participation in the 
 
study will be explained to all potential study subjects. Written informed 
 
consent must be obtained before the subject can begin any screening 
 
procedures that are not considered standard patient care. Subjects who 
 
have undergone the screening procedures and have met the entry criteria 
 
will be randomized into the study and assigned to treatment by the 
 
Unblinded Pharmacist. Subjects will be randomized in a computer-
 
generated, blinded block, 1:1 ratio to treatment with 60mL of either 0.2% 
 
ropivacaine (120mg) or a dilution of liposomal bupivacaine (266mg). 
 
 
The Pharmacy and Emergency Medicine (EM) members will be the only 
 
unblinded study team members. All other members, including the Trauma 
 
team and Clinical Research Coordinator (CRC), will remain blinded. 
 
 
The unblinded Investigational Drug Service (IDS) Pharmacy at UC Davis 
 
Health (UCDH) will be responsible for blinding and drug preparation. 
 
Investigational Product (IP) will be prepared in three 35mL Luer lok 
 
syringes, each containing 20mL of IP, for a total dose of 60mL. In addition 
 
to a patient-specific institutional label, masking/amber tape will also be 
 
affixed to the syringes in order to reduce the risk of drug recognition by a 
 
supporting procedure nurse. During the procedure, nursing care of the 
 
patient will temporarily transition from the primary bedside nurse to a 
 
supporting procedure nurse. The supporting procedure nurse will 
 
remain blinded and will assist primarily with assessments and recording 
 
of vital signs (but will not work directly with the IP). 
 
 
For patients randomized to receive ropivacaine, IP will be prepared via 
 
straight draw of ropivacaine 0.2% (120mg) and equally divided into three 
 
syringes. For patients randomized to receive liposomal bupivacaine 
 
(266mg), a dilution will be prepared, using 20mL of liposomal bupivacaine 
 
(Exparel®) 1.3% (13.3mg/mL) and 40mL of 0.9% NaCl. While the stability 
 
of ropivacaine drawn into a syringe is longer than 4 hours at room 
 
temperature, in order to maintain the blind, all IP will be given a stability of 
 
4 hours at room temperature. 
 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 7 of 19 
Version date: 4-4-19 
 
 
 
The three syringes will be dispensed in a tamper-proof opaque bag and 
 
will be transported between the Pharmacy and Emergency Department by 
 
either a Pharmacy member or CRC. The tamper-proof opaque bag will 
 
contain a note of “CAUTION,” that the content of the bag contain 
 
unblinding information. 
 
 
The unblinded administering ED Physician will receive the IP and confirm 
 
that the opaque bag has not been tampered with. Prior to breaking the 
 
seal for drug administration, the unblinded ED Physician will ensure that 
 
the blinded primary nurse has transferred care to the unblinded procedure 
 
nurse, and that all blinded members of the healthcare team have left the 
 
exam room. 
 
 
An unblinded Emergency Department staff will perform an ultrasound-
 
guided fascia iliaca compartment block (FICB) per the institutional ER 
 
protocol, using 60mL of either ropivacaine 0.2% (266mg) or a diluted 
 
solution of liposomal bupivacaine (266mg).  
 
 
      The patient will be placed on a continuous pulse oximetry and telemetry 
monitoring. Using standard sterile technique, a dermal wheel will be 
created using 0.25% bupivacaine.   Under ultrasound guidance, a blunt 
tipped needle will be inserted under the fascia iliacus muscle just inferior 
to the inguinal ligament and lateral to the neuro-vascular bundle.  After a 
negative aspiration, the designated local anesthetic will be infused slowly 
over several minutes in 5 ml increments with aspiration between to the 5 
ml increments to confirm extravascular insertion.  The volume and dosing 
will be as listed above. 
           Immediately following the procedure, to prevent unblinding of blinded   
           personnel, the syringes will be discarded per standard institutional  
           procedures into opaque Sharps containers.Upon completion, the patient  
           will remain on telemetry monitoring for 4 hours. 
 
           The patient will be blinded and all members of the healthcare team will be  
           blinded from the point of transfer of care from the Emergency Department  
           physicians to the receiving service. 
 
 
Both groups will be able to receive as needed analgesia per the primary 
attending service. (e.g., oral hydrocodone/acetaminophen 5/325 mg or 
narcotic IV push as needed for breakthrough pain).   
 
 
Patients enrolled in the study will be given a light blue wristband for 
identification to alert physicians regarding restrictions for anesthetics. 
Additionally, an automatic alert notification will be given by the Electronic 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 8 of 19 
Version date: 4-4-19 
 
 
Medical Record system if additional local anesthetics are ordered for the 
patient.  
 
     Pain Assessment 
     Objective pain assessment will be evaluated by the UCDMC nursing staff 
per local standard of care which is every four hours while the patient is 
awake using a numeric rating scale (NRS) of 0 to 10 with a pain score of 0 
being defined as: no pain, 1-4 mild pain, 5-7 defined as moderate pain, 
and 8-10 defined as severe pain.  
 
Study Definitions 
Acute and hospital-related adverse effects and study outcomes will be 
collected and tracked prospectively during the FICB and throughout the 
hospital stay, as appropriate per endpoint.  
 
 
During hospital stay study outcomes 
Data collection will include total amount of opioids administered to study 
patients in morphine equivalents (see Appendix) and the use of other 
analgesic medications during this time period.  Adjunctive analgesic use 
including non-steroidal anti-inflammatory drugs, acetaminophen, and 
gabapentin will be quantified. Use of additional adjunctive agents such as 
muscle relaxants also will be collected.  
All objective pain and agitation scores reported by the NRS will be 
collected; duration of supplemental oxygen requirement; number of 
episodes of oxygen desaturation (arterial O2 sat below 92%); morning 
incentive spirometer and peak flow measurements; 24-hour antiemetic 
(e.g., promethazine; ondansetron) pharmacotherapy; time to first bowel 
movement; and need for anti-hallucination or anti-delirium 
pharmacotherapy. 
Additional outcomes: hospital lengths of stay; time from study drug 
initiation to maximum allowable ambulation per injury pattern; post-
discharge opioid type and dosage provided at the time hospital discharge 
prescription; and patient report of chronic pain syndromes. Adverse effects 
including the incidence of hypertension requiring antihypertensive 
pharmacotherapy in addition to the patients home regimen, hypotension 
(SBP < 90 mmHg) requiring fluid bolus/vasoactive pharmacotherapy, 
tachycardia requiring pharmacologic intervention (defined as HR greater 
than 100 bpm), bradycardia (defined as HR below 60 beats per minute 
with symptoms or hypotension), respiratory depression (apnea; transition 
to higher level of respiratory support), emesis, hallucinatory reactions or 
experiences per patient interview, and pruritus per physical exam. 
 
The study will be stopped if ≥2 patients receiving the active study drug 
develop the same Grade 3 adverse reaction (Adverse Event Severity 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 9 of 19 
Version date: 4-4-19 
 
 
Definition defined previously) or if one patient develops a Grade 4 or 
higher adverse reaction.   
 
 
13) 
Data and Specimen Banking 
 
Not applicable.  
 
14) 
Data Management and Confidentiality 
Each patient will be assigned a unique study ID number at the time of 
study entry. Study information stored by the research personnel at 
UCDMC, which may include name and medical record number, will be 
kept strictly confidential and available only to the principal investigator and 
trained staff assigned to this study. All information will be kept secure in 
locked file cabinets accessible only by research personnel. All identifiers 
for recruitment purposes will be destroyed within 2 years of completion of 
study. 
 
 
Statistical Analysis 
Data will be presented as means ± standard errors of the mean (primary 
endpoint) and proportions ± interquartile ranges (secondary endpoint).  
Following assessment for normality, primary endpoint data will either be 
subjected to parametric unpaired two-sided t-tests or nonparametric 
Wilcoxon rank sum test Mann-Whitney two sample statistic.  Significance 
will be set at p = 0.05.  Secondary endpoint proportions will be assessed 
using either nonparametric chi-square tests or Fisher’s exact test. 
 
Other data such as ICU and hospital lengths of stay and adverse events 
will be collected, summarized, and described.  Exploratory analyses these 
data may be attempted, but these will be hypothesis generating, given the 
small sample size used in this pilot study. 
 
15) Provisions to Monitor the Data to Ensure the Safety of              
Subjects 
     
This study involves minimal risk to the patient, however, the DoD requires 
an independent research monitor for all clinical studies and thus a medical 
monitor will be assigned.  Dr. Gregory Jurkovich, MD, Professor of 
Surgery and Vice Chair of Surgery will act as the Data Safety Monitor for 
this study.   Any unanticipated adverse event meeting grade 3 or grade 4 
as listed below per the FDA’s guidance for industry,  will be reported to the 
study medical monitor.  The medical monitor will keep a database if the 
reported events and will report any of the above adverse events to the 
FDA’s MedWatch.  In addition, subjects having experience an adverse 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 10 of 19 
Version date: 4-4-19 
 
 
event of Grade 3 or 4 will be followed by the PI for the duration of their 
hospitalization.   
 
 
The greatest risk for systemic toxicity is at the time of administration and 
most often as a result of inadvertent intravenous injection of the drug with 
rapid onset of symptoms.  The procedure will be performed per UCDMC’s 
“Hip Fracture Protocol” which includes routine fascia iliaca compartment 
blocks, a provider training protocol and routine ultrasound guidance.  The 
protocol also includes telemetry monitoring, continuous pulse oximetry 
and q 15 min neurologic assessments for 30 min following injection.  In 
addition, the patients will remain on telemetry for an additional 4 hours 
monitoring for any delayed events. 
 
Following this 4 hour period, evaluation and capture of adverse events will 
continue until the completion of the 96 hour study period.  This will consist 
of nursing evaluation and vitals every 4 hours around the clock and on an 
as needed basis.   The study coordinator will evaluate for any potential 
events on a daily basis throughout the study period.  The PI or co-PI will 
be notified directly of any severe adverse event at the time of the event.  
 
The definitions of an adverse event are in line with the WHO-UMC system 
for standardized case causality assessment.   
 
 
Causality term 
Assessment criteria* 
Certain 
•  Event or laboratory test abnormality, with plausible time 
relationship to drug intake 
•  Cannot be explained by disease or other drugs 
•  Response to withdrawal plausible (pharmacologically, 
pathologically) 
•  Event definitive pharmacologically or phenomenologically (i.e. an 
objective and specific medical disorder or a recognised 
pharmacological phenomenon) 
•  Rechallenge satisfactory, if necessary 
Probable/ 
Likely 
•  Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
•  Unlikely to be attributed to disease or other drugs 
•  Response to withdrawal clinically reasonable 
•  Rechallenge not required 
Possible 
•  Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
•  Could also be explained by disease or other drugs 
•  Information on drug withdrawal may be lacking or unclear 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 11 of 19 
Version date: 4-4-19 
 
 
Unlikely 
•  Event or laboratory test abnormality, with a time to drug intake 
that makes a relationship improbable (but not impossible) 
•  Disease or other drugs provide plausible explanations 
Conditional/ 
Unclassified 
•  Event or laboratory test abnormality 
•  More data for proper assessment needed, or 
•  Additional data under examination 
Unassessable/ 
Unclassifiable 
•  Report suggesting an adverse reaction 
•  Cannot be judged because information is insufficient or 
contradictory 
•  Data cannot be supplemented or verified 
 
 
The severity of the any potential reaction will be grade using the FDA’s 
guidance for industry.   They have been modified to meet the study 
characteristics and are listed below.   
 
ADVERSE EVENT SEVERITY DEFINITIONS 
 
 
Vital Signs * 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Dysrhythmia  
Unsustained sinus or 
atrial rhythm  < 10 
seconds 
Unsustained 
ventricular rhythm 
<10 secs in duration 
or sustained sinus 
rhythms that are 
asymptomatic  
Any rhythm 
requiring treatment 
or a change in 
patient level of 
care 
A ventricular rhythm 
>10 secs, requiring 
CPR, cardiac arrest, or
any rhythm requiring 
continuous 
intravenous 
di
ti
Fever (°C) ** 
(°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats per 
minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats per 
minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) - 
mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension (diastolic) - 
mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension (systolic) – 
mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – breaths 
per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
*     Subject should be at rest for all vital sign measurements. 
**   Oral temperature; no recent hot or cold beverages or smoking. 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 12 of 19 
Version date: 4-4-19 
 
 
*** When resting heart rate is between 60 – 100 beats per minute.  Use clinical judgement 
when characterizing bradycardia among some healthy subject populations, for example, 
conditioned athletes. 
 
Systemic (General) 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity or 1 – 2 
episodes/24 hours 
Some interference 
with activity or > 2 
episodes/24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Dizziness 
No interference 
with activity or 1 – 2 
episodes/24 hours 
Some interference 
with activity or > 2 
episodes/24 hours 
Prevents daily 
activity, requires 
outpatient IV 
medication 
Persistent or 
associated with a 
mechanical fall.   
Diarrhea 
2 – 3 loose stools or 
< 400 gms/24 hours 
4 – 5 stools or 
400 – 800 gms/24 
hours 
6 or more watery 
stools or 
> 800gms/24 hours 
or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Constipation 
Dry, hard, painful 
stool.   
No bowel movement 
for 48 hours 
Requiring rectal 
suppository 
or 
enemas.  
ER visit or 
hospitalization 
Requiring digital 
dissimpaction , 
colonic perforation.  
Headache 
No interference with 
activity 
Repeated use of non- 
narcotic pain 
reliever > 24 hours or 
some interference 
with activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Methemoglobinemia 
Less than 15%; 
mostly 
asymptomatic, 
cyanosis 
15% or greater; 
cyanosis, 
lightheadedness, 
headache, tachycardia,
fatigue, dyspnea, or 
lethargy 
30% or greater; 
respiratory 
depression, altered 
sensorium, coma, 
shock, seizures 
70% or greater; severe 
hypoxia, cardiac arrest 
 
       
 
16) 
Withdrawal of Subjects 
a) Stopping Criteria – This study involves a single dose medication; 
therefore, individual stopping criteria will not be related to the continued 
administration of study drug, but rather ability of the subject to continue to 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 13 of 19 
Version date: 4-4-19 
 
 
participate in the follow-up evaluations.  The following clinical situations 
and the methods of follow-up to deal with them are as follows:   
(1) If a subject experiences an adverse event (AE) that renders them 
incapable of continuing with the remaining study assessments, the 
subject is to be discontinued.  A final evaluation will be performed 
so that the subject’s study participation can be terminated in a safe 
and orderly manner.   
(2) Patients will be free to discontinue the study at any time, without 
prejudice to future treatment. These subjects will be encouraged to 
complete at least the remaining safety assessments.   
(3) Patients will be removed from the study if they refuse either the 
study drug administration or fail to comply with study procedures.   
(4) In the event that a subject chooses to withdraw from research after 
data collection has been performed, no additional data will be 
collected after time of withdrawal.  
(5) There are no foreseeable circumstances necessitating the 
withdrawal of subjects from research without their consent.  
 
b) Unblinding Criteria 
(1) The blinding of therapy administered will be removed during the 
study period if evidence of local anesthetic toxicity is present based 
on the following:   
(a) Central nervous system reactions manifested by one of the 
following:  paresthesia, acute anxiety, tinnitus or seizure.   
(b) Cardiac reactions manifested by one of the following:  life 
threatening arrhythmia (ventricular arrhythmia, new onset heart 
block, new onset QT prolongation, hypotension unresponsive to 
fluid resuscitation or requiring vasopressor support or CPR.   
(c) Systemic Allergic reactions manifested by anaphylaxis.   
 
17) 
Risks to Subjects 
 
Pharmacologic risk:  
Administrations of local anesthetics is common place in medical practice, 
however, there are adverse reactions.   Those more frequent are listed 
below per each specific anesthetic.    
 
Liposomal bupivacaine:  
Very Common Adverse Reactions (≥10%): nausea, constipation, and 
vomiting.  
Common Adverse Reactions (≥2% to <10%): pyrexia, dizziness, edema 
peripheral, anemia, hypotension, pruritus, tachycardia, headache, 
insomnia, anemia postoperative, muscle spasms, hemorrhagic anemia, 
back pain, somnolence, and procedural pain.  

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 14 of 19 
Version date: 4-4-19 
 
 
 
Ropivacaine:  
 
Incidence of ≥5% in all clinical studies (N=3988): hypotension 
(37%), nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever 
(9.2%), pain (8%), postoperative complications (7.1%), anemia (6.1%), 
paresthesia (5.6%), headache (5.1%), pruritus (5.1%), and back pain 
(5%).  
Incidence 1 to 5%: Urinary retention, dizziness, rigors, hypertension, 
tachycardia, anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, 
dyspnea, cramps, and urinary tract infection.  
 
 
There is also the potential risks of severe life-threatening adverse effects 
associated with the administration of local anesthetics which are due 
primarily to toxic systemic concentrations.  Risks are associated with toxic 
plasma concentrations and can be characterized as central nervous 
system, cardiovascular and allergic reactions and local tissue toxicity. 
Despite the sustained release and potential for systemic toxicity, in studies 
to date, the safety profile of Exparel does not appear to differ in a clinically 
significant way from standard bupivacaine HCl. For the doses studied as 
part of the FDA clinical development program, there is no evidence that 
Exparel produces tissue toxicity in the short or long term, that it adversely 
affects wound healing, or that it is any more likely than bupivacaine HCl to 
cause neurological or cardiac toxicity with systemic absorption or 
inadvertent injection.    
  
The greatest risk for systemic toxicity is at the time of administration and 
most often as a result of inadvertent intravenous injection of the drug with 
rapid onset of symptoms.  As a result, FICBs will be administered in the 
emergency room where trained personnel and equipment are available to 
promptly treat patients who show evidence of neurological or cardiac 
toxicity.  The procedure will be performed per UCDMC’s “Hip Fracture 
Protocol” and will include telemetry monitoring, continuous pulse oximetry 
and q 15 min neurologic assessments for 30 min following injection.  In 
addition, the patients will remain on telemetry for an additional 4 hours for 
monitor for any delayed events.  The FICB is performed laterally, distant 
from the neurovascular bundle, and under ultrasound guidance minimizing 
the risk if intravenous injection.  The lipid emulsion of the liposomal 
bupivacaine results in a white milky appearance similar to that of propofol. 
Steps taken to minimize inadvertent medication error include a recent 
manufacture change in propofol labeling and storage, handling and 
delivering of the study drug by the IDS at UCDMC. Patients that exhibit 
any of the signs or symptoms listed in 16b, will be removed from blinding 
and 20% lipid emulsion will be administered.     
 
Privacy Risk  

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 15 of 19 
Version date: 4-4-19 
 
 
There may also be risks to the subject’s privacy.  The Researchers will 
store study records and other information about subjects in a secure 
location and will grant access only to those with a need to know.   
 
Randomization Risk 
Patients will be assigned to a treatment program by chance, and the 
treatment subjects will receive may prove to be less effective or to have 
more side effects than the other study treatments(s) or other available 
treatments. 
 
18) 
Potential Benefits to Subjects 
Subjects randomized to the liposomal bupivacaine arm may experience 
improvement in pain management, use of fewer opioids that may reduce 
incidence of untoward effects including respiratory depression, central 
nervous system depression, and gastrointestinal dysfunction and 
subsequently speed recovery with improved mobilization and cooperation 
with physical therapy.  
 
There may be no immediate benefit to any patient involved in the study. 
However, future treatment may be influenced by the outcomes discovered 
in this study. 
 
19) 
Vulnerable Populations 
 We do not intend to enroll subjects from vulnerable populations. 
 
20) 
Multi-Site Research 
 
Not applicable. This is a single institution based research study. 
 
21) 
Community-Based Participatory Research 
 
Not applicable. 
 
22) 
Sharing of Results with Subjects 
 
Any peer-reviewed manuscripts that result from this study will be made  
 
available to subjects upon request. 
 
23) 
Setting 
The study will be conducted at the UC Davis Medical Center located at            
2315 Stockton Blvd., Sacramento, CA 95817.  
 
24) 
Resources Available 
All staff has also been delegated research specific responsibilities 
by the PI who is compliant and up to date with all required training: 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 16 of 19 
Version date: 4-4-19 
 
 
1. Principal Investigator—Coordination of study activity, patient 
identification, collection of study data, reporting of results 
2. Co-Principal Investigator—Collection of study data, patient 
identification, data entry,  reporting of results 
3. Co-investigator— Collection of study data and reporting of 
results 
4. Co-investigator— Collection of study data and reporting of 
results 
5. Co-investigator— Collection of study data and reporting of 
results 
6. Co-investigator— Collection of study data and reporting of 
results 
7. Co-investigator— Collection of study data and reporting of 
results 
8. Co-investigator— Collection of study data and reporting of 
results 
9. Co-investigator— Collection of study data and reporting of 
results 
10. Co-investigator— Collection of study data and reporting of 
results 
11. Co-investigator— Collection of study data and reporting of 
results 
12. Co-investigator— Collection of study data and reporting of 
results 
13. Co-investigator— Collection of study data and reporting of 
results 
14.  Co-investigator— Collection of study data and reporting of 
results 
15. Co-investigator— Collection of study data and reporting of 
results 
16. Co-investigator— Collection of study data and reporting of 
results 
17. Co-investigator— Collection of study data and reporting of 
results 
18. Co-investigator— Collection of study data and reporting of 
results 
19.  ED Physicians- The unblinded ED physician will assist with 
collection of study data and reporting of results 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 17 of 19 
Version date: 4-4-19 
 
 
20. Surgical fellow- Collection of study data and reporting of results 
21. Pharmacist— drug acquisition, storage, randomization/blinding 
and administration.  
22. Research Manager—Collection of study data, data entry, IRB  
management 
23. Data Manager—data acquisition, data analysis, and electronic 
medical records review.  
24. Research Coordinator— patient recruitment, administering 
consent, and performing data collection 
 
 
25) 
Provisions to Protect the Privacy Interests of Subjects 
In the emergency department, potential subjects will be approached 
by one of the PI’s or clinical research coordinator to gauge interest 
in participating. If the subject declines, no other attempts will be 
made.  
In order to help the subjects feel at ease, all conversations will be 
discreet and will occur in private patient areas.  
Only the PI and research staff is permitted to access information 
about the subject in regards to the study. 
 
26) 
Compensation for Research-Related Injury 
  Subjects are instructed that it is important they promptly tell the person in     
charge if they believe that they have been injured because of taking part  
in this study. For subjects who are injured as a result of being in this study, 
the University of California will provide necessary medical treatment. 
Depending on the circumstances, the costs of the treatment may be 
covered by the University or may be billed to the subject’s insurance 
company just like other medical costs. 
 
27) 
Economic Burden to Subjects                                                               
There are no perceived costs for subject participation in this study. 
 
28) 
Consent Process 
• Consent will be performed by either one of the PI’s, co-
investigators or a clinical research coordinator.  
• Consent will take place at UC Davis Medical Center, 2315 
Stockton Blvd., Sacramento, CA 95817. 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 18 of 19 
Version date: 4-4-19 
 
 
• Prospective subjects will be provided the consent form in person 
during their hospital admission. They will be given sufficient time 
to review the consent form and discuss with friends and family. 
We will ensure that subjects’ questions have been answered 
prior to the consent form being signed.  
• Patients will be re-consented if changes to the protocol affect 
their study involvement or the risks change. 
• The PI will be following “SOP: Informed Consent Process for 
Research (HRP-090).” 
• Potential subjects will be advised that study participation is 
voluntary and refusal to participate will involve no penalty or loss 
of benefits to which they would be otherwise entitled. They will 
be advised that participation in this study may not provide any 
benefit(s) to them. They will also be advised of the potential 
risks and alternate treatment options, and they will be given 
sufficient time to consider their decision.  
• Subjects must be at least 18 years old to participate in this 
study. 
 
HIPAA Authorization for Research  
A HIPAA Authorization will be signed by each subject during the 
initial consent process. 
 
 Non-English Speaking Subjects  
 
 Non-English speaking subjects are not excluded from participation in this 
 study. For potential subjects who do not speak English, current UC Davis 
 IRB policies HRP-090 and HRP-091 for enrolling such subjects will be 
 adhered to.  
 
Waiver or Alteration of the Consent Process (consent will not be 
obtained, required information will not be disclosed, or the research 
involves deception)  
N/A  
 
Subjects who are not yet adults (infants, children, teenagers)  
N/A  
 
Cognitively Impaired Adults  
 
This study is not designed to enroll cognitively-impaired subjects. 
 

IND 128561 
Bupivacaine 
UCDMC/Brown 
 
Page 19 of 19 
Version date: 4-4-19 
 
 
29) 
Process to Document Consent in Writing 
Informed consent for this study will be documented in writing per 
SOP HRP-091, Written Documentation of Consent. 
 
30) 
Drugs or Devices 
     The blinding and drug preparation will be performed by the investigational    
 
drug service (IDS) at UCDMC.  Following informed consent, patients will 
undergo computer generated, blinded block, 1:1 randomization. The 
blinding will be maintained up to the time of breaking the seal for drug 
administration. Necessary measure will be followed to maintain patient 
blinding.  An ultrasound guided fascia iliaca compartment block (FICB) 
with either 266mg (60 ml) of liposomal bupivacaine or 120mg (60 ml) of 
0.2% ropivacaine. Both groups will be able to receive as needed analgesia 
per the primary attending service. (e.g., oral hydrocodone/acetaminophen 
5/325 mg or narcotic IV push as needed for breakthrough pain).  Patients 
will remain blinded throughout the hospitalization.   
 
a) The involved drugs are:  
i)  Liposomal bupivacaine (Exparel®, Pacira Pharmaceuticals, 
Parsippany, NJ) is a long-acting formulation of bupivacaine HCl, an 
amide-type local anesthetic/analgesic that is FDA approved for single 
dose infiltration into a surgical site to provide post-surgical analgesia.  
After local administration, bupivacaine is slowly released from the 
liposomes resulting in prolonged plasma levels and analgesia for 96 
hours.   
ii) Ropivacaine HCl(Naropin®, AstraZeneca Pharmaceuticals) is an 
amide-type local anesthetic/analgesic which is FDA approved for local 
and regional anesthesia for acute pain management.  This includes 
local infiltration, regional nerve and epidural blocks, both single dose 
and continuous infusion.