Conditions: Bunionectomy Hallux Valgus
Keywords: EXPAREL Bupivacaine Analgesia
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 185
Healthy volunteers: no

Brief summary:
The study is conducted sequentially in two parts.

Part A: The purpose is to obtain information on pharmacokinetic (PK) profile, pharmacodynamics (PD), efficacy, safety, and to assess the performance of 266 mg EXPAREL vs 133 mg EXPAREL.

Part B: The purpose is to evaluate the efficacy and safety of the preferred dosage of EXPAREL from Part A compared with bupivacaine HCl.

Detailed description:
This is a Phase 3, multicenter, randomized, double-blind, active controlled study in approximately 180 subjects undergoing bunionectomy. The study will be conducted in two parts (Part A and Part B). Part A will be completed and analyzed before enrollment in Part B is initiated.

Subjects may be screened up to 45 days prior to the day of surgery but eligibility must be re-confirmed on the day of surgery prior to randomization.

The following screening procedures will be performed after the informed consent form (ICF) is signed (if not standard of care): assess eligibility, record medical/surgical history, record prior and concomitant medications, record demographics and baseline characteristics, record subject height and weight for body mass index (BMI) calculation, assess chronic opioid use in the past 30 days, conduct urine pregnancy test for women of childbearing potential, perform 12-lead EKG, record serious adverse events (SAEs) starting when the ICF is signed, and record medications for treatment of SAEs.

On Day 1, prior to sciatic nerve block, study staff will review Pain Rating Guide with the subject and record their responses to:

* Numeric rating scale (NRS) score on the worst pain of their operative foot in the last 30 days.
* NRS score on the average pain of their operative foot in the last 30 days.

Part A will enroll approximately 60 subjects undergoing bunionectomy into 1 of 3 arms. They will be randomized 1:1:1 to either EXPAREL 266 mg, EXPAREL 133 mg, or 0.25% bupivacaine HCl (50mg). Part A subjects will be asked to perform sensory function assessments, perform motor function assessments and obtain PK samples. Based on the findings of the interim analysis after completion of Part A, the study may stop for futility or proceed to Part B. Part B is a 2-arm study with 120 subjects being randomized 1:1 to either the better performing dosage of EXPAREL from Part A (266mg or 133mg) or 0.25% bupivacaine HCl (50mg).

All eligible subjects will receive Celecoxib 200 mg, orally (PO) pre-operatively within four hours prior to surgery.

Part A: On Day 1, Subjects will be randomized (1:1:1) to receive a sciatic (in the popliteal fossa) nerve block with a single dose of either: EXPAREL 266 mg, EXPAREL 133 mg, or 0.25% bupivacaine HCl (50 mg).

Part B: will continue enrolling with one of the EXPAREL arms (EXPAREL 266 mg arm or EXPAREL 133 mg arm) and the bupivacaine HCl arm. Therefore, the EXPAREL study arm that fails to show efficacy (conditional power less than 30% in the Part A analysis) will be dropped and the study will continue with two study arms. The final analysis will include subjects from both Part A and Part B.

1. If the conditional power of one EXPAREL arm is less than 30% and the other EXPAREL arm is greater than or equal to 30%:

   * The EXPAREL arm with conditional power less than 30% will be dropped in Part B.
2. If both EXPAREL arms have a conditional power greater than or equal to 30%:

   * If the conditional power of the 266 mg EXPAREL arm is more than 10% greater than the conditional power of the 133 mg EXPAREL arm, then the 266 mg EXPAREL arm will be kept and the 133 mg EXPAREL arm will be dropped. Otherwise, the 133 mg EXPAREL arm will be kept and the 266 mg EXPAREL arm will be dropped in Part B.
3. If the conditional power of both treatment arms is less than 30%:

   * The study will stop for futility

All subjects will receive a dose of 1000 mg of intravenous (IV) acetaminophen at the time of surgical incision. All subjects will receive one post-operative dose of 1000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). The maximum total dose will not exceed 2000 mg. No additional acetaminophen is permitted after the second IV acetaminophen dose.

Medications will be administered on an as needed (PRN) basis; opioids should not be given on a predetermined schedule.

After 96 hours, the analgesic regimen may be adjusted for each subject individually as deemed appropriate by the physician responsible for postsurgical care.

NRS Pain intensity scores (for pain experiencing in operative foot right now, for the worst pain experienced in the operative foot in the last 24 hours, and for the average pain in the operative foot in the last 24 hours) will be asked from the end of surgery to 96 hours post-surgery at designated timepoints.

Subjects in Part A and Part B will be discharged after the completion of the 168h and 96h assessments, respectively.

For the assessment of adverse events (AEs), SAEs, and concomitant medication use, a follow-up phone call will be made on Post Surgery Day (POD) 14 (±3 days).

Arms:
arm 1: subjects randomized to this treatment arm will receive 20 mL (266 mg) EXPAREL mixed with 10 mL saline arm 2: subjects randomized to this treatment arm will receive 10 mL (133 mg) EXPAREL mixed with 20 mL saline arm 3: Subjects randomized to this treatment arm will receive 20 mL (50 mg) 0.25% bupivacaine HCl mixed with 10 mL saline arm 4: Subjects randomized to this treatment arm will receive 20 mL (266 mg) EXPAREL mixed with 10 mL saline OR 10 mL (133 mg) EXPAREL mixed with 20 mL saline. Dose will be determined following interim analysis of Part A. arm 5: subjects randomized to this treatment arm will receive 20 mL (50 mg) 0.25% bupivacaine HCl mixed with 10 mL saline

Interventions: intervention 1: Bupivacaine liposome injectable suspension 266 mg intervention 2: Bupivacaine HCl intervention 3: Bupivacaine liposome injectable suspension 133 mg
Intervention descriptions: intervention 1: Sciatic nerve block in the popliteal fossa with EXPAREL 266 mg intervention 2: Sciatic nerve block in the popliteal fossa with Bupivacaine HCl intervention 3: Sciatic nerve block in the popliteal fossa with EXPAREL 133 mg

Protocol document:
Prot_000.pdf: 
Pacira Pharmaceuticals, Inc. 
 
 
 
DISCLOSURE: REDACTED CLINICAL STUDY PROTOCOL AMENDMENT 2 
 
Title: A Phase 3, Randomized, Double-Blind, Active-Controlled, Multicenter Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of EXPAREL vs. Bupivacaine HCl Administered as a Sciatic (in 
the Popliteal Fossa) Nerve Block for Postsurgical Analgesia in Subjects Undergoing Bunionectomy 
NCT Number: NCT05157841 
Protocol Number: 402-C-334 
 
Clinical Study Protocol Amendment 2, Approval Date: 24-Feb-2022 
 
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black bar) to protect either personally identifiable information or company confidential 
information.  
 
This may include, but is not limited to, redaction of the following: 
 
• 
Named persons or organizations associated with the study. 
• 
Proprietary information, such as scales or coding systems which are considered confidential 
information under prior agreements with license holder. 
• 
Other information as needed to protect confidentiality of Pacira Pharmaceuticals, Inc. or partners, 
personal information, or to otherwise protect the integrity of the clinical study.  
 
The information contained in the following document is the property of Pacira Pharmaceuticals, Inc. and 
should not be shared or used for any purpose other than for which it was provided. 


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Pacira Pharmaceuticals, Inc. 
 
    402-C-334 (Sciatic Nerve Block) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
6 of 73  
24 Feb 2022 
 
Treatment Arms for Part B: 
On the day of surgery, subjects will receive an ultrasound-guided sciatic (in the popliteal fossa) nerve block 
with one of the following treatments: 
• 
EXPAREL 266 arm: subjects randomized to this treatment arm will receive 20 mL (266 mg) 
EXPAREL mixed with 10 mL saline 
OR 
EXPAREL 133 arm: subjects randomized to this treatment arm will receive 10 mL (133 mg) 
EXPAREL mixed with 20 mL saline 
• 
Bupivacaine HCl arm: subjects randomized to this treatment arm will receive 20 mL (50 mg) 
0.25% bupivacaine HCl mixed with 10 mL saline 
Block Procedure:  
Subjects may be lightly sedated with 1 to 2 mg of midazolam intravenously (IV) before the block procedure. 
The study drug (EXPAREL 266 mg, EXPAREL 133 mg, or bupivacaine HCl) will be administered under 
ultrasound guidance 90 min (±30 min) prior to surgery. A confirmatory ultrasound video will be taken during 
hydrodissection and infiltration of the study drug, with the needle in place to ensure accurate block placement. 
The Investigator will provide the videos to the sponsor within 24 hours from end of the block procedure that 
will be reviewed by an independent ultrasound adjudication committee to evaluate the accuracy of study drug 
administration. Only two unblinded study drug administrators (anesthesiologist) will be assigned per site to 
perform the block procedures, unless approved in advance in writing by the Sponsor on a case-by-case basis. 
The designated study drug administrators (anesthesiologist) will not participate in any other study related 
assessments after randomization. 
A peripheral nerve stimulator will be used before infiltrating the study drug to obtain a response (i.e., muscle 
twitch). 
For all study arms, a total volume of 30 mL will be administered as a sciatic nerve block (in the popliteal 
fossa).  
 
Pre-operative Medication and Anesthesia:  
All eligible subjects will also receive the following medication within four hours prior to surgery: 
• 
Celecoxib 200 mg, orally (PO). 
Gabapentinoids will not be allowed. 
 
Anesthesia and Intra-operative Medication: 
All subjects in Part A and Part B will receive a Mayo field block with 20mL 0.5% bupivacaine HCl 
after study drug administration (i.e., in the operating room immediately prior to surgical incision). The 
Mayo field block should be performed by the surgeon. 
 
All subjects will receive a dose of 1000 mg of intravenous (IV) acetaminophen at the time of surgical incision. 
 
Propofol is permitted for induction and intra-operative sedation. Intravenous (IV) Fentanyl will be allowed 
for intraoperative pain control (Fentanyl dose not to exceed 1 ug/kg unless deemed medically necessary). 
 
Further details on allowed/restricted perioperative medications are included in protocol Section 11.6.1 and 
Section 11.6.2.  
 
Study Schema:   


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Table 1: 
Time and Events Schedule of Study Procedures (Screening through Day 14) 
 
 
Screen-
ing 
Visit1  
Day of 
Surgery 
(Prior to 
Surgery) 
O
R 
P
A
C
U 
Time from End of Surgery (h) 
 
Health 
Care 
Facility
Dis-
charge3 
POD 
14 Call 
±3 
days 
6 
±2 
12 
±2 
18 
±2 
24 
±2 
30 
±2 
36 
±2 
42 
±2 
48 
±2 
54 
±2 
60 
±2 
66 
±2 
72 
±2 
78 
±3 
84 
±3 
90 
±3 
96 
±3 
120-168 
±32 
Obtain ICF* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility * 
X 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record medical/ surgical 
history* 5   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect height/weight for 
BMI calculation* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
characteristics* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record prior and 
concomitant medications 5 
X 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for 
WOCBP 
X 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform 12-lead EKG6 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Review Pain Rating Guide 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record worst and average 
pain (NRS) in the last 
30 days 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize subject; prepare 
study drug 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record pre-op and post-op 
scheduled medications7  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Capture ultrasound video for 
nerve block and send to 
sponsor 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Mayo field block 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record block start/end 
times8     
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record surgery start and end 
times 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record intra-op medication 
administered   
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record PACU time in and 
out 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: AE=adverse event; BMI=Body Mass Index; h=hour(s); HCF=health care facility; ICF=informed consent form; IPO=International Pain Outcome; min=minute(s); 
NRS=numeric rating scale; NSAID=nonsteroidal anti-inflammatory drug; OR=Operating Room; PACU=Post-Anesthesia Care Unit; PO=by mouth/orally administered; POD=Post-
operative Day; SAE=serious adverse event; WOCBP=women of childbearing potential. 
 
*  No more than 45 days before scheduled surgery day 
1. Subjects may be screened on the same day as health care facility admission/surgery (with ample time for the informed consent process) or up to 45 days prior to surgery but 
eligibility will be re-confirmed on day the of surgery prior to randomization. Screening procedures that are standard of care at the institution may be completed prior to written 
informed consent. Any screening procedures that are not SOC must be completed after written informed consent is obtained. 
2. For Part A subjects only: A 12-lead EKG will be performed, and Vital sign will be measured and recorded at additional time points 120 (±3h), 144 (±3h), and at 168 (±3h). 
3.   Subjects in Part A and Part B will be discharged after 168 h and 96 h assessments, respectively. 
4. Eligibility, prior medications, urine pregnancy test and urine drug screen to be assessed prior to randomization; review of Pain Rating Guide and worst and average pain scores 
over the previous 30 days to be assessed prior to study drug administration. 
5. Relevant medical/surgical history within the last 5 years (including all ongoing history, regardless of start date) should be recorded, with the exception of history that is relevant 
to the surgery, in which case all years should be recorded.  Prior medications taken within 30 days of randomization (including all ongoing medications, regardless of start date) 
will be recorded. 
 
 
 
O
R 
P
A
C
U 
Time from End of Surgery (h) 
 
 
 
 
Screen-
ing 
Visit1 
Day of 
Surgery 
(Prior to 
Surgery) 
6 
±2 
12 
±2 
18 
±2 
24 
±2 
30 
±2 
36 
±2 
42 
±2 
48 
±2 
54 
±2 
60 
±2 
66 
±2 
72 
±2 
78 
±3 
84 
±3 
90 
±3 
96 
±3 
120-168 
±32 
Health 
Care 
Facility
Dis-
charge3 
POD 
14 
Call 
±3 
days 
Record scheduled NRS 
scores9,10 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Measure and record vital 
signs11 
 
X4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record scheduled worst and 
average NRS scores (24-
hour recall)9,10 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Record unscheduled NRS 
immediately prior to 
breakthrough pain 
medication12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record breakthrough pain 
medication12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record day and time of HCF 
admission and discharge 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Record AEs/SAEs13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform unscheduled 
neurological assessment14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject satisfaction 
questionnaire (IPO) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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6.  A baseline 12-lead EKG must be performed at screening visit. A 12-lead EKG must be performed if a subject experiences an AESI or an SAE (see footnote 15) 
7.   Record all pre-operative and post-operative scheduled analgesic medication (celecoxib and acetaminophen). 
8. Block to be administered 90 min (±30 min) prior to surgery.  
9. The NRS pain intensity assessment should not be completed after any physical activity, including the motor block assessment. If that is not possible, to assess pain intensity at 
rest, the subject should rest quietly in a supine or seated position that does not exacerbate subject’s postsurgical pain for 5-10 minutes before assessing the pain score using the 
NRS.  If a subject is asleep, the subject will not be awakened to assess pain. If the subject awakens within the assessment window, a pain score will be collected then.  
10. Pain scores (24 h recall) once daily (i.e., worst/average pain) will be collected at 24 (±2 h), 48 (±2 h), 72 (±2 h), and 96 (±3 h) post-surgery. Pain scores (current pain) will be 
collected by the study staff beginning at PACU admission (±5 min); q15 min in PACU (±5 min); at PACU discharge (±5 min) then q6h (±2 h) from end of surgery to 72 hours 
post-surgery and q6h (±3 h) from 78-96 hours post-surgery.  
11. Vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation and blood pressure) will be measured after the subject has rested in a supine position for at least 5 
minutes. Vital signs will be measured before study drug administration, upon arrival in the PACU (±5 min), at PACU discharge (±5 min), then q6h (±2 h) from end of surgery 
to 72 hours post-surgery and q6h (±3 h) from 78-96 hours post-surgery, and at hospital discharge. Additionally, for Part A subjects: 120 h (±3 h), 144 h (±3 h), and 168 h (±3 h). 
Vital signs must be measured and recorded if a subject experiences an AESI or an SAE (see footnote 15) 
12. Oxycodone will be administered on an as needed (PRN) basis for breakthrough pain through 96 hours post-surgery; opioids should not be given on a pre-determined schedule. 
Immediate release oral (PO) oxycodone will be administered in a stepwise approach: 
• 
Initial dose of 5 mg oxycodone may be offered. 
• 
If the initial opioid dose is insufficient for pain relief, an additional 5 mg oxycodone may be offered up to a maximum of 10 mg (total dose). 
 If a subject is unable to tolerate PO medication (or the PO oxycodone pain relief is insufficient), IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) may 
be administered.   
13.  Document all AEs with an onset after the subject is randomized and SAEs with an onset after the subject signs the ICF. 
14. An unscheduled neurological assessment will be conducted once daily if a subject experiences an AESI or an SAE, until resolution of symptoms (see footnote 15). 
15. In case an AE of special interest (AESI) or serious AE (SAE) occurs during the study, if the investigator or medical monitor considers that the event may be related to study 
treatment or suggests the possible occurrence of local anesthetic systemic toxicity (LAST; with or without the need for treatment [e.g., intralipids]), an unscheduled PK blood 
sample, 12-lead EKG, and vital signs must be collected. Neurological assessments will be conducted according to the study site’s standard of care at least once daily until 
resolution of symptoms. 
 
 
 


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Table 2: 
Pharmacokinetic and Pharmacodynamic Assessments (Part A Subjects only) 
 
 
Post-study Drug Administrationa 
 
 
Day of Study Drug Administration to Post-operative Day 4 (POD 4) 
POD 5 
POD 6 
POD 7 
Time Window 
Up to 
15 mins 
before 
blocks 
15m 
30m 
45m 
1h 
2h 
8h 
12h 
24h 
30h 
48h 
60h 
72h 
84h 
96h 
120h 
144h 
168h 
±5m 
±5m 
±5m 
±15m 
±30m 
±30m 
±30m 
±1h 
±1h 
±1h 
±2h 
±2h 
±2h 
±3h 
±3h 
±3h 
±3h 
Collect PK blood 
sample; Record 
date and time of 
blood sampleb 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess and record 
sensory and 
motor functionc,d  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: h=hour; m=minute; PK=pharmacokinetic 
a. 
All timepoints are from end of block administration. 
b. 
An unscheduled PK sample must be collected if a subject experiences an AESI or an SAE (see footnote 15 in Table 1) 
c. 
Once the offset of light touch sensation is recorded and documented in both locations, no further scheduled sensory assessments are required. Once the offset of motor block 
is recorded and documented, no further scheduled motor assessments are required. Pharmacodynamic assessments must be performed by blinded, trained, licensed medical 
staff (e.g., Physician, Registered Nurse, Physician Assistant) and documented on the Investigator’s study delegation log. A limited number of study staff should perform the 
sensory/motor assessments.  
d. When subject is in surgery, no sensory or motor function assessments will be conducted. 


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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ....................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS ...........................................................................................18 
4. 
LIST OF ACRONYMS/ABBREVIATIONS .............................................................23 
5. 
ETHICS ......................................................................................................................25 
5.1. 
Institutional Review Board/Independent Ethics Committee ......................................25 
5.2. 
Ethical Conduct of the Study ......................................................................................25 
5.3. 
Subject Information and Consent ...............................................................................25 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE .................25 
7. 
INTRODUCTION ......................................................................................................25 
7.1. 
Indication ....................................................................................................................26 
7.2. 
Current Therapies/Treatments ....................................................................................26 
7.3. 
EXPAREL (Bupivacaine Liposome Injectable Suspension) ......................................27 
7.4. 
Summary of Human Experience with EXPAREL ......................................................28 
7.5. 
Rationale for the Study ...............................................................................................28 
8. 
OBJECTIVES .............................................................................................................29 
8.1. 
Primary Objective .......................................................................................................29 
8.2. 
Secondary Objectives .................................................................................................29 
9. 
OVERALL STUDY DESIGN AND PLAN ...............................................................29 
9.1. 
Study Design ...............................................................................................................29 
9.2. 
Duration of the Study and Subject Participation ........................................................30 
9.2.1. 
Study Stopping Rules .................................................................................................31 
9.3. 
Discussion of Study Design ........................................................................................31 
10. 
STUDY POPULATION .............................................................................................32 
10.1. 
Inclusion Criteria ........................................................................................................32 
10.2. 
Exclusion Criteria .......................................................................................................32 
10.3. 
Removal of Subjects from Therapy or Assessment ....................................................33 
10.3.1. 
Withdrawal Secondary to Adverse Events .................................................................34 
10.3.2. 
Voluntary or Study Investigator Withdrawal .............................................................34 


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10.3.3. 
Early Termination Assessments .................................................................................35 
11. 
TREATMENTS ..........................................................................................................35 
11.1. 
Treatments to be Administered ...................................................................................35 
11.1.1. 
Study Drug Administration Considerations................................................................36 
11.1.2. 
Bupivacaine HCl Administration Considerations ......................................................36 
11.2. 
Identity of the Investigational Products ......................................................................37 
11.2.1. 
Description of EXPAREL ..........................................................................................37 
11.2.2. 
Description of Reference Product ...............................................................................37 
11.2.3. 
Description of Volume Expansion Agent ...................................................................37 
11.3. 
Method of Assigning Subjects to Treatment ..............................................................37 
11.3.1. 
Randomization Scheme ..............................................................................................37 
11.3.2. 
Randomization Procedures .........................................................................................37 
11.3.3. 
Replacement of Subjects .............................................................................................37 
11.4. 
Selection of Doses in the Study ..................................................................................38 
11.5. 
Blinding ......................................................................................................................38 
11.5.1. 
Unblinding Procedures ...............................................................................................38 
11.5.2. 
Blinding Procedure .....................................................................................................38 
11.6. 
Prior and Concomitant Therapy and Medications ......................................................39 
11.6.1. 
Prior to Study Drug Administration ...........................................................................39 
11.6.2. 
Perioperative ...............................................................................................................40 
11.6.3. 
Post-surgery ................................................................................................................41 
11.7. 
Postsurgical Pain Medication for Breakthrough Pain .................................................41 
11.8. 
Treatment Compliance ................................................................................................42 
11.9. 
Accountability of Study Drug .....................................................................................42 
12. 
STUDY ENDPOINTS AND MEASUREMENTS ....................................................42 
12.1. 
Efficacy Assessments .................................................................................................42 
12.2. 
Efficacy Endpoints ......................................................................................................43 
12.3. 
Safety Assessments .....................................................................................................43 
12.4. 
Safety Endpoints .........................................................................................................43 
12.5. 
Pharmacokinetic Assessments (Part A Subjects) .......................................................44 
12.6. 
Pharmacokinetic Endpoints (Part A Subjects) ............................................................44 
12.7. 
Pharmacodynamic Assessments (Part A Subjects).....................................................44 


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12.8. 
Pharmacodynamic Endpoints (Part A Subjects) .........................................................45 
12.9. 
Appropriateness of Measures .....................................................................................45 
13. 
STUDY PROCEDURES ............................................................................................45 
13.1. 
Instructions for Conducting Procedures and Measures ..............................................46 
13.1.1. 
Pain Intensity Assessment ..........................................................................................46 
13.1.2. 
Subject Satisfaction with Postsurgical Pain Control ..................................................47 
13.1.3. 
Pharmacokinetic Assessments (Part A Subjects) .......................................................47 
13.1.4. 
Pharmacodynamic assessment (Part A Subjects) .......................................................47 
13.2. 
Study Procedures ........................................................................................................47 
13.2.1. 
Obtaining Informed Consent ......................................................................................47 
13.2.2. 
Screening ....................................................................................................................48 
13.2.3. 
Baseline Procedures (Prior to Study Drug Administration) .......................................48 
13.3. 
Nerve Block Procedure ...............................................................................................49 
13.3.1. 
Procedures for Sciatic (in the Popliteal Fossa) Nerve Block ......................................50 
13.4. 
Post-Block Assessments .............................................................................................50 
13.5. 
Mayo Field Block Procedure ......................................................................................51 
13.5.1. 
Procedures for Mayo Field Block ...............................................................................51 
13.6. 
Intraoperative Procedures ...........................................................................................51 
13.7. 
Post-Anesthesia Care Unit Procedures .......................................................................52 
13.8. 
Postsurgical Assessments from End of Surgery through Discharge ..........................52 
13.9. 
Health Care Facility Discharge ...................................................................................53 
13.10. 
Unscheduled Visits .....................................................................................................54 
13.11. 
Postsurgical Day 14 Phone Call .................................................................................54 
14. 
ADVERSE EVENT REPORTING ............................................................................54 
14.1. 
Adverse Events ...........................................................................................................54 
14.1.1. 
Definitions ..................................................................................................................54 
14.1.2. 
Recording Adverse Events .........................................................................................55 
14.1.3. 
Severity of Adverse Events ........................................................................................55 
14.1.4. 
Relationship of Adverse Events to Study Drug ..........................................................56 
14.1.5. 
Outcome of Adverse Events .......................................................................................56 
14.1.6. 
Action Taken with Subject Due to an Adverse Event ................................................57 
14.1.7. 
Adverse Events of Special Interest .............................................................................57 


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14.2. 
Serious Adverse Events ..............................................................................................58 
14.2.1. 
Definition of a Serious Adverse Event .......................................................................58 
14.2.2. 
Reporting Serious Adverse Events .............................................................................59 
15. 
STATISTICAL METHODS .......................................................................................59 
15.1. 
Study Hypothesis ........................................................................................................59 
15.2. 
Study Endpoints ..........................................................................................................60 
15.3. 
Determination of Sample Size ....................................................................................60 
15.4. 
Analysis Populations ..................................................................................................60 
15.5. 
Handling Subject Dropouts and Discontinuations ......................................................61 
15.6. 
Statistical Analyses .....................................................................................................61 
15.6.1. 
Baseline Characteristics ..............................................................................................61 
15.6.2. 
Study Procedure Compliance .....................................................................................61 
15.6.3. 
Efficacy Analyses .......................................................................................................61 
15.6.4. 
Safety Analyses ..........................................................................................................62 
15.6.4.1. 
Pharmacokinetic Analyses ..........................................................................................62 
15.6.4.2. 
Adverse Events ...........................................................................................................62 
15.7. 
Significance Testing ...................................................................................................62 
15.8. 
Interim Analyses .........................................................................................................62 
16. 
REFERENCES ...........................................................................................................64 
17. 
INVESTIGATOR AGREEMENT .............................................................................66 
18. 
APPENDICES ............................................................................................................67 
18.1. 
Appendix 1: Pain Intensity Scores using the Numeric Rating Scale (NRS) ..............68 
18.2. 
Appendix 2: Subject Satisfaction Questionnaire ........................................................69 
18.3. 
Appendix 3: Sensory Function Assessment (Light Touch Test) (Part A 
Subjects) .....................................................................................................................70 
18.4. 
Appendix 4: Motor Function Test (Part A Subjects) ..................................................72 
18.5. 
Appendix 5: ASA Physical Status Classification System ..........................................73 
 
 
LIST OF TABLES 
Table 1: 
Time and Events Schedule of Study Procedures (Screening through Day 14) ..........14 
Table 2: 
Pharmacokinetic and Pharmacodynamic Assessments (Part A Subjects only) ..........17 


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LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................30 
 
 
 


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4. 
LIST OF ACRONYMS/ABBREVIATIONS 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ASA 
American Society of Anesthesiologists 
AUC 
Area Under the Curve 
BMI 
Body mass index 
Cmax 
Maximum plasma concentration 
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CL/F 
Apparent clearance 
CRF 
Case report form 
d 
Day 
eCRF 
Electronic case report form 
ED 
Emergency Department 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCF 
HCl 
Health care facility 
Hydrochloride 
h 
Hour(s) 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IPO 
International Pain Outcome 
IRB 
Institutional Review Board 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric rating scale 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
OMED 
Oral morphine equivalent 
OR 
Operating room 
PACU 
Post-anesthesia care unit 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PO 
Oral 
POD 
Post-operative day 
PRN 
As needed 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
t1/2el 
Apparent terminal elimination half-life 
Tmax 
Time to maximum plasma concentration 
TEAE 
Treatment-emergent adverse event 


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THC 
Tetrahydrocannabinol 
US 
United States 
Vd 
Apparent volume of distribution 
 


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5. 
ETHICS 
5.1. 
Institutional Review Board/Independent Ethics Committee 
Prior to enrolling subjects into this study, each study site will obtain the approval of an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) that complies with the International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) and/or the United States (US) 
Food and Drug Administration (FDA) Title 21 Code of Federal Regulations (CFR) Part 56. 
Attention is directed to the basic elements that are required to be incorporated into the informed 
consent form (ICF) under 21 CFR Part 50.25 and ICH GCP. 
5.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the clinical research guidelines established by the 
FDA Title 21 CFR, Parts 50, 54, 56, and 312, and the ICH GCP. Study documents will be 
maintained in accordance with applicable regulations. 
5.3. 
Subject Information and Consent 
Before a subject undergoes any study-specific screening procedures, the Investigator or designee 
will thoroughly explain to the subject the purpose of the study, the associated procedures, and any 
expected effects and potential adverse reactions. A copy of the IRB-approved ICF will be provided 
to the subject, who will be given sufficient time and opportunity to inquire about the details of the 
study and decide whether or not to participate. The subject, and the study staff with whom he or 
she discusses the ICF, will sign and date the ICF. A photocopy of the signed ICF will be given to 
the subject. 
The Investigator will explain to the subject that he or she is completely free to decline entry into 
the study and may withdraw from the study at any time, for any reason, without risking his or her 
medical care. Similarly, the Investigator and/or Pacira Pharmaceuticals, Inc. (“Pacira”) will be free 
to withdraw the subject at any time for safety or administrative reasons. Any other requirements 
necessary for the protection of the human rights of the subject will also be explained, according to 
the current ICH GCP (E6) and the Declaration of Helsinki (1964, and as amended through 2000 
[Edinburgh]).  
6. 
INVESTIGATORS AND STUDY ADMINISTRATION 
STRUCTURE 
Information regarding the Investigators, study sites, laboratories, and other service providers is 
available upon request to the IRB/IECs and regulatory agencies. 
7. 
INTRODUCTION 
Postsurgical pain is one of the most common forms of acute pain (Schug 1993; Carr 1999).  
In contrast to chronic pain, for which no adaptive value has been demonstrated, acute pain is the 
normal physiological response to tissue insult or injury and has adaptive value by serving as a 
warning of danger or damage.  Most acute pain is either treatable or avoidable, especially when it 
occurs in a clinical setting.  However, if acute pain is poorly or inappropriately treated, it may 


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progress to chronic pain (Perkins 2000; Petersen-Felix 2002).  Thus, effectively modulating the 
response to acute pain may be considered a primary step in the prevention of chronic pain (Stephen 
2003).  The suboptimal management of acute pain has been recognized as a problem by clinicians 
for more than 50 years (Papper 1952; Marks 1973) and has been formally identified as a public 
health concern by various societies and government institutions worldwide.   
In 1992, the US Agency for Health Care Policy and Research developed guidelines for the 
management of postoperative pain in the hopes of increasing awareness of the consequences of 
poor pain control in the postoperative setting and promoting better pain management techniques 
(Stephen 2003).  These consequences, which include delayed healing, longer hospitalization, and 
the development of chronic pain, are significant not only from the patient’s perspective (decrease 
in functionality and quality of life) but also from the health economic perspective (increase in 
healthcare resource utilization and costs).  
A multimodal approach to postoperative analgesia, using a combination of agents (e.g., opioids, 
local anesthetics, non-steroidal anti-inflammatory drugs [NSAIDs]), and delivery techniques 
(patient-controlled analgesia, epidural and regional blocks) is currently recognized as best practice 
for pain management (Breivik 1995a; Breivik 1995b; American Society of Anesthesiologists 
[ASA] Task Force 1995; Dahl 2000).  
EXPAREL® was developed to extend pain relief with a single-dose administration without the 
use of indwelling catheters and to decrease the requirement for supplemental opioid medications.  
A New Drug Application (NDA) for EXPAREL was submitted as a 505(b)(2) application and 
subsequently approved by the US FDA on October 28, 2011 (NDA 022-496). On 2018, the FDA 
approved EXAPREL for interscalene brachial plexus nerve block for adults. On March 22, 2021, 
FDA approved EXPAREL use in patients 6 years of age and older for single-dose infiltration to 
produce postsurgical local analgesia.  
7.1. 
Indication 
EXPAREL was initially approved by the US FDA in 2011 for single-dose administration into the 
surgical site to produce postsurgical analgesia.  The indication was amended and approved by the 
US FDA in 2018 to read: “EXPAREL is indicated for single-dose infiltration in adults to produce 
postsurgical local analgesia and as an interscalene brachial plexus block to produce postsurgical 
regional analgesia.  Safety and efficacy have not been established in other nerve blocks.”   
The indication was further amended and approved by the US FDA in March 2021 to read: 
“EXPAREL is indicated: 
• In patients aged 6 years and older for single-dose infiltration to produce postsurgical local 
analgesia 
• In adults as an interscalene brachial plexus nerve block to produce postsurgical regional 
analgesia.” 
7.2. 
Current Therapies/Treatments 
Effective postsurgical pain control is a critical element in patient recovery following surgery, as the 
majority of patients may experience significant pain, particularly in the first few days.  Improved 


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postsurgical pain management contributes to better healing, faster patient mobilization, shortened 
hospital stays, and reduced healthcare costs (ASA Task Force 1995). 
Current modalities of postsurgical analgesic treatment include infiltration and nerve block with 
local anesthetic agents, usually combined with the systemic administration of analgesics 
(multimodal therapy).  Multimodal therapy usually includes opioid medications, NSAIDs, and/or 
acetaminophen provided through a variety of routes including intravenous, transdermal patch, and 
oral administration.  Opioids are widely used and considered amongst the most powerful 
analgesics; however, they also have considerable drawbacks, including time and resources 
required for monitoring opioid-related side effects.  A reduction in the use of postoperative opioids 
is desirable to decrease the incidence and severity of opioid-induced adverse effects, such as 
respiratory depression, nausea, vomiting, constipation, somnolence, pruritus, and urinary 
retention.   
Postoperative pain is a predictable component of the postoperative process, which is often poorly 
managed, resulting in clinical and physiological changes that increase morbidity and mortality 
(inability to ambulate early, etc.), diminish quality of life, and extend length of stay, thereby 
increasing hospital expenditures (Oderda 2007) and reducing patient satisfaction.  Effective relief 
of acute pain with minimal opioid complications, on the other hand, may improve clinical 
outcomes, avoid complications (like delay in regaining bowel function or an inability to tolerate 
liquid and solid oral intake), and conserve healthcare resources.  As such, the Joint Commission 
on Accreditation of Healthcare Organizations (JCAHO) requires that all healthcare facilities 
practice adequate pain management and monitor opioid-related adverse events (AEs) (Apfelbaum 
2003). 
7.3. 
EXPAREL (Bupivacaine Liposome Injectable Suspension) 
Bupivacaine is one of the longer-acting local anesthetics, but even so it has a limited duration of 
action after local administration, usually less than 8 hours. EXPAREL (Pacira Pharmaceuticals, 
Inc., [“Pacira”]) is a bupivacaine liposome injectable suspension. It consists of microscopic 
spherical, multivesicular liposomes (DepoFoam® drug delivery system) organized in a 
honeycomb-like structure comprising numerous non-concentric internal aqueous chambers 
containing a bupivacaine base at a concentration of 13.3 mg/mL. Each chamber is separated from 
adjacent chambers by lipid membranes. The lipids (phospholipids, cholesterol, and triglycerides) 
are naturally occurring or close analogs of endogenous lipids. Bupivacaine is slowly released from 
the DepoFoam particles by a complex mechanism involving reorganization of the barrier lipid 
membranes and subsequent diffusion of the drug over an extended period of time.  
EXPAREL was approved by the US FDA in 2011 for administration into the surgical site to 
produce postsurgical analgesia. The active ingredient (bupivacaine) and inactive ingredient 
(DepoFoam) of EXPAREL are each contained, though separately, in FDA-approved products. 
• Bupivacaine hydrochloride (HCl) solution, a well-characterized anesthetic/analgesic, 
with more than 35 years of use in the US. 
• DepoFoam, a liposomal extended-release formulation contained in the marketed 
product DepoCyt® (1999). The form of DepoFoam used in EXPAREL has a slightly 
different mixture of liquid components than that used in DepoCyt. 


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7.4. 
Summary of Human Experience with EXPAREL 
As of July 2021, the EXPAREL clinical development program consists of 41 premarketing clinical 
studies: 21 Phase 1 studies, 7 Phase 2 studies, 13 Phase 3 studies; in addition, 21 Phase 4 
(postmarketing) studies have been completed. Since its approval, EXPAREL has been 
administered to over 9 million subjects in the US (Investigator’s Brochure). 
EXPAREL was well tolerated and had a favorable safety profile when administered as a field 
block, as an interscalene brachial plexus nerve block, and as a combined popliteal and adductor 
canal block in varying degrees of vascularity in subjects undergoing various surgical procedures.  
The frequency and types of events are consistent with the profile of other local anaesthetics.  
At doses up to 665 mg of EXPAREL, no central nervous system (CNS) or cardiovascular system 
AEs observed with high doses of bupivacaine hydrochloride (HCl) solution have been observed 
with EXPAREL. Two thorough QTc studies have been conducted; EXPAREL did not cause 
significant QTc prolongation even at the highest dose evaluated.   
Across all studies, the types and the incidence rates of treatment-emergent AEs (TEAEs) were 
similar between the EXPAREL All Doses group (all doses combined) and the bupivacaine HCl 
group.  The incidence rate for each of the three most common TEAEs (nausea, constipation, and 
vomiting) was lower in the EXPAREL All Doses group than in the bupivacaine HCl group.   
Study 402-C-333 was conducted to examine the magnitude and duration of the analgesic effect 
achieved with a single dose of EXPAREL and EXPAREL admixed with bupivacaine HCl 
administered as a combined popliteal and adductor canal block to subjects undergoing lower 
extremity surgeries. EXPAREL (133 mg) was demonstrated to be safe and well tolerated when 
administered as a single dose as a combined popliteal and adductor canal block. The most frequent 
AEs (ie, nausea, constipation, hypoaesthesia, headache) are consistent with those previously seen 
with EXPAREL [EXPAREL USPI], suggesting that administration as a combined block doesn’t 
alter the known safety profile of EXPAREL. 
Please see the EXPAREL Full Prescribing Information for safety information regarding the use of 
EXPAREL (liposome bupivacaine injectable suspension) for the treatment of postsurgical pain. 
Please refer to the Investigator’s Brochure for additional information regarding the completed 
studies.    
7.5. 
Rationale for the Study 
Pacira is investigating the pharmacokinetics (PK), efficacy, and safety of EXPAREL administered 
as a sciatic (in the popliteal fossa) nerve block in adult subjects undergoing bunionectomy.  
A dose of 20 mL (266 mg) EXPAREL with 10 mL of saline or a dose of 10 mL (133 mg) 
EXPAREL with 20 mL saline is expected to provide prolonged pain relief after this painful 
procedure compared with 20 mL (50mg) 0.25% bupivacaine HCl with 10 mL saline when injected 
in the sciatic nerve (in the popliteal fossa). 


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8. 
OBJECTIVES 
The study objectives following the administration of study drug as a sciatic (in the popliteal fossa) 
nerve block in subjects undergoing bunionectomy are listed below. 
8.1. 
Primary Objective 
To compare the magnitude of the postsurgical analgesic effect following a single dose of 
EXPAREL vs. 0.25% bupivacaine HCl. 
8.2. 
Secondary Objectives 
• To compare the total postsurgical opioid consumption (in oral morphine equivalents) 
from 0 to 96 hours following a single dose of EXPAREL vs. 0.25% bupivacaine HCl 
• To compare the percentage of opioid-free subjects post-surgery through 96 hours 
following a single dose of EXPAREL vs. 0.25% bupivacaine HCl 
• To compare the time to first opioid consumption post-surgery, following a single dose 
of EXPAREL vs. 0.25% bupivacaine HCl 
• To characterize and compare the magnitude of the duration of motor and sensory 
block following a single dose of EXPAREL vs. 0.25% bupivacaine HCl 
• To assess the safety and pharmacokinetic (PK) profile of EXPAREL or 0.25% 
bupivacaine HCl 
9. 
OVERALL STUDY DESIGN AND PLAN 
9.1. 
Study Design 
This is a Phase 3, multicenter, randomized, double-blind, active controlled study in approximately 
180 subjects undergoing bunionectomy. The study will be conducted in two parts (i.e., Part A and 
Part B).  All subjects in Part A and Part B will receive a Mayo field block with 20mL 0.5% 
bupivacaine HCl after study drug administration (i.e., in the operating room immediately prior to 
surgical incision). 
Part A (Efficacy, Safety, PK, and PD): 
Part A will enroll approximately 60 subjects undergoing bunionectomy to obtain information on 
PK profile, pharmacodynamics (PD), efficacy, and safety. Subjects will be randomized (1:1:1) to 
receive a combined sciatic (in the popliteal fossa) nerve block with EXPAREL 266 mg, EXPAREL 
133 mg, or 0.25% bupivacaine HCl.  
 
Part B (Efficacy and Safety): 
Part B will enroll approximately 120 subjects undergoing bunionectomy to evaluate the efficacy 
and safety of EXPAREL compared with bupivacaine HCl. Based on the findings of the interim 
analysis after completion of Part A, the study may stop for futility or proceed to Part B. Part B will 
continue enrolling with one of the EXPAREL study arms and the bupivacaine HCl study arm. 


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Therefore, the EXPAREL study arm that fails to show efficacy (conditional power less than 30%) 
will be dropped and the study will continue with two study arms. The final analysis will include 
subjects from both Part A and Part B. 
An adaptive study design will be used in this study. An unblinded interim analysis will be 
conducted by an independent party after completion of Part A enrollment with completed 
assessment data for the primary efficacy outcome. The conditional power of success for the 
primary efficacy outcomes comparing each of the two EXPAREL arms (EXPAREL 266 arm and 
EXPAREL 133 arm) to the bupivacaine HCl arm will be calculated: 
1. If the conditional power of one EXPAREL arm is less than 30% and the other EXPAREL 
arm is greater than or equal to 30%: 
• The EXPAREL arm with conditional power less than 30% will be dropped in Part B. 
 
2. If both EXPAREL arms have a conditional power greater than or equal to 30%: 
• If the conditional power of the 266 mg EXPAREL arm is more than 10% greater than the 
conditional power of the 133 mg EXPAREL arm, then the 266 mg EXPAREL arm will 
be kept and the 133 mg EXPAREL arm will be dropped. Otherwise, the 133 mg 
EXPAREL arm will be kept and the 266 mg EXPAREL arm will be dropped in Part B. 
 
3. If the conditional power of both treatment arms is less than 30%: 
• The study will stop for futility. 
Figure 1: 
Study Schema 
  
9.2. 
Duration of the Study and Subject Participation 
Participation will begin upon signing of the ICF. No more than 45 days should pass between 
signing the ICF and study drug administration. Study drug administration will be on the same day 


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of surgery. A follow-up phone call will occur on Post-operative Day (POD) 14 (±3 days). 
Therefore, each subject may participate in the study for up to a maximum of 62 days. 
9.2.1. 
Study Stopping Rules 
If Pacira, the Investigator, or officials from regulatory authorities discover conditions during the 
study that indicate that the study or study site should be terminated, this action may be taken after 
Pacira has consulted with appropriate regulatory authorities and notified the Investigator(s). 
The Pacira Medical Monitor and Pharmacovigilance team will review all serious adverse events 
reported from Pacira clinical studies on an ongoing basis and in real time (i.e., as the events are 
reported). The Medical Monitor is responsible for temporarily pausing the study if the type, 
frequency, or seriousness/severity of such events suggests a potential threat to the safety of the 
study subjects. If such action is taken, a thorough review of all available data will be performed. 
Based on the results of this review and discussions with Investigators and/or regulatory authorities, 
the study may be restarted or permanently terminated as warranted. 
The following adverse event study stopping rules will be applied: 
• The study will be stopped after 1 death where a clear alternate cause is not readily apparent. 
• The study will be stopped after 2 non-fatal serious adverse events where a clear alternate cause 
is not readily apparent. 
• The study will be stopped after 2 moderate to severe symptoms deemed definitely related to 
local anesthetic systemic toxicity. 
This trial design also includes efficacy stopping rules using group sequential design stopping rules 
as described in Section 15.8. 
In addition, any death will be thoroughly reviewed, and appropriate action taken. 
9.3. 
Discussion of Study Design 
This Phase 3, multicenter, randomized, double-blind, active-controlled study will enroll 
approximately 180 subjects to evaluate the efficacy and safety of EXPAREL and 0.25% 
bupivacaine HCl when administered as a sciatic (in the popliteal fossa) nerve block in subjects 
undergoing bunionectomy. The study will be conducted in two parts (i.e., Part A and Part B). 
Only Part A subjects (60 subjects) will provide blood samples for PK assessments and will be 
assessed for PD. Subjects will provide information on efficacy and safety of 20 mL EXPAREL 
(266 mg) mixed with 10 mL saline, 10 mL (133 mg) EXPAREL mixed with 20 mL saline, and 20 
mL (50 mg) 0.25% bupivacaine HCl mixed with 10 mL saline.  
Part B will assess the efficacy and safety of 20 mL EXPAREL (266 mg) mixed with 10 mL saline 
or 10 mL (133 mg) EXPAREL mixed with 20 mL saline, and 20 mL (50 mg) 0.25% bupivacaine 
HCl mixed with 10 mL saline in 120 subjects undergoing bunionectomy.  
The three treatment arms of the study for Part A are as follows: 
• EXPAREL 266 arm: subjects randomized to this treatment arm will receive 20 mL 
(266 mg) EXPAREL mixed with 10 mL saline. 


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• EXPAREL 133 arm: subjects randomized to this treatment arm will receive 10 mL 
(133 mg) EXPAREL mixed with 20 mL saline. 
• Bupivacaine HCl arm: subjects randomized to this treatment arm will receive 20 mL 
(50 mg) 0.25% bupivacaine HCl mixed with 10mL saline. 
The two treatment arms of the study for Part B are as follows: 
• EXPAREL 266 arm: subjects randomized to this treatment arm will receive 20 mL 
(266 mg) EXPAREL mixed with 10 mL saline. 
OR 
EXPAREL 133 arm: subjects randomized to this treatment arm will receive 10 mL 
(133 mg) EXPAREL mixed with 20 mL saline. 
• Bupivacaine HCl arm: subjects randomized to this treatment arm will receive 20 mL 
(50 mg) 0.25% bupivacaine HCl mixed with 10mL saline. 
For all arms, a total volume of 30 mL will be administered as a sciatic nerve block (in the popliteal 
fossa). 
10. 
STUDY POPULATION 
Approximately 180 adult subjects undergoing bunionectomy will be enrolled in the study. 
10.1. 
Inclusion Criteria 
Subjects eligible for study entry must meet all of the following criteria: 
1. Male or female, ages 18 or older at screening 
2. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3 (see Appendix 5, 
Section 18.5) 
3. Able to provide informed consent, adhere to the study schedule, and complete all study 
assessments 
4. Primary surgical indication is related to a bunion deformity (i.e., hallux valgus) and 
subject is scheduled to undergo a distal metaphyseal osteotomy procedure (e.g., Austin 
procedure as opposed to Lapiplasty, Lapidus bunionectomies or base wedge 
bunionectomies) 
5. Indicated to undergo elective (i.e., not emergency) bunionectomy 
6. Body Mass Index (BMI) ≥18 and <40 kg/m2 
10.2. 
Exclusion Criteria 
A subject will not be eligible for the study if any of the following criteria are met: 
1. 
Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications 
for which an alternative is not named in the protocol (e.g., amide-type local anesthetics, 
opioids, bupivacaine HCl, NSAIDs) 


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2. 
Concurrent painful physical condition (e.g. arthritis, fibromyalgia, cancer) that may 
require analgesic treatment with NSAIDs or opioids in the post dosing period for pain 
that is not strictly related to the foot surgery and which, in the Investigator’s opinion, 
may confound the post dosing assessments 
3. 
Inadequate sensory function of the foot/ankle as assessed by the Investigator. 
4. 
History of, suspected, or known addiction to or abuse of illicit drug(s), prescription 
medicine(s), or alcohol within the past 2 years 
5. 
Administration of an investigational drug within 30 days or 5 elimination half-lives of 
such investigational drug, whichever is longer, prior to study drug administration, or 
planned administration of another investigational product or procedure during the 
subject’s participation in this study 
6. 
Previous participation in an EXPAREL study 
7. 
Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of 
the Investigator, could interfere with study assessments or compliance 
8. 
Currently pregnant, nursing, or planning to become pregnant during the study  
9. 
Clinically significant medical disease that, in the opinion of the Investigator, would make 
participation in a clinical study inappropriate. This includes diabetic neuropathy, 
coagulation or bleeding disorders, severe peripheral vascular disease, renal insufficiency, 
hepatic dysfunction or other conditions that would constitute a contraindication to 
participation in the study 
10. Currently on a neuromodulating agent (e.g., gabapentin, pregabalin [Lyrica], duloxetine 
[Cymbalta], etc.) 
11. Current use of systemic glucocorticoids within 30 days of randomization in this study 
12. Use of dexmedetomidine HCl (Precedex®) or clonidine within 3 days of study drug 
administration 
13. Any use of marijuana (including tetrahydrocannabinol (THC) and cannabidiol (CBD)) 
within 30 days prior to randomization, or planned use during the course of the study 
14. Chronic opioid use within 30 days prior to randomization (average ≥30 oral morphine 
equivalents/day) 
Given the COVID-19 pandemic, the subject must be medically fit/cleared for surgery by the 
Investigator. If there is a concern about a subject's recent or potential exposure to COVID-19, or 
if the subject is not medically fit/cleared for surgery due to suspected COVID-19 illness/symptoms 
(or other serious illness), the subject must be excluded per Exclusion criterion #9. 
10.3. 
Removal of Subjects from Therapy or Assessment 
Every reasonable effort will be made to maintain subject compliance and participation in the study. 
Reasons for discontinuation of any subject from the study will be recorded. 


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If any clinically significant event or condition is uncovered during the study period (e.g., excessive 
bleeding, acute sepsis) that might render the subject medically unstable or compromise the 
subject’s postsurgical course, the subject should be withdrawn from the study and the event or 
condition should be reported as an AE or SAE. 
If a subject withdraws from the study and has an ongoing AE, every effort must be made to follow 
up on such events until satisfactory resolution is obtained or further follow-up is otherwise no 
longer warranted. 
10.3.1. 
Withdrawal Secondary to Adverse Events 
If a subject, experiences an AE that renders the subject incapable of continuing with the remaining 
assessments, the subject will be discontinued from further participation in the study. A final 
evaluation, including the early termination assessments (see Section 10.3.3), should be performed 
so that the subject’s study participation can be terminated in a safe and orderly manner.  
Any subject who discontinues because of an AE should be instructed to notify the study personnel 
of any abnormal symptoms and to come to the study site if medical evaluation is needed and the 
urgency of the situation permits. Any subject exhibiting AEs will receive appropriate treatment at 
the discretion of the Investigator until resolution of the AE.  
This study involves a single administration of the study drug; therefore, subjects should not be 
terminated from the ongoing study assessments as long as they are willing and able to continue 
with the follow-up schedule according to the protocol. For emergencies and other unscheduled 
visits to a medical facility other than the study site, medical records must be obtained by the 
Investigator and appropriate information captured in the subject’s case report form (CRF). 
In addition, the subject may be withdrawn from the study if the subject meets the following 
criterion during or after the surgery:  
Any clinically significant event or condition uncovered during the surgery (e.g., excessive 
bleeding, acute sepsis) that, in the opinion of the Investigator, renders the subject medically 
unstable or complicates the subject’s postsurgical course. 
10.3.2. 
Voluntary or Study Investigator Withdrawal 
Subjects are free to discontinue from the study at any time, without prejudice to future treatment. 
A subject may be discontinued from the study if the subject refuses study treatment (i.e., sciatic 
[in the popliteal fossa] nerve block) or refuses to comply with study procedures. Subjects should 
be encouraged to complete the study safety assessments. Reasons for discontinuation from the 
study will be recorded. 
If a subject is discontinued by the Investigator or voluntarily withdraws from the study after 
receiving the study drug, the subject will be asked to complete a final evaluation, including the 
early termination assessments (see Section 10.3.3), so that the subject can be withdrawn in a safe 
and orderly manner. 
After termination from the study, the subject may be followed for safety including monitoring of 
AEs through POD 14. 


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10.3.3. 
Early Termination Assessments 
In case of early termination, the following assessments shall be performed:  
• Record date, time, and reason of withdrawal 
• Review adverse events; any ongoing AEs/SAEs will need to be followed to resolution 
• Record responses to pain assessment:  
− Pain intensity scores on the NRS as “On a scale from 0 to 10, where 0 equals no 
pain and 10 equals the worst possible pain, how much pain are you experiencing 
in your operative foot right now?” 
− Pain intensity scores on the NRS as “On a scale from 0 to 10, where 0 equals no 
pain and 10 equals the worst possible pain, what was the worst pain in your 
operative foot in the last 24 hours?” 
− Pain intensity scores on the NRS as “On a scale from 0 to 10, where 0 equals no 
pain and 10 equals the worst possible pain, what was the average pain in your 
operative foot in the last 24 hours?” 
11. 
TREATMENTS 
11.1. 
Treatments to be Administered 
Treatment Arms for Part A: 
Part A is a 3-arm study. On the day of surgery, subjects will receive an ultrasound-guided sciatic 
(in the popliteal fossa) nerve block with one of the following treatments: 
• EXPAREL 266 arm: subjects randomized to this treatment arm will receive 20 mL 
(266 mg) EXPAREL mixed with 10 mL saline 
• EXPAREL 133 arm: subjects randomized to this treatment arm will receive 10 mL 
(133 mg) EXPAREL mixed with 20 mL saline 
• Bupivacaine HCl arm: subjects randomized to this treatment arm will receive 20 mL 
(50 mg) 0.25% bupivacaine HCl mixed with 10 mL saline 
Treatment Arms for Part B: 
Part B is a 2-arm study. On the day of surgery, subjects will receive an ultrasound-guided sciatic 
(in the popliteal fossa) nerve block with one of the following treatments: 
• EXPAREL 266 arm: subjects randomized to this treatment arm will receive 20 mL 
(266 mg) EXPAREL mixed with 10 mL saline 
OR 
EXPAREL 133 arm: subjects randomized to this treatment arm will receive 10 mL 
(133 mg) EXPAREL mixed with 20 mL saline 
• Bupivacaine HCl arm: subjects randomized to this treatment arm will receive 20 mL 
(50 mg) 0.25% bupivacaine HCl mixed with 10 mL saline 


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Block Procedure:  
Subjects may be lightly sedated with 1 to 2 mg of midazolam IV before the block procedure. The 
study drug (EXPAREL or 0.25% bupivacaine HCl) will be administered under ultrasound 
guidance 90 min (±30 min) prior to surgery.  A confirmatory ultrasound video will be taken during 
hydrodissection and infiltration of the study drug, with the needle in place to ensure accurate block 
placement. The Investigator will provide the videos to the sponsor within 24 hours from end of the 
block procedure that will be reviewed by an independent ultrasound adjudication committee to 
evaluate the accuracy of study drug administration. Only two unblinded study drug administrators 
(anesthesiologist) will be assigned per site to perform the block procedures, unless approved in 
advance in writing by the Sponsor on a case-by-case basis. The designated study drug 
administrators (anesthesiologist) will not participate in any other study related assessments after 
randomization. 
A peripheral nerve stimulator will be used before infiltrating the study drug to obtain a response 
(i.e., muscle twitch).  
For all arms, the total volume (30 mL) will be administered as the sciatic (in the popliteal fossa) 
nerve block.  
11.1.1. 
Study Drug Administration Considerations 
As described in the EXPAREL Full Prescribing Information (March 2021), no agents are to be 
admixed with EXPAREL (e.g., epinephrine, dexamethasone, clonidine) other than bupivacaine 
HCl. Lidocaine and other local anesthetics are not permitted to be locally administered during the 
surgery because they are known to interact with EXPAREL, resulting in the displacement of 
bupivacaine and elevated plasma levels. When a topical antiseptic is applied to the surgical site, 
the solutions should not be allowed to come in contact with each other (e.g., the area must be dry 
before EXPAREL is administered). Upon discovering use of any prohibited therapy and/or 
medication during or after surgery, the Investigator should document all events that led to the 
deviation, write a note to file, and notify the Pacira Medical Monitor accordingly. 
EXPAREL may not be administered to a subject if the vial has been open for more than 4 hours. 
In order to prevent EXPAREL from settling, invert and re-invert vials of EXPAREL multiple times 
to re-suspend the particles immediately prior to withdrawal from the vial. Similarly, gently 
inverting and re-inverting the syringe prior to administration is recommended.  
The maximum dosage of EXPAREL should not exceed 266 mg.  
11.1.2. 
Bupivacaine HCl Administration Considerations 
Given the potential risk of severe adverse effects associated with bupivacaine HCl, the study sites 
must be equipped to manage subjects with any evidence of cardiac, neurological, or respiratory 
toxicity.   
Bupivacaine HCl is contraindicated in subjects with a known hypersensitivity to amide-like local 
anesthetics. Caution must be exercised to prevent incidental intravenous administration of 
bupivacaine during block placement. 


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11.2. 
Identity of the Investigational Products 
11.2.1. 
Description of EXPAREL 
EXPAREL (bupivacaine liposome injectable suspension) is formulated as a sterile, non-pyrogenic, 
white to off-white, preservative-free homogenous suspension of bupivacaine encapsulated into 
multivesicular liposomes (DepoFoam drug delivery system). Bupivacaine is present at a nominal 
concentration of 13.3 mg/mL. For this study, EXPAREL will be provided in 20 mL, 1.3% 
(13.3 mg/mL) single-use, clear glass vials. EXPAREL vials should be stored refrigerated at 2°C 
to 8°C (36°F to 46°F). 
11.2.2. 
Description of Reference Product 
The reference product is 0.25% bupivacaine HCl administered via a sciatic (in the popliteal 
fossa) nerve block. 
11.2.3. 
Description of Volume Expansion Agent 
Normal saline (0.9% sodium chloride solution) will be used for study drug volume expansion. 
11.3. 
Method of Assigning Subjects to Treatment 
11.3.1. 
Randomization Scheme 
This is a randomized study. Subjects in Part A will enroll approximately 60 total subjects 
undergoing bunionectomy randomized 1:1:1 in the EXPAREL 266 arm, EXPAREL 133 arm and 
bupivacaine HCl arm. 
Part B will enroll approximately 120 total subjects undergoing bunionectomy, 60 subjects in each 
treatment arm; EXPAREL 266 or EXPAREL 133 arm, and the bupivacaine HCl arm. The 
randomization code will be generated by a centralized randomization system, which will also be 
used to communicate subject randomizations to study sites. All randomized subjects will have both 
a unique subject identifier and a unique randomization code. No subject or randomization code 
identifiers will be reused once assigned. 
11.3.2. 
Randomization Procedures 
Once a subject is identified as being qualified for the study in accordance with the eligibility 
criteria (see Section 10.1 and Section 10.2), the Investigator or designee will obtain a 
randomization assignment on the day of surgery. The subject will be considered randomized into 
the study once the study treatment is assigned. 
11.3.3. 
Replacement of Subjects 
Subjects who withdraw from the study before receiving study drug may be replaced. Once a subject 
number is assigned, subject numbers will not be reused; subjects enrolled to replace those who 
withdraw will be assigned a unique subject number and randomized to treatment according to the 
procedures outlined above. Subjects who are randomized but are withdrawn from the study before 
receiving the study drug or do not undergo the surgical procedure may be replaced. Additionally, 


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subjects may be replaced if insufficient and/or incomplete data are noted on PK profiles or efficacy 
endpoints. 
11.4. 
Selection of Doses in the Study 
During the clinical development of EXPAREL, single doses ranging from 2 mg to 665 mg have 
been safely administered via various routes. Pharmacokinetic studies have shown that because 
EXPAREL releases bupivacaine gradually as the lipid structure breaks down, administration of 
EXPAREL 266 mg results in a maximum plasma concentration equivalent to that seen with 
standard bupivacaine HCl 100 mg. Clinical studies have shown that, for wound infiltration, a total 
dose of 266 mg (20 mL) of EXPAREL is safe and efficacious. Based on this experience, the FDA-
approved marketed dose of 266 mg was deemed appropriate for this study.  
As a part of the clinical development program, a Phase 3 study (402-C-333) evaluating the PK, 
PD, efficacy, and safety of EXPAREL as a combined sciatic nerve (in popliteal fossa) and 
saphenous nerve (in adductor canal) block in subjects undergoing lower extremity surgeries was 
conducted. Both EXPAREL (266 mg) and EXPAREL admix arms were safe, compared to the 
bupivacaine HCl arm. Pacira would like to evaluate and compare efficacy and safety along with 
PK concentrations of EXPAREL 266 mg, EXPAREL 133 mg, and bupivacaine HCl 50 mg to 
determine the most appropriate (efficacious and safe) dose for the current study population. 
11.5. 
Blinding 
11.5.1. 
Unblinding Procedures 
Blinded study personnel should not be unblinded to the subject treatment assignments during the 
study. The Investigator will have the ability to unblind a subject through the randomization system 
if it is felt that subject safety warrants such unblinding. However, if possible, the Investigator 
should discuss the safety issues with the Pacira Medical Monitor before attempting such 
unblinding. Any unblinding will be documented through immediate notification of the Pacira study 
team and the Investigator within the interactive response technology system used for 
randomization. The reason for unblinding will be documented. Any accidental unblinding events 
(i.e., through mishaps in the operating room or miscommunication among study staff) must be 
reported to Pacira immediately. Any unblinding performed through the randomization system will 
be recorded as a transaction, and the appropriate study personnel will be notified that such a 
transaction occurred. Any incidence(s) of unblinding will be noted in the clinical study report with 
a full discussion of the events leading to the decision to unblind. 
11.5.2. 
Blinding Procedure 
EXPAREL and 0.25% bupivacaine HCl are visually distinguishable; therefore, to maintain the 
double-blind study design, the individuals preparing and administering study drug, or transporting 
unblinded drug will not be allowed to perform any of the study assessments after randomization 
(with the possible logistical exception of drawing blood in the operating room (OR) to be processed 
by blinded staff for the PK assessments) or reveal the assigned study treatment to any other 
members of the study team at any time. Additionally, efforts will be made to prevent the subject 
from observing the study drug syringe. Syringes containing study drug will need to be gently 


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inverted several times to re-suspend any settling of the study drug that may have occurred prior to 
administration. The administration of study drug will be recorded using the minimal amount of 
information necessary to avoid unblinding staff who will be participating in blinded procedures. 
Staff members conducting study-specific, postsurgical assessments and the subjects will remain 
blinded to the assigned treatment throughout the study in part by not being present during the 
administration of the nerve block. The site PI must be blinded to the study drug and will not be 
involved in and/or present during study drug administration. 
If a subject, experiences an SAE, Pacira will not automatically unblind the subject’s treatment, 
unless it is necessary to manage treatment of the SAE. Expedited SAEs will be unblinded by Pacira 
for regulatory reporting purposes. 
At each site, only the designated unblinded study staff member will receive unblinded 
randomization assignments; the designated unblinded pharmacist or administrator will be 
responsible for preparing study drug.  Only the two designated unblinded study drug administrators 
(anesthesiologist) at each site will be permitted to administer study drug. 
No crossover will be permitted between the blinded and unblinded study site personnel throughout 
the study.    The assignment of site monitors will also be segregated. Blinded monitors will review 
CRFs, clinic charts, and all other study-related documents that do not disclose the allocation of 
study treatment. Care should be taken in recording and review of OR records to not record 
information in an unblinded fashion. Pharmacy or any other clinic records providing unblinded 
information (e.g., randomization, study drug preparation, study drug accountability, study drug 
administration) will be reviewed by specialized unblinded monitors who will notify Pacira of 
treatment noncompliance. 
The independent review committee conducting the interim analyses will not be blinded to the study 
drug. 
Additional details are outlined in the study-specific Blinding Plan. 
11.6. 
Prior and Concomitant Therapy and Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary. 
The number and percent of subjects taking concomitant medications will be tabulated for each 
treatment arm by Anatomic Therapeutic Chemical class and preferred terms. 
11.6.1. 
Prior to Study Drug Administration 
All subjects will receive the following medications within 4 hours prior to surgery: 
• Celecoxib 200 mg (PO) 
Other permitted Prior Medications and Therapy: 
• 1 to 2 mg of midazolam (Versed) 
• Ondansetron 
Restricted Prior Medications and Therapy: 


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• Systemic glucocorticosteroids and neuromodulating agents (e.g., gabapentin, 
pregabalin [Lyrica], duloxetine [Cymbalta], etc.) 
• Long-acting or sustained release opioid medications and NSAIDs (except for low-dose 
aspirin used for cardio protection) are not permitted within 3 days of study drug 
administration.  
• Dexmedetomidine HCl (Precedex) or clonidine use is not permitted within 3 days of 
study drug administration. 
• Scopolamine Patch is not permitted. 
• No opioid medications are permitted within 24 hours of study drug administration.  
• Use of an investigational product within 30 days or 5 elimination half-lives of such 
investigational drug, whichever is longer, prior to study drug administration, or planned 
administration of another investigational product or procedure during the subject’s 
participation in this study is not permitted. 
• No drugs (other than the described bupivacaine HCl admixture) are to be admixed with 
study drug (e.g., epinephrine, dexamethasone, clonidine).  
• Lidocaine and other local anesthetics will not be permitted to be locally administered 
in the area of the nerve block administration other than use in a superficial cutaneous 
wheal for needle insertion. 
11.6.2. 
Perioperative 
All subjects will receive a Mayo field block with 20 mL 0.5% bupivacaine HCl after study drug 
administration (i.e., in the operating room immediately prior to surgical incision). The Mayo field 
block should be performed by the surgeon. 
All subjects will receive a dose of 1000 mg of intravenous (IV) acetaminophen at the time of 
surgical incision. 
Other Permitted Medications:  
• Single-dose administration of ondansetron or metoclopramide may be used intra-
operatively for nausea/vomiting prevention.  
• Propofol is permitted for induction and intra-operative sedation. 
Restricted Medications: 
• General anesthesia and opioid sedation are not permitted. Neuraxial or regional 
anesthesia technique (except the investigational related blocks) are not permitted. 
• Intraoperative use of opioids (except fentanyl, not to exceed 1 ug/kg unless deemed 
medically necessary) and ketamine will not be permitted.  
• The use of dexamethasone, acetaminophen/paracetamol, ketorolac, or other NSAIDs 
will not be permitted preemptively or intraoperatively except for emergency use to treat 
an AE.  


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• Lidocaine and other local anesthetics will not be permitted to be locally administered 
in the area of the nerve block administration. 
11.6.3. 
Post-surgery 
All subjects will receive one post-operative dose of 1000 mg IV acetaminophen, administered 
approximately 8 hours after the first dose (approximately 8 hours after incision). The maximum 
total dose will not exceed 2000 mg. No additional acetaminophen is permitted after the second IV 
acetaminophen dose. 
Other Permitted Medications: 
• Ondansetron or metoclopramide may be used for postoperative nausea and vomiting.  
• Postsurgical pain medications for breakthrough pain as outlined in Section 11.7.  
Restricted Medications: 
• No other analgesics, including fentanyl, are permitted within 96 hours after surgery.  
• Scopolamine patch is not permitted. 
• Patient Controlled Analgesia is not permitted.  
• Dexmedetomidine HCl (Precedex) use is prohibited.  
• Lidocaine (except, if used as a local anesthetic at the site of IV placement) and other 
local anesthetics will not be permitted to be locally administered in the area of the nerve 
block administration through POD 7. 
• Systemic glucocorticosteroids and neuromodulating agents (e.g., gabapentin, 
pregabalin [Lyrica], duloxetine [Cymbalta], etc.) 
11.7. 
Postsurgical Pain Medication for Breakthrough Pain 
An unscheduled pain intensity assessment using the NRS (measured as “On a scale from 0 to 10, 
where 0 equals no pain and 10 equals the worst possible pain, how much pain are you experiencing 
in your operative foot right now?”) must be completed immediately prior to administration of any 
breakthrough pain medication up to 96 hours post-surgery. 
Medications will be administered on an as needed basis; opioids should not be given on a pre-
determined schedule.  
• Immediate release PO oxycodone may be administered in a stepwise approach:  
− Initial dose of 5 mg oxycodone may be offered; 
− If the initial opioid dose is insufficient for pain relief, an additional 5 mg oxycodone 
may be offered up to a maximum of 10 mg (total dose). 
• If a subject is unable to tolerate PO medication or the PO oxycodone pain relief is insufficient, 
IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) may be administered. 


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No NSAIDs or other opioids including Tramadol are allowed for the breakthrough pain 
management per protocol. No Acetaminophen (other than the scheduled IV acetaminophen) 
should be used for breakthrough pain. 
For study purposes, it is important to standardize pain management modalities during the first 96 
hours post-surgery. Therefore, the study staff must adhere closely to the treatment options and 
requirements noted in the protocol. After 96 hours, the analgesic regimen may be adjusted for each 
subject individually as deemed appropriate by the physician responsible for the postsurgical care. 
All postsurgical analgesics administered, must be recorded through hospital discharge. 
11.8. 
Treatment Compliance 
Study drug (EXPAREL or bupivacaine HCl)  administration will be performed by an unblinded 
study Investigator (anesthesiologist) qualified by experience and training. 
All details of study drug administration, including dose volume and start and stop time, will be 
recorded in a blinded fashion in the source and eCRF. 
11.9. 
Accountability of Study Drug 
The Investigator or designee (e.g., pharmacist) ) is responsible for maintaining current and accurate 
inventory records. At a minimum, the Investigator or designee will maintain accurate records 
demonstrating dates and units of drug received, lot numbers, subjects to whom drug was 
administered, and accounts of any drug destroyed accidentally or deliberately. The Investigator 
must retain vials containing used, unused, or expired study drug for return or destruction, as 
instructed by Pacira, following confirmation of drug accountability data by an unblinded study 
monitor. A record of drug return or destruction will be maintained and provided to Pacira. 
Inventory records must be readily available for inspection by the unblinded study monitor and 
appropriate regulatory authorities at any time. A copy of the inventory records, drug accountability 
information, and notice of return or destruction will be returned to Pacira at the end of the study. 
Only authorized personnel identified by the Investigator will have the ability to access and 
administer the study drug. 
12. 
STUDY ENDPOINTS AND MEASUREMENTS 
12.1. 
Efficacy Assessments 
• Pain intensity measured using the NRS as “On a scale from 0 to 10, where 0 equals no 
pain and 10 equals the worst possible pain, how much pain are you experiencing in 
your operative foot right now?” will be assessed: 
− Upon arrival in the Post-anesthesia Care Unit (PACU) (±5 min) 
− Every 15 minutes in the PACU (±5 min) 
− At PACU discharge (±5 min) 


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− Every 6 hours from the end of surgery until 96 hours post-surgery: 6h (±2h), 12h 
(±2h), 18h (±2h), 24h (±2h), 30h (±2h), 36h (±2h), 42h (±2h), 48h (±2h), 54h (±2h), 
60h (±2h), 66h (±2h), 72h (±2h), 78h (±3h), 84h (±3h), 90h (±3h), and 96h (±3h) 
• An unscheduled NRS assessment will be obtained immediately prior to administration 
of any breakthrough pain medication until 96 hours post-surgery. 
• Pain intensity using the NRS once daily at 24h, 48h, 72h, and 96h measured as “On a 
scale from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, what 
was the worst pain in your operative foot in the last 24 hours?”  
• Pain intensity using the NRS once daily at 24h, 48h, 72h, and 96h measured as “On a 
scale from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, what 
was the average pain in your operative foot in the last 24 hours?”  
Subjects will be instructed to focus all NRS pain intensity ratings on the operative 
foot, and no other locations where they may be experiencing pain. 
• In addition, subject satisfaction with pain management using 1 question from the 
International Pain Outcome (IPO) questionnaire will be recorded at 96 hours (±3h) 
post-surgery.  
12.2. 
Efficacy Endpoints 
Primary Endpoint: 
• The area under the curve (AUC) of the NRS pain intensity scores from 0 to 96 hours 
post-surgery  
Secondary Endpoints:  
• Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 0 
to 96 hours post-surgery 
• Percentage of opioid-free subjects through 96 hours 
• Time to first opioid consumption post-surgery 
• Worst and average NRS pain intensity scores at 24h, 48h, 72h, and 96h from the end 
of surgery. 
12.3. 
Safety Assessments 
The following safety assessments will be conducted by blinded study staff at the time points 
specified: 
• SAEs will be recorded from the time of informed consent and AEs will be recorded 
from the time of randomization through POD 14. 
12.4. 
Safety Endpoints 
• Incidence of treatment-emergent AEs and SAEs from the start of block procedure 
through POD 14 


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12.5. 
Pharmacokinetic Assessments (Part A Subjects) 
Blood samples for PK assessment will be obtained from Part A subjects. A total of 17 PK samples 
will be collected for each subject. These samples will be obtained at pre-dose (up to 15 min before 
block), 30 min (±5 min), 45 min (±5 min), and 1 h (±15 min), 2 h (±30 min), 8 h (±30 min), 12h 
(±30 min), 24h (±1h), 30h (±1h), 48h (±1h), 60h (±2h), 72h (±2h), 84h (±2h), 96h (±3h), 120h 
(±3h), 144h (±3h), and 168h (±3h) hours from end of block procedure. (See Table 2). 
12.6. 
Pharmacokinetic Endpoints (Part A Subjects) 
The following PK endpoints will be determined: 
• Area under the plasma concentration-versus-time curve (AUC) 
• Maximum plasma concentration (Cmax) and time of Cmax (Tmax) 
• The apparent terminal elimination half-life (t1/2el) 
• Apparent clearance (CL/F) 
• Apparent volume of distribution (Vd) 
12.7. 
Pharmacodynamic Assessments (Part A Subjects) 
Pharmacodynamic assessments must be performed by blinded, trained, licensed medical staff (e.g., 
Physician, Registered Nurse, Physician Assistant) and documented on the Investigator’s study 
Delegation Log. A limited number of study staff should perform the sensory/motor assessments. 
Assessment of sensory function (Light Touch Assessment): 
Sensory function will be assessed using a tongue depressor to evaluate light touch. Sensory 
function will assessed at pre-dose (up to 15 min before block), 15 min (±5 min), 30 min (±5 min), 
45 min (±5 min), 1 h (±15 min), 2 h (±30 min), 8 h (±30 min), 12 h (±30 min), 24 h (±1 h), 30 h 
(±1 h), 48 h (±1 h), 60 h (±2 h), 72 h (±2 h), 84 h (±2 h), 96 h (±3 h), 120 h (±3 h), 144 h (±3 h), 
and 168 h (±3 h) from the end of the nerve block procedure, or until full sensory function has 
returned to baseline (pre-block) levels (see Appendix 3, Section 18.4). Each light touch area of 
assessment will be rated independently. Additional unscheduled assessments may be performed, 
particularly around the surgery, if no onset of block is noted on the last scheduled assessment prior 
to surgery. 
For sensory assessment, both locations identified below will be assessed for light touch. If on the 
168h assessment there is a sensory deficit, the incident will be recorded as an AE. The physician 
will assess the subject for other etiologies that may explain the persistent sensory deficit. If the 
sensory deficit persists on 168h, the subject is to return for unscheduled visit(s) at the Investigator's 
discretion until the sensory function has returned. 
Sensory function assessment will include the following two locations: 
1. Proximal - Lateral aspect of the lower leg (3-4 cm above ankle) 
2. Distal - Sole of the foot 


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Onset of sensory block will be defined as the earliest timepoint with loss of light touch sensation 
along the distribution of the target nerve distal to the site of the block. 
Offset of sensory block will be defined as the first timepoint of return of light touch sensation 
along the distribution of the target nerve distal to the site of the block. After offset of sensory 
assessments are noted (light touch sensation in both test areas in a single assessment), no 
subsequent assessments will be required. 
Duration of sensory block will be defined as the time between onset and offset of light touch 
sensation. 
 
Assessment of motor function: 
Motor function (onset and offset of motor block) will be assessed by voluntary active movement 
of the foot. This will be used to determine the onset and duration of motor blockade. The motor 
function test will be performed at pre-dose (up to 15 min before block), 15 min (±5 min), 30 min 
(±5 min), 45 min (±5 min), 1h (±15 min), 2h (±30 min), 8h (±30 min), 12h (±30 min), 24h (±1h), 
30h (±1h), 48h (±1h), 60h (±2h), 72 h (±2h), 84h (±2h), 96h (±3h), 120h (±3h), 144h (±3h), and 
168h (±3h) from end of block procedure, or until full motor function has returned to pre-dose 
levels (see Appendix 4, Section 18.3). Once the offset of motor block is recorded and documented, 
no further scheduled motor assessments are required. Additional unscheduled assessments may be 
performed, particularly around the surgery, if no onset of block is noted on the last scheduled 
assessment prior to surgery.  
Onset of motor block will be defined as the earliest timepoint with partial or no foot movement.  
Offset of motor block will be defined as resolution of the motor block with complete foot 
movement. After offset of motor block is noted, no subsequent assessments will be conducted. 
Duration of motor block will be defined as time between onset and offset of motor block (see 
Appendix 4, Section 18.3). 
12.8. 
Pharmacodynamic Endpoints (Part A Subjects) 
The following pharmacodynamics endpoints will be determined: 
• Median time to onset of sensory block and motor block 
• Median duration of sensory block and motor block 
12.9. 
Appropriateness of Measures 
Endpoints selected for this study were based on validated methodologies and other well-
established clinical measurements used in the peer reviewed literature. Measurements were further 
refined in this study based on previous nerve block experience with EXPAREL and other Phase 3 
or 4 studies. 
13. 
STUDY PROCEDURES 
A time and events schedule for all study procedures is provided in Table 1 and Table 2. 


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13.1. 
Instructions for Conducting Procedures and Measures 
All PK, sensory/motor function assessments, and safety assessments conducted after baseline (pre-
dose) will be timed from the end of the block. End of block procedure is defined as the time of 
completion of study drug administration after the sciatic (in the popliteal fossa) nerve block. 
All NRS scores, vital signs, and EKG to be collected after surgery will be timed from the end of 
surgery. 
At timepoints when multiple assessments coincide, assessments will be performed in the following 
sequence: pain intensity assessment, sensory assessments, motor assessment, blood draw for PK 
assessment as applicable, vital signs, 12-lead EKG.  
The start of surgery is defined as the time of the first incision. The end of surgery is defined as 
the time recorded in the surgical record. Postsurgical is defined as after the end of surgery.  
Postsurgical analgesia and collection of study data will take place under the supervision of study 
staff at the site. 
13.1.1. 
Pain Intensity Assessment 
Pain intensity will be assessed using an 11-point NRS (0-10) as follows: 
• Pain intensity scores on the NRS as “On a scale from 0 to 10, where 0 equals no pain 
and 10 equals the worst possible pain, how much pain are you experiencing in your 
operative foot right now?” will be assessed: 
− Upon arrival in the PACU (±5 min) 
− Every 15 mins in the PACU (±5 min) 
− Prior to PACU discharge (±5 min) 
− Every 6 hours from the end of surgery until 96 hours: 6 h (±2 h), 12 h (±2 h), 
18 h (±2 h), 24 h (±2 h), 30 h (±2 h), 36 h (±2 h), 42 h (±2 h), 48 h (±2 h), 54 h 
(±2 h), 60 h (±2 h), 66 h (±2 h), 72 h (±2 h), 78 h (±3 h), 84 h (±3 h), 90 h (±3 h), 
and 96 h (±3 h)  
− If a subject is asleep, the subject will not be awakened to assess pain. If the subject 
awakens within the assessment window, a pain score will be collected then. 
− Study staff will be instructed not to complete the NRS pain intensity score after any 
physical activity, including the motor block assessment. If that is not possible, to 
assess pain intensity at rest, the subject should rest quietly in a supine or seated 
position that does not exacerbate his or her postsurgical pain for 5-10 minutes 
before entering the pain score using the NRS. Subjects will also be required to 
provide unscheduled pain assessments prior to consumption of any breakthrough 
pain medication. 
− An unscheduled NRS assessment will be obtained immediately prior to 
administration of any breakthrough pain medication until 96 hours post-surgery. 


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• Pain intensity using the NRS at 24 (±2h), 48 (±2h), 72 (±2h), and 96 (±3h) post-surgery 
measured as “On a scale from 0 to 10, where 0 equals no pain and 10 equals the worst 
possible pain, what was the worst pain in your operative foot in the last 24 hours?”  
• Pain intensity using the NRS at 24 (±2h), 48 (±2h), 72 (±2h), and 96 (±3h) post-surgery 
measured as “On a scale from 0 to 10, where 0 equals no pain and 10 equals the worst 
possible pain, what was the average pain in your operative foot in the last 24 hours?”  
Subjects will be instructed to focus all NRS pain intensity ratings on the operative 
foot, and no other locations where they may be experiencing pain. 
13.1.2. 
Subject Satisfaction with Postsurgical Pain Control 
Subject satisfaction with pain management using 1 question from the International Pain Outcome 
(IPO) questionnaire will be recorded at 96 hours (±3 h) post-surgery. (see Appendix 2, 
Section 18.2). 
13.1.3. 
Pharmacokinetic Assessments (Part A Subjects) 
Blood samples for PK assessment will be obtained from select subjects. A total of 17 PK samples 
will be collected for each subject. These samples will be obtained at pre-dose (up to 15 min before 
block), 30 min (±5 min), 45 min (±5 min), and 1h (±15 min), 2h (±30 min), 8h (±30 min), 12h 
(±30 min), 24h (±1h), 30h (±1h), 48h (±1h), 60h (±2h), 72h (±2h), 84 h (±2h), 96h (±3h), 120h 
(±3h), 144h (±3h), and 168h (±3h) from end of block procedure. (See Table 2). 
13.1.4. 
Pharmacodynamic assessment (Part A Subjects) 
Onset and duration of sensory block will be assessed using the light touch assessment to 
characterize the sensory block (see Appendix 4, Section 18.3).  
Onset and duration of motor block will be assessed using the movement of the foot to characterize 
the motor block (see Appendix 3, Section 18.4). 
Pharmacodynamic assessments must be performed by blinded, trained, licensed medical staff (e.g., 
Physician, Registered Nurse, Physician Assistant) and documented on the Investigator’s study 
Delegation Log. A limited number of study staff should perform the sensory/motor assessments. 
13.2. 
Study Procedures 
13.2.1. 
Obtaining Informed Consent 
Potential subjects undergoing bunionectomy will be approached by the Investigator and/or the 
study staff for informed consent up to 45 days before the surgery. Subjects may be consented on 
the day of the surgery, if the consent process is started early with ample time for the subject to 
review the ICF and have all questions answered by the Investigator/study staff prior to providing 
informed consent.  


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13.2.2. 
Screening 
Subjects may be screened up to 45 days prior to the day of surgery but eligibility should be re-
confirmed on the day of surgery. Screening procedures that are standard of care at the institution 
may be completed prior to written informed consent and documented within the 45-day time 
window. Any screening procedures that are not standard of care must be completed after written 
informed consent is provided and prior to randomization. 
The following screening procedures will be performed after the ICF is signed (if not standard of 
care):  
• Assess eligibility  
• Record medical/surgical history  
o As a general guidance, relevant medical/surgical history within the last 5 years 
(including all ongoing history, regardless of start date) should be recorded in the 
electronic CRF (eCRF), with the exception of history that is relevant to the 
bunionectomy, in which case all years should be recorded. 
o If a site’s standard process includes detailed collection of all history (regardless of 
relevance/age), only the relevant items should be recorded in the eCRF as 
outlined above; an asterisk or similar indicator can be used in the source 
documentation to indicate the relevant items that should be included in the eCRF 
for source data verification purposes. 
• Record prior medications  
− Prior medications taken within 30 days of randomization (including all ongoing 
medications, regardless of start date) will be recorded in the eCRF. 
• Record demographics and baseline characteristics 
• Record subject height and weight for BMI calculation  
• Assess chronic opioid use in the past 30 days (average ≥30 oral morphine 
equivalents/day) 
• Assess marijuana (including THC or CBD) use in the past 30 days 
• Conduct urine pregnancy test for women of childbearing potential 
• Perform 12-lead EKG 
• Record SAEs from the time the ICF is signed 
• Record medications for treatment of SAEs 
13.2.3. 
Baseline Procedures (Prior to Study Drug Administration) 
• On the day of surgery, before performing any pain assessments, study staff will review 
the study Pain Rating Guide with the subject. 


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• On the day of surgery, before administration of the block, the Investigator/study staff 
must record responses to the following pain assessments:  
− Pain intensity scores on the NRS as “On a scale from 0 to 10, where 0 equals no 
pain and 10 equals the worst possible pain, what was the worst pain in your 
operative foot in the last 30 days?”  
− Pain intensity scores on the NRS as “On a scale from 0 to 10, where 0 equals no 
pain and 10 equals the worst possible pain, what was the average pain in your 
operative foot in the last 30 days?” 
• Conduct urine pregnancy test for women of childbearing potential 
• Conduct urine drug screen 
• Vital signs will be measured and recorded after the subject has rested in a supine 
position for at least 5 minutes 
• Record changes to concomitant medications since screening  
• Confirm eligibility and randomize subject 
• Record AEs/ SAEs  
• Instruct the subjects on duties and responsibilities for assessment completion 
• Part A subjects:  
− Perform sensory function assessment (pre-dose (up to 15 min before block)) 
− Perform motor function assessment pre-dose (up to 15 min before block)) 
− Obtain blood sample for PK assessment within 15 minutes before block 
13.3. 
Nerve Block Procedure  
• Subjects may be lightly sedated with 1 to 2 mg of IV midazolam before the block 
procedure. 
• Disinfect the area where the block will be administered 
• Administer study drug as a sciatic (in the popliteal fossa) nerve block using ultrasound 
and nerve stimulator 90 min (±30 min) prior to surgery (unblinded staff only with 
shielding of the subject’s vision of the study drug syringe) 
• Record start and end times of study drug administration 
• Record concomitant medications 
• Record AEs/ SAEs  
• Ultrasound video must be captured from the beginning of hydrodissection until the end 
of study drug administration. Send ultrasound video to study sponsor within 24 hours 
from the end of block procedure 


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Note: Specific supplies listed below provided by the Sponsor in the study drug 
administration kits are subject to change based on availability. 
13.3.1. 
Procedures for Sciatic (in the Popliteal Fossa) Nerve Block 
A: Placement of ultrasound probe: 
• Position the patient supine with the leg placed on an elevated footrest or lateral 
(operative side up). Using a linear probe, place the ultrasound probe in the popliteal 
fossa, 3 to 5 cm above the popliteal crease in the transverse orientation. 
• Start scanning within the popliteal fossa to identify the popliteal artery and vein. The 
tibial nerve will lie posterior to the vascular structures (i.e., popliteal artery and vein).  
• Start scanning where the sciatic nerve splits into the peroneal and tibial nerves but 
still enclosed in the connective tissue sheath (perineural sheath). 
B: Insertion of needle into perineural sheath: 
• Use a 100 mm, insulated needle connected to a nerve stimulator, initially set at 0.8-
1.0 mA. 
• Needle insertion will occur on the lateral thigh using an in-plane needle approach 
from lateral to medial. 
• The needle should be advanced in plane until the needle tip has pierced the sciatic 
nerve sheath (perineural sheath). 
• Once the needle has pierced the surrounding sheath, an appropriate motor response 
with peripheral nerve stimulation at 0.8- 1.0 mA should be obtained (Dorsiflexion or 
eversion for the peroneal nerve and plantar flexion or inversion for the tibial nerve is 
expected).  
Note: The goal is to split the injectate equally between the two nerves using motor stimulation as 
a guide.  
C: Saline hydrodissection for fascial plane confirmation: 
Once the perineural sheath has been penetrated by the needle, use saline (1-2 mL) to 
confirm needle placement. 
D: Study drug administration: 
Inject 30 mL of the study drug admixture in the sheath, between the peroneal and 
tibial nerves. 
13.4. 
Post-Block Assessments 
The following assessments will be conducted in Part A subjects only: 
• Assess sensory and motor function (onset and offset of block) 
− Perform sensory/motor function assessments at 15 min (±5 min), 30 min 
(±5 min), 45 min (±5 min), 1h (±15 min), 2h (±30 min), 8h (±30 min), 12h (±30 


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min), 24h (±1h), 30 h (±1h), 48h (±1h), 60h (±2h), 72h (±2h), 84h (±2h), 96h 
(±3h), 120h (±3h), 144h (±3h), and 168h (±3h) from the end of the block 
procedure, or until full sensory/motor function has returned to pre-dose levels 
after one evaluation. The light touch and motor function tests will be rated 
independently from each other. 
• Collect scheduled PK blood samples. These samples will be obtained at 30 min (±5 
min), 45 min (±5 min), 1h (±15 min), 2h (±30 min), 8h (±30 min), 12 h (±30 min), 24h 
(±1h), 30h (±1h), 48h (±1h), 60h (±2h), 72h (±2h), 84h (±2h), 96h (±3h), 120h (±3h), 
144h (±3h), and 168h (±3h) from end of block procedure. (See Table 2). 
For all study subjects:  
• Record AEs/ SAEs 
• Record concomitant medications  
13.5. 
Mayo Field Block Procedure 
• Position the patient supine (the leg may be placed on an elevated footrest) 
• Disinfect the area where the block will be administered as is standard for the facility 
• Administer Mayo field block prior to surgery in the operating room 
• Record start and end times of administration 
• Record AEs/ SAEs  
13.5.1. 
Procedures for Mayo Field Block 
• Raise a skin wheal proximally and dorsally in the first intermetatarsal space  
• Advance the needle in the dorsomedial to plantar-medial direction injecting 3-5 mL 
of 0.5% bupivacaine HCl  
• Advance the needle in the dorsomedial to dorso-lateral direction injecting 3-5 mL of 
0.5% bupivacaine HCl  
• Advance the needle in the dorsolateral to plantar-lateral direction injecting 3-5 mL of 
0.5% bupivacaine HCl  
• Advance the needle in the plantar-medial to plantar-lateral direction injecting 3-5 mL 
of 0.5% bupivacaine HCl  
• The block should encircle the entire metatarsal bone 
13.6. 
Intraoperative Procedures 
• Record type of sedation 
• Record intraoperative drugs administered and doses  
• Record date and start/end times of surgery  


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• Record AEs/ SAEs  
• Record concomitant medications  
13.7. 
Post-Anesthesia Care Unit Procedures 
• Record date/time of admission to and discharge from the PACU 
• Record AEs/ SAEs  
• Record concomitant medications  
• Record pain intensity scores (using the NRS) measured as “On a scale from 0 to 10, 
where 0 equals no pain and 10 equals the worst possible pain, how much pain are you 
experiencing in your operative foot right now?”  will be assessed: 
− Upon arrival in the Post-anesthesia Care Unit (PACU) (±5 min) 
− Every 15 minutes in the PACU (±5 min) 
− At PACU discharge (±5 min) 
• Record an unscheduled pain intensity scores (using the NRS) measured as “On a 
scale from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, how 
much pain are you experiencing in your operative foot right now?” immediately prior 
to administration of any breakthrough pain medication. 
• Record date, time, and dosage of any breakthrough pain medication 
• Measure and record vital signs as follows: 
− Upon arrival  in the PACU (±5 min)  
− At PACU discharge (±5 min)       
• For Part A subjects only: 
− Collect scheduled PK blood sample(s)  
− Perform sensory and motor function assessments 
13.8. 
Postsurgical Assessments from End of Surgery through Discharge 
• Record pain intensity scores (NRS) (see Appendix 1, Section 18.1) measured as “On a 
scale from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, how 
much pain are you experiencing in your operative foot right now?” from the end of 
surgery to 96 hours post-surgery as follows: 
− Every 6 hours from the end of surgery to 96-hour post-surgery, i.e.,  
6h (±2h), 12h  (±2h), 18h (±2h), 24h  (±2h), 30h (±2h), 36h (±2h), 42h (±2h), 48h 
(±2h), 54h (±2h), 60h (±2h), 66h (±2h), 72h (±2h), 78h (±3h), 84h (±3h), 90h (±3h), 
and 96h (±3h). 
− If a subject is asleep, the subject will not be awakened to assess pain. If the subject 
awakens within the assessment window, a pain score will be collected then. 


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− Study staff will be instructed not to complete the NRS pain intensity score after any 
physical activity, including the motor block assessment. If that is not possible, to 
assess pain intensity at rest, the subject should rest quietly in a supine or seated 
position that does not exacerbate his or her postsurgical pain for 5-10 minutes 
before entering the pain score using the NRS. 
• Record an unscheduled pain intensity score (using the NRS) measured as “On a scale 
from 0 to 10, where 0 equals no pain and 10 equals the worst possible pain, how 
much pain are you experiencing in your operative foot right now?” immediately prior 
to administration of any breakthrough pain medication until 96 hours post-surgery. 
• Record pain intensity scores (using the NRS) at 24 (±2 h), 48 (±2 h), 72 (±2 h), and 
96 (±3 h) post-surgery, measured as “On a scale from 0 to 10, where 0 equals no pain 
and 10 equals the worst possible pain, what was the worst pain in your operative foot 
in the last 24 hours?” 
• Record pain intensity scores (using the NRS) at 24 (±2 h), 48 (±2 h), 72 (±2 h), and 
96 (±3 h) post-surgery, measured as “On a scale from 0 to 10, where 0 equals no pain 
and 10 equals the worst possible pain, what was the average pain in your operative 
foot in the last 24 hours?” 
• Record subject’s satisfaction with pain management using 1 question from the 
International Pain Outcome (IPO) questionnaire at 96 hours (±3 h) post-surgery. 
• Record AEs/ SAEs.  
• Record concomitant medications. 
• Record vital signs (i.e., blood pressure, pulse, respiratory rate, oxygen saturation, and 
body temperature) after the subject has rested in a supine position for at least 5 minutes. 
See Table 1  
• Perform 12-lead EKG. See Table 1  
• For Part A subjects only:  
− Collect scheduled PK blood sample(s).  
− Perform sensory and motor function assessments. 
To mitigate the risk from falls, subjects will be required to be non-weight bearing for at least 
2 weeks post-surgery, unless the Investigator determines a limited touch down or partial weight 
bearing for balance with a walker assist device is more appropriate to reduce the risk of fall. 
13.9. 
Health Care Facility Discharge 
• Subjects in Part A who undergo PK analysis, sensory and motor function assessments 
will be discharged after the completion of the 168h assessments. Subjects in Part B will 
be discharged after the completion of the 96h assessments. 
• Record date and time of health care facility discharge.  


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13.10. 
Unscheduled Visits 
• If a sensory or motor function deficit persists on POD 7 (168h post-surgery), the subject 
is to return for unscheduled visit(s) at the Investigator's discretion through POD 14 or 
until the sensory or motor function has returned to baseline, whichever occurs first.  
• Record concomitant medications including all analgesic medication.  
• Record AEs/SAEs. 
13.11. 
Postsurgical Day 14 Phone Call 
• Ask the subject about any new AEs, SAEs and the resolution of any ongoing adverse 
event(s) since discharge. Record any adverse event information. 
• Ask the subject about any concomitant medication(s) taken, since discharge from the 
health care facility. 
14. 
ADVERSE EVENT REPORTING 
Consistent with the current regulatory guidance provided by the US FDA CFR Part 312 and the 
ICH GCP, AEs and SAEs are defined in Section 14.1.1 and Section 14.2.1, respectively.  
The concepts of AEs and SAEs represent regulatory instruments used to evaluate and monitor the 
safety of clinical study subjects. Therefore, these terms only apply in light of their regulatory 
definition. The term serious, in a regulatory sense, does not necessarily mean severe. The SAE 
concept is used primarily to identify, during the conduct of the study, those SAEs that may require 
expedited reporting to regulatory authorities. 
14.1. 
Adverse Events  
14.1.1. 
Definitions 
Definition of Adverse Event: Any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment about 
causality. An AE can arise from any use of the drug (e.g., off-label use in combination with another 
drug) and from any route of administration, formulation, or dose, including an overdose.  
An AE can be any unfavorable and unintended change in a body structure or body function. 
Adverse events include any clinically significant deterioration of a subject’s medical status. The 
AE may involve any organ or system and can be represented by the new onset or deterioration of 
a disease, a syndrome, a symptom, a physical sign, as well as by findings and results of 
instrumental examinations and laboratory tests. Any medically relevant and untoward change after 
the subject signs the ICF, including frequency or pattern changes for a fluctuating condition (e.g., 
migraine) is considered an AE.  
An AE that occurs after the administration of the study treatment is considered a treatment-
emergent adverse event (TEAE).  


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Definition of Adverse Reaction: Any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event.  
Definition of Suspected Adverse Reaction: Any AE for which there is a reasonable possibility that 
the drug caused the AE. A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any AE caused by a drug. Suspected adverse 
reactions are a subset of all AEs for which there is a reasonable possibility that the drug caused the 
event.  
14.1.2. 
Recording Adverse Events 
It is the responsibility of the Investigator to document all AEs with an onset after the subject is 
randomized and SAEs with an onset after the subject signs the ICF. For the purpose of this study, 
all AEs that occur through POD 14 must be recorded regardless of whether or not they are 
considered related to study drug. Any AEs occurring after POD 14 only need to be reported if 
considered related to study drug by Investigator. Whenever feasible, AE terms must be 
documented as medical diagnoses (highest possible level of integration); otherwise, the AEs must 
be reported separately as individual signs or symptoms. Only one AE per record should be recorded 
in the AE CRF; for example, an AE of nausea and vomiting would be listed as two separate events: 
the event of nausea and the event of vomiting. If a diagnosis is established after symptoms are 
recorded on the AE CRF, the diagnosis must be recorded, and the symptoms removed. Whenever 
possible, abnormal laboratory results must be reported as their clinical corollary (e.g., low 
potassium should be recorded as hypokalemia).  
A continuous AE with varying grades of severity must be recorded as one AE. The highest grade 
of severity experienced by that subject during the course of the continuous AE must be recorded.  
Any condition noted before the subject signs the ICF will be listed as Medical History (this 
includes conditions prior to randomization) and is considered a pre-existing condition. If a pre-
existing condition changes (i.e., becomes more severe or more frequent) at any time after the ICF 
is signed, or after randomization, it is considered an AE. Note: A change in treatment for a pre-
existing condition (e.g., new high blood pressure medication), does not necessarily indicate an AE.  
Information recorded on the AE CRF will include the AE term, the date and time of onset, severity, 
seriousness, relationship to study drug, action taken with subject due to AE, and the outcome of 
the AE, including the date and time of resolution, if applicable. 
14.1.3. 
Severity of Adverse Events 
In general, the severity of an AE should be categorized using the following guidelines:  
Mild:  
An AE that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.  
Moderate:  An AE that is discomforting and interferes with normal everyday activities.  
Severe:  
An AE that prevents normal everyday activities.  
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); however, the event itself, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is based 


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on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
14.1.4. 
Relationship of Adverse Events to Study Drug 
The Investigator must assess the relationship of the AE to study drug after careful medical 
consideration on a case-by-case basis. General guidelines are provided below.  
Unrelated: A causal relationship between the study drug and the AE can be easily ruled out 
(e.g., based on the temporal sequence, absence of a reasonable pathophysiological 
mechanism, or direct evidence of actual cause). 
Unlikely: 
A clinical event with a temporal relationship to study drug administration which 
makes a causal relationship improbable and in which other drugs, chemicals, or 
underlying disease provide a plausible explanation; 
Possible: 
A clinical event with a reasonable time sequence to administration of the study 
drug but which could also be explained by a concurrent disease or other drugs or 
chemicals; 
Probable: 
A clinical event with a reasonable time sequence to administration of the study 
drug unlikely to be attributed to a concurrent disease or other drugs or chemicals 
and which follows a clinically reasonable response on withdrawal (dechallenge);  
Definite: 
The pharmacological properties of the study drug(s) or of the substance class, and 
the course of the AE after dechallenge and, if applicable, after rechallenge, and/or 
specific 
test 
indicate 
involvement 
of 
the 
study 
drug(s) 
in 
the 
occurrence/worsening of the AE, and no indication of other causes exists. 
14.1.5. 
Outcome of Adverse Events 
The Investigator will assess the outcome of the AE after careful medical consideration, on a case-
by-case basis. General guidelines are provided below: 
Recovered/Resolved:  
The event resolved and the subject recovered from the AE  
Recovered/Resolved 
with Sequelae:  
The initial event resolved but has a continuing abnormal 
condition as a result of the AE  
Not Recovered/ Not 
Resolved:  
At the time of the last assessment, the event was ongoing, with 
an undetermined outcome. Note: ongoing AEs are not to be 
considered resolved as a result of death  
Recovering/Resolving:  
At the time of the last assessment, the event was decreasing in 
frequency, severity, etc., and a resolution was expected  
Fatal:  
The AE directly caused death  


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Unknown:  
There was an inability to access the subject or the subject’s 
records to determine the outcome (e.g., subject withdrew consent 
or was lost to follow-up)  
 
14.1.6. 
Action Taken with Subject Due to an Adverse Event 
The Investigator will provide any actions taken regarding the subject (e.g., treatment, diagnostic 
tests, laboratory tests, or therapy) for each reported AE.  
• None 
• Medication 
• Non-pharmaceutical therapy (the specific therapy used must be recorded in the CRF)  
• Discontinued from study 
• Other (the specific action taken must be recorded) 
14.1.7. 
Adverse Events of Special Interest 
Based on review of all peripheral nerve blocks, the following conditions will be considered to be 
adverse events of special interest upon review of the AEs: 
• Falls 
• Persistent tingling1  
• Persistent numbness1  
• Persistent weakness1  
• Hypersensitivity  
• Seizures  
• Tremors  
• Dizziness  
• Hematoma formation  
• Cardiovascular depression  
• Dyspnea  
• Cardiovascular arrest  
• Altered sensorium  
• Visual disturbances  
• Local anesthetic systemic toxicity (LAST) 


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1Persistent: Any condition (e.g., tingling, numbness, or sensory/motor weakness 
affecting the nerve block region, after the study drug administration) that persists for 
greater than 168 hours from the time of onset. 
In case an AE of special interest (AESI) or serious AE (SAE) occurs during the study, if the 
investigator or medical monitor considers that the event may be related to study treatment or 
suggests the possible occurrence of local anesthetic systemic toxicity (LAST; with or without the 
need for treatment [e.g., intralipids]), an unscheduled PK blood sample, 12-lead EKG, and vital 
signs must be collected. Neurological assessments will be conducted according to the study site’s 
standard of care at least once daily until resolution of symptoms. 
Investigators, study coordinators, and patient study assessors will be trained on adverse event 
ascertainment in general, with a special focus directed to signs and symptoms that may represent 
evidence of systemic toxicity. All AEs of special interest will be managed per standard of care and 
should be reported to the Medical Monitor and recorded in the database.  
14.2. 
Serious Adverse Events 
14.2.1. 
Definition of a Serious Adverse Event 
Definition of a SAE: An AE or suspected adverse reaction is considered “serious” if, in the view 
of either the Investigator or Pacira, it results in any of the following outcomes:  
• Death1 
• A life-threatening AE2 
• Inpatient hospitalization or prolongation of existing hospitalization3 
• A persistent or significant incapacity4 
• Congenital anomaly/birth defect5 
• Medically significant6 
1Death: Any event resulting in a subject’s death must be reported as an SAE. However, death, in 
and of itself, is not an AE; it is an outcome. The cause of death is the AE. Therefore, the 
Investigator must make every effort to obtain and document the cause of death for all subjects who 
die during the study. If, despite all efforts, the cause of death remains unknown, the AE must be 
documented as an “unspecified fatal event.”  
2Life-threatening: An AE is considered life-threatening if, in the view of either the Investigator 
or Pacira, its occurrence places the subject at immediate risk of death. It does not include an AE 
that had it occurred in a more severe form might have caused death.  
3Hospitalization: It should be noted that hospitalization, in and of itself, does not represent an 
SAE. It is the AE leading to the subject’s hospitalization that becomes “serious” when it requires 
inpatient care. Consequently, an SAE must not be reported in case of preplanned hospitalizations 
for a pre-existing condition that did not worsen during the study. However, any medical condition 
that delays a subject’s discharge from the hospital (i.e., prolonged hospitalization) or requires the 
subject to be readmitted must be reported as an SAE.  


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    402-C-334 (Sciatic Nerve Block) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
 
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HA: The AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery for the EXPAREL 
arm is less than that of the bupivacaine HCl arm. 
EXPAREL arm denotes either EXPAREL 266 arm or EXPAREL 133 arm, to be selected based 
on Part A analysis. 
15.2. 
Study Endpoints 
The endpoints to be assessed in this study are listed in Section 12.2 (Efficacy Endpoints), 
Section 12.6 (PK Endpoints) and Section 12.4 (Safety Endpoints). 
15.3. 
Determination of Sample Size 
The total sample size for Part A and B was calculated based on the primary outcome measure of 
NRS pain intensity scores. A sample size of 80 subjects per study arm (1:1 randomization, 80 
EXPAREL, 80 Bupivacaine HCl) provides at least 85% power to detect a treatment difference of 
110 units in the AUCs (SD=230) comparing EXPAREL arm with Bupivacaine HCl arm at one-
sided 0.025 significance level. 
An adaptive study design will be used in this study. An unblinded interim analysis will occur after 
completion of Part A enrollment with completed assessment data for the primary efficacy outcome. 
The conditional power of success for the primary efficacy outcomes comparing each of the two 
EXPAREL arms (EXPAREL 266 arm and EXPAREL 133 arm) to the bupivacaine HCl arm will 
be calculated: 
1. If the conditional power of one EXPAREL arm is less than 30% and the other EXPAREL arm 
is greater than or equal to 30%: 
• The EXPAREL arm with conditional power less than 30% will be dropped in Part B. 
2. If both EXPAREL arms have a conditional power greater than or equal to 30%: 
• If the conditional power of the 266 mg EXPAREL arm is more than 10% greater than the 
conditional power of the 133 mg EXPAREL arm, then the 266 mg EXPAREL arm will be 
kept and the 133 mg EXPAREL arm will be dropped. Otherwise, the 133 mg EXPAREL 
arm will be kept and the 266 mg EXPAREL arm will be dropped in Part B. 
3. If the conditional power of both treatment arms is less than 30%: 
• The study will stop for futility. 
15.4. 
Analysis Populations 
The following analysis sets are planned: 
Safety: The safety analysis set will include all randomized subjects who receive study drug. All 
analyses will be based on actual treatment received. 
Efficacy: The efficacy analysis set will include all randomized subjects who receive the study drug, 
undergo the planned surgery, and have at least one post-study drug administration NRS pain 
assessment. All analyses will be based on randomized treatment regardless of actual treatment 
received. 


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Pharmacokinetic: The pharmacokinetic analysis set will include all subjects in Part A who receive 
study drug and who provide sufficient samples to allow for calculation of PK parameters required 
for analysis. 
Pharmacodynamic: The pharmacodynamics analysis set will include all subjects in Part A who 
receive study drug and who provide sufficient data to allow for calculation of PD parameters 
required for analysis. 
15.5. 
Handling Subject Dropouts and Discontinuations 
Methods for dealing with missing data for other endpoints will be described in the SAP. 
15.6. 
Statistical Analyses 
15.6.1. 
Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment arm. 
Baseline is defined as the last non-missing assessment of a given assessment prior to the first dose 
of the trial drug unless otherwise specified. 
15.6.2. 
Study Procedure Compliance 
In each analysis set, the percentage and number of subjects who were screened and the percentage 
and number of subjects who failed to complete the study, including reasons for discontinuation, 
will be displayed by treatment arm. 
15.6.3. 
Efficacy Analyses 
All efficacy analyses will be based on the efficacy analysis set and will be analyzed according to 
the randomized treatment. 
The primary efficacy analysis endpoints are AUC of NRS pain intensity scores from 0-96 hours 
post-surgery, and they will be analyzed using ANCOVA model with treatment as a main effect. 
Additional covariates may be included. Each of the EXPAREL group will be compared to 
Bupivacaine HCl group. Based on the model, the least squared mean (LSM) difference between 
each of the EXPAREL groups and bupivacaine HCl group will be estimated with two-sided 95% 
confidence interval. 
Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 0 to 96 hours 
will be summarized by treatment arm and overall. To test the difference between each of the 
EXPAREL group and Bupivacaine HCl group, an ANCOVA model will be used. Time to first 
postsurgical opioid medication will be analyzed using the Kaplan-Meier survival method. Worst 
and average NRS pain intensity scores through 24h, 48h, 72h, and 96h from the end of surgery 
will be summarized by treatment arm and overall. 
Summary statistics (n, mean, median, standard deviation, minimum, maximum) will be shown for 
each continuous measure of efficacy by treatment arm and overall. Number and percentage of 
subjects in each category will be shown for each categorical measure of efficacy by treatment arm 
and overall. 


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All assessments will be presented in by-subject data listings. 
15.6.4. 
Safety Analyses 
All safety analyses will be based on actual treatment received. 
15.6.4.1. Pharmacokinetic Analyses 
Pharmacokinetic parameters will be estimated from the PK analysis set, using plasma drug 
concentration-time profiles, where appropriate, by non-compartmental analysis. 
Actual sampling time will be used for all calculations of the PK parameters. If there is any doubt 
in the actual time a sample was taken, then the scheduled time will be used. 
Descriptive statistics will be used to summarize the PK parameters. 
15.6.4.2. Adverse Events 
Adverse event verbatim terms will be mapped to preferred terms and related system organ class 
using the Medical Dictionary for Regulatory Activities (MedDRA). Events that start prior to the 
start of study drug administration will be identified in a by-subject listings. Incidence rates of 
TEAEs and the proportion of subject prematurely withdrawn from the study due to a TEAE will 
be shown for each treatment arm. Incidence rates will also be displayed for each treatment arm for 
TEAEs by severity and separately by relationship. If severity of an AE is not reported, then for 
tables of AEs by severity, the event will be classified as ‘Severe’ and will be footnoted for the 
table to indicate this imputation. If relationship to study drug is not reported for an AE, then for 
tables of study-drug related AEs, the event will be assigned the relationship of ‘definite’. Incidence 
rates of SAEs will also be shown for each treatment arm. All incidence rates will be categorized 
and displayed by system organ class and preferred term. 
15.7. 
Significance Testing 
All tests will be either one-sided on a significance level of 0.025 or two-sided on a significance 
level of 0.05. 
15.8. 
Interim Analyses 
An unblinded interim analysis will occur after completion of Part A enrollment with completed 
assessment data for the primary efficacy outcome. Efficacy will be evaluated and compared 
between study arms. Based on the findings of the interim analysis, the study may stop for futility 
or proceed to Part B.  
The conditional power of success for the primary efficacy outcomes comparing each of the two 
EXPAREL arms (EXPAREL 266 arm and EXPAREL 133 arm) to the bupivacaine HCl arm will 
be calculated: 
1. If the conditional power of one EXPAREL arm is less than 30% and the other EXPAREL 
arm is greater than or equal to 30%: 
• The EXPAREL arm with conditional power less than 30% will be dropped in Part B. 


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    402-C-334 (Sciatic Nerve Block) 
EXPAREL® 
 
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2. If both EXPAREL arms have a conditional power greater than or equal to 30%: 
• If the conditional power of the 266 mg EXPAREL arm is more than 10% greater than the 
conditional power of the 133 mg EXPAREL arm, then the 266 mg EXPAREL arm will 
be kept and the 133 mg EXPAREL arm will be dropped. Otherwise, the 133 mg 
EXPAREL arm will be kept and the 266 mg EXPAREL arm will be dropped in Part B. 
3. If the conditional power of both treatment arms is less than 30%: 
• The study will stop for futility. 
Full details on the interim analysis will be covered in a prospective interim analysis plan. 


Pacira Pharmaceuticals, Inc. 
 
    402-C-334 (Sciatic Nerve Block) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
 
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16. 
REFERENCES 
American Society of Anesthesiologists Task Force on Pain Management. Practice guidelines for 
acute pain management in the postoperative setting. A report by the American Society for 
Anesthesiologist Task Force on Pain Management, Acute Pain Section. Anesthesiology. 
1995;82:1071−1081.  
Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: results from a national 
survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 
2003;97(2):534−540. 
Breivik H, Hogstrom H, Niemi G, et al. Safe and effective post-operative pain relief: 
introduction and continuous quality-improvement of comprehensive post-operative pain 
management programs. Bailliére’s Clin Anaesthesiol. 1995a;9:423–460. 
Breivik H. Benefits, risks and economics of post-operative pain management programs. Baillière’s 
Clin Anaesthesiol. 1995b;9:403–422. 
Carr DB, Goudas LC. Acute pain. Lancet. 1999;353: 2051–2058. 
Carroll NV, Miederhoff PA, Cox FM, et al. Costs incurred by outpatient surgical centers in 
managing postoperative nausea and vomiting. J Clin Anesth. 1994;6(5):364−369.  
Chernin T. Painkillers and pill popping. Drug Topics. 2001;15:31. 
Dahl V, Raeder JC. Non-opioid postoperative analgesia. Acta Anaesthesiol Scand. 2000;44:1191–
203. 
EXPAREL Full Prescribing Information, March 2021.  
EXPAREL Investigator’s Brochure, Edition 23, 21 October 2021. 
Feierman DE, Kronenfeld M, Gupta PM, et al. Liposomal bupivacaine infiltration into the 
transversus abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: 
results from a cohort of 13 patients. J Pain Res. 2014;7:477-482. 
Marks RM, Sacher EJ. Undertreatment of medical inpatient pain with narcotic analgesics. 
Ann Intern Med. 1973;78:173–181. 
Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical 
hospitalizations: impact on cost and length of stay. Ann Pharmacother. 2007;41(3):400−406. 
Papper EM, Brodie BB, Rovenstein EA. Postoperative pain: its use in the comparative evaluation 
of analgesics. Surgery. 1952;32:107–109. 
Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. 
Anesthesiology. 2000;93:1123–33. 


Pacira Pharmaceuticals, Inc. 
 
    402-C-334 (Sciatic Nerve Block) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
 
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Petersen-Felix S, Curatolo M. Neuroplasticity — an important factor in acute and chronic pain. 
Swiss Med Weekly. 2002;132:273–278. 
Rothaug J, Zaslansky R, Schwenkglenks M, et al. Patients’ perception of postoperative pain 
management: validation of the International Pain Outcomes (IPO) questionnaire. J Pain. 2013; 
14(11), 1361–1370.  
Schug SA, Large RG. Economic considerations in pain management. Pharmacoeconomics. 
1993;3:260–7;9.  
Stephen J, Laskin C, Pashos B et al. The burden of acute postoperative pain and the potential role 
of the COX-2-specific inhibitors. Rheumatology. 2003;42(3): iii40–iii52.  
Viscusi ER. New and emerging treatment options for acute postoperative pain in the inpatient 
setting: Barriers to effective pain management. Medscape Pharmacists. 2009. 


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17. 
INVESTIGATOR AGREEMENT  
 
Printed Name of Investigator:   
 
Printed Title/Position: 
 
 
 
 
I have reviewed this protocol (including Appendices) and agree:  
• To assume responsibility for the proper conduct of the study at this site;  
• To conduct the study in compliance with this protocol, with any future amendments, and 
with any other study conduct procedures provided by Pacira Pharmaceuticals, Inc. a wholly 
owned subsidiary of Pacira Biosciences, Inc. (“Pacira”) or designee. I also agree to comply 
with Good Clinical Practice and all regulatory requirements;  
• Not to implement any changes to the protocol without agreement from Pacira or designee 
and prior review and written approval from the Independent Ethics Committee, except where 
it is necessary to eliminate an immediate hazard to the subjects or for administrative aspects 
of the study (where permitted by applicable regulatory requirements);  
• That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and with other relevant information (e.g., the Investigator’s 
Brochure);  
• To ensure that all persons assisting me with the conduct of this study are adequately informed 
about the investigational product(s) and about their study-related duties and functions as 
described in this protocol;  
• That I am aware that regulatory authorities may require Investigators to disclose all 
information about significant ownership interests and/or financial ties related to the Sponsor 
and/or the investigational product(s). Consequently, I agree to disclose all such significant 
financial information to Pacira and to update this information promptly if any relevant 
changes occur during the course of the study through 1 year following completion of the 
study. I also agree that any information regarding my significant financial interest related to 
Pacira and/or the investigational product(s) will be disclosed to the regulatory authorities by 
Pacira.  
 
 
_________________________________ 
                                _______________________________ 
Signature of Investigator 
 
 
 
 
                                Date 


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    402-C-334 (Sciatic Nerve Block) 
EXPAREL® 
 
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18. 
APPENDICES 
 
 


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18.1. 
Appendix 1: Pain Intensity Scores using the Numeric Rating Scale 
(NRS) 
Pain intensity will be measured using the 11-point NRS. The subject will be asked to rate their 
worst or average pain on a scale of 0 (no pain) - 10 (worst possible pain).  
• Pain intensity using the NRS measured as “On a scale from 0 to 10, where 0 equals no pain 
and 10 equals the worst possible pain, what was the worst pain in your operative foot in 
the last 30 days?” and “On a scale from 0 to 10, where 0 equals no pain and 10 equals the 
worst possible pain, what was the average pain in your operative foot in the last 30 days?” 
will be assessed at Baseline/Day of surgery 
• Pain intensity using the NRS measured as “On a scale from 0 to 10, where 0 equals no pain 
and 10 equals the worst possible pain, how much pain are you experiencing in your 
operative foot right now?” will be assessed: 
− Upon arrival in the PACU (±5 min) 
− Every 15 minutes in the PACU (±5 min) 
− At PACU discharge (±5 min) 
− Every 6 hours from the end of surgery until 96 hours post-surgery: 6h (±2h), 12h (±2h), 
18h (±2h), 24h (±2h), 30h (±2h), 36h (±2h), 42h (±2h), 48h (±2h), 54h (±2h), 60h 
(±2h), 66h (±2h), 72h (±2h), 78h (±3h), 84h (±3h), 90h (±3h), and 96h (±3h) 
− If a subject is asleep, the subject will not be awakened to assess pain. If the subject 
awakens within the assessment window, a pain score will be collected then 
− Study staff will be instructed not to complete the NRS pain intensity score after the 
subject has completed any physical activity, including the motor block assessment. If 
that is not possible, to assess pain intensity at rest, the subject should rest quietly in a 
supine or seated position that does not exacerbate his or her postsurgical pain for 5-10 
minutes before entering the pain score using the NRS. 
− An unscheduled NRS assessment will be obtained immediately prior to 
administration of any breakthrough pain medication until 96 hours post-surgery  
• Pain intensity using the NRS measured as “On a scale from 0 to 10, where 0 equals no 
pain and 10 equals the worst possible pain, what was the worst pain in your operative 
foot in the last 24 hours?” and “On a scale from 0 to 10, where 0 equals no pain and 10 
equals the worst possible pain, what was the average pain in your operative foot in the 
last 24 hours?” will be assessed on the Day of surgery (prior to surgery): 
− At 24h (±2h), 48h (±2h), 72h (±2h), and 96h (±3h) post-surgery.  
 
 
 
 


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EXPAREL® 
 
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18.2. 
Appendix 2: Subject Satisfaction Questionnaire 
For the purposes of this study, only 1 question from the International Pain Outcome (IPO) 
Questionnaire (Rothaug 2013) will be used. Subject satisfaction will be recorded once 96 hours 
(±3 h) post-surgery.  
 
Dear Sir/Madam,  
Please answer the following questions about your pain control after surgery 
Circle the one number that best shows how satisfied you are with the results of your pain treatment 
since your surgery: 
 
 
 


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18.3. 
Appendix 3: Sensory Function Assessment (Light Touch Test) (Part 
A Subjects) 
Pharmacodynamic assessments must be performed by blinded, trained, licensed medical staff (e.g., 
Physician, Registered Nurse, Physician Assistant) and documented on the Investigator’s study 
Delegation Log. A limited number of study staff (blinded to study drug assignment) should 
perform the sensory/motor assessments. 
For the sensory function assessment, the subject’s sensitivity to light touch in the distal part of 
innervated dermatomes of the sciatic nerve will be assessed with their eyes closed using a tongue 
depressor. Sensory function will assessed at pre-dose (up to 15 min before block), 15 min (±5 
min), 30 min (±5 min), 45 min (±5 min), 1h (±15 min), 2h (±30 min), 8h (±30 min), 12h (±30 
min), 24h (±1h), 30h (±1h), 48h (±1h), 60h (±2h), 72h (±2h), 84h (±2h), 96h (±3h), 120h (±3h), 
144h (±3h), and 168h (±3h) from the end of the nerve block procedure, or until full sensory 
function has returned to baseline (pre-block) levels. Each light touch area of assessment will be 
rated independently. Additional unscheduled assessments may be performed, particularly around 
the surgery, if no onset of block is noted on the last scheduled assessment prior to surgery. 
For sensory assessment, both locations identified below will be assessed for light touch. If on the 
168h assessment there is a sensory deficit, the incident will be recorded as an AE. The physician 
will assess the subject for other etiologies that may explain the persistent sensory deficit. If the 
sensory deficit persists on 168h, the subject is to return for unscheduled visit(s) at the Investigator's 
discretion until the sensory function has returned. 
Sensory function assessment will include the following two locations: 
1. Proximal - Lateral aspect of the lower leg (3-4 cm above ankle) 
2. Distal - Sole of the foot 
The intent of applying the tongue depressor to the contralateral leg is to establish a reference 
sensation to compare to the test area. The subject is to determine if the sensation on the 
contralateral leg is the same as the test area (“Yes” = the same) or if there is a decreased sensation 
or not the same sensation (“NO” = not the same). 
The test may be repeated in case of ambiguous or inconsistent responses until the examiner is 
satisfied with the accuracy of the assessment. The assessments will be conducted single-blinded 
(i.e., the subject will be instructed to close their eyes). 
After offset of sensory assessments are noted (return of light touch sensation in both test areas in 
a single assessment), no subsequent assessments will be required. 
 
Tongue Depressor Assessment 
The tongue depressor assessment procedures are as follows: 
• The subject will be instructed to close their eyes before the application of the wooden 
tongue depressor. 
• Instruct the subject you will be touching the subject on both legs and they will be asked if 
the touch sensation is the same (YES) or not the same (NO) when comparing each side. 


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• For the subject’s reference, the end of the tongue depressor is dragged over the 
contralateral assessment area with consistent light touch. 
• The end of the tongue depressor is then dragged over the corresponding test assessment 
area with consistent light touch. 
• The subject will be asked if the touch sensation of the tongue depressor is the same 
(YES) or not the same (NO) when comparing each side.  
• Record the subject’s response (YES or NO) to the touch sensation in the assessment area.  
• Proceed to test the other area as above. 
 
 


Pacira Pharmaceuticals, Inc. 
 
    402-C-334 (Sciatic Nerve Block) 
EXPAREL® 
 
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18.4. 
Appendix 4: Motor Function Test (Part A Subjects) 
 
Pharmacodynamic assessments must be performed by blinded, trained, licensed medical staff (e.g., 
Physician, Registered Nurse, Physician Assistant) and documented on the Investigator’s study 
Delegation Log. A limited number of study staff (blinded to study drug assignment) should 
perform the sensory/motor assessments. 
Motor function (onset and offset of motor block) will be assessed by active movement of the 
foot. This will be used to determine the duration of the motor blockade. 
 
The motor function test will be performed at pre-dose (up to 15 min before block), 15 min (±5 
min), 30 min (±5 min), 45 min (±5 min), 1h (±15 min), 2h (±30 min), 8h (±30 min), 12h (±30 
min), 24h (±1h), 30h (±1h), 48h (±1h), 60h (±2h), 72h (±2h), 84h (±2h), 96h (±3h), 120h (±3h), 
144h (±3h), and 168h (±3h) from the end of the block procedures, or until full motor function 
has returned to pre-dose levels after one evaluation.  
 
Additional unscheduled assessments may be performed, particularly around the surgery, if no 
onset of block is noted on the last scheduled assessment prior to surgery. 
 
If on 168 h assessment there is a motor function deficit, the incident will be recorded as an AE. 
The physician will assess the subject for other etiologies that may explain the persistent motor 
deficit. If the motor deficit persists on 168 h, the subject is to return for unscheduled visit(s) at the 
Investigator's discretion until the motor function has returned. 
 
Motor Function Test 
The motor function test procedures are as follows: 
• The subject will be supine and asked to flex and extend the foot of the study leg. 
• The level of foot movement will be noted as either: 
• partial or no foot movement  
• complete foot movement 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
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EXPAREL® 
 
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18.5. 
Appendix 5: ASA Physical Status Classification System   
Last approved by the ASA House of Delegates on October 15, 2014 
 
ASA PS 
Classification 
Definition 
Examples, including, but not limited to: 
ASA I 
A normal healthy patient Healthy, non-smoking, no or minimal alcohol use 
ASA II 
A patient with mild 
systemic disease 
Mild diseases only without substantive functional 
limitations. Examples include (but not limited to): 
current smoker, social alcohol drinker, pregnancy, 
obesity (30 < BMI < 40), well-controlled DM/HTN, 
mild lung disease 
ASA III 
A patient with severe 
systemic disease 
Substantive functional limitations; One or more 
moderate to severe diseases. Examples include (but 
not limited to): poorly controlled DM or HTN, 
COPD, morbid obesity (BMI ≥40), active hepatitis, 
alcohol dependence or abuse, implanted pacemaker, 
moderate reduction of ejection fraction, ESRD 
undergoing regularly scheduled dialysis, premature 
infant PCA < 60 weeks, history (>3 months) of MI, 
CVA, TIA, or CAD/stents. 
ASA IV 
A patient with severe 
systemic disease that is a 
constant threat to life 
Examples include (but not limited to): recent ( < 3 
months) MI, CVA, TIA, or CAD/stents, ongoing 
cardiac ischemia or severe valve dysfunction, 
severe reduction of ejection fraction, sepsis, DIC, 
ARD or ESRD not undergoing regularly scheduled 
dialysis 
ASA V 
A moribund patient who 
is not expected to survive 
without the operation 
Examples include (but not limited to): ruptured 
abdominal/thoracic aneurysm, massive trauma, 
intracranial bleed with mass effect, ischemic bowel 
in the face of significant cardiac pathology or 
multiple organ/system dysfunction 
ASA VI 
A declared brain-dead 
patient whose organs are 
being removed for donor 
purposes 
ARD=acute respiratory distress; ASA=American Society of Anesthesiologists; BMI=body mass index; 
CAD=coronary artery disease; COPD=chronic obstructive pulmonary disease; CVA=cerebrovascular accident; 
DIC=disseminated intravascular coagulation; DM=diabetes mellitus; ESRD=end-stage renal disease; 
HTN=hypertension; MI=myocardial infarction; PCA=postconceptional age; PS=physical status; TIA=transient 
ischemic attack  

SAP_001.pdf: 
Pacira Pharmaceuticals, Inc. 
 
 
 
DISCLOSURE: REDACTED STATISTICAL ANALYSIS PLAN 
 
Title: A Phase 3, Randomized, Double-Blind, Active-Controlled, Multicenter Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of EXPAREL vs. Bupivacaine HCl Administered as a Sciatic (in 
the Popliteal Fossa) Nerve Block for Postsurgical Analgesia in Subjects Undergoing Bunionectomy 
NCT Number: NCT05157841 
Protocol Number: 402-C-334 
 
Statistical Analysis Plan Version 1.2, Approval Date: 08-Dec-2022 
 
Certain information within this statistical analysis plan has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information.  
 
This may include, but is not limited to, redaction of the following: 
 
• 
Named persons or organizations associated with the study. 
• 
Proprietary information, such as scales or coding systems which are considered confidential 
information under prior agreements with license holder. 
• 
Other information as needed to protect confidentiality of Pacira Pharmaceuticals, Inc. or partners, 
personal information, or to otherwise protect the integrity of the clinical study.  
 
The information contained in the following document is the property of Pacira Pharmaceuticals, Inc. and 
should not be shared or used for any purpose other than for which it was provided. 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Phase 3, Randomized, Double-Blind, Active-Controlled, Multicenter Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL vs. 
Bupivacaine HCl Administered as a Sciatic (in the Popliteal Fossa) Nerve 
Block for Postsurgical Analgesia in Subjects Undergoing Bunionectomy 
 
 
Protocol No.: 402-C-334 
IND No.: 069,198  
Study Phase: 3 
Study Drug: EXPAREL (bupivacaine liposome injectable suspension) 
Original Protocol Date 23 September 2021 
Amendment 2 Date 24 February 2022 
Sponsor: Pacira BioSciences, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 
 
  
SAP Prepared by: 
 
 
Pharma Data Associates, LLC 
SAP Date/Version 08 December / Version 1.2 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira Biosciences, Inc.  
It should not be reproduced, revealed, or sent to third parties other than Institutional Review 
Boards/Independent Ethics Committees and the Investigator’s research support staff participating in the 
conduct of the study without the prior written authorization of Pacira Biosciences, Inc. 
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SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharma Data Asociates, LLC 
 
Date 
 
 
 
 
 
 
 
 
 
Pacira BioSciences, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Pacira BioSciences, Inc. 
 
 
Date  
 
 
 
 
 
 
 
 
 
 
Pacira BioSciences, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Pacira BioSciences, Inc. 
Date 
 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS 
5 
2. 
INTRODUCTION 
6 
3. 
CHANGE TO THE PROTOCOL TERMINOLOGY OR SPECIFIED METHODS OR TO THE 
PREVIOUS SIGNED-OFF SAP 
6 
4. 
STUDY OBJECTIVES 
7 
4.1. 
Primary Objective 
7 
4.2. 
Secondary Objectives 
7 
5. 
STUDY OVERVIEW 
7 
6. 
DEFINITIONS 
15 
7. 
STUDY ASSESSMENTS 
18 
7.1. 
Efficacy Assessment 
18 
7.1.1. 
Pain Intensity Assessment 
18 
7.1.2. 
Opioid Dose Conversion 
19 
7.1.3. 
Subject Satisfaction with Pain Management 
20 
7.2. 
Pharmacokinetic assessments (Part A only) 
20 
7.3. 
Pharmacodynamic Assessments (Part A only) 
20 
7.3.1. 
Assessment of Sensory Block 
20 
7.3.2. 
Assessment of Motor Block 
21 
7.4. 
Safety Assessments 
22 
7.5. 
Change in the Study Design and Its Effect on the Statistical Analysis 
22 
8. 
ANALYSIS SETS 
22 
9. 
STUDY ENDPOINTS 
23 
9.1. 
Efficacy Endpoints 
23 
9.1.1. 
Primary Endpoint 
23 
9.1.2. 
Secondary Endpoints 
23 
9.1.3. 
Exploratory Endpoints 
23 
9.2. 
Safety Endpoints 
24 
9.3. 
Pharmacokinetic (PK) Endpoints (Part A only) 
24 
9.4. 
Pharmacodynamic (PD) Endpoints (Part A only) 
24 
10. 
METHODS OF STATISTICAL ANALYSIS 
24 
10.1. 
General Principles 
24 
10.2. 
Handling Missing Values 
26 
10.2.1. 
Total Post-Surgical Opioid Consumption 
26 
10.2.2. 
NRS Pain Intensity Scores 
26 
10.2.3. 
Adverse Event or Concomitant Medication Date or Time 
27 
10.2.4. 
Adverse Event Severity or Relationship to Study Drug 
28 


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10.2.5. 
Time to Event 
28 
10.3. 
Subject Disposition 
28 
10.4. 
Description of Demographics and Baseline Characteristics 
29 
10.4.1. 
Demographics 
29 
10.4.2. 
Baseline Characteristics 
29 
10.4.3. 
Medical and Surgical History 
30 
10.4.4. 
Surgery Characteristics 
30 
10.4.5. 
Intraoperative, Prior, and Concomitant Medications 
30 
10.4.6. 
Protocol Deviations 
31 
10.4.7. 
Measurements of Treatment Compliance 
31 
10.5. 
Efficacy Analysis 
31 
10.5.1. 
Adjustments for 2-Stage Design and Multiplicity 
32 
10.5.2. 
Primary Efficacy Endpoint 
33 
10.5.3. 
Secondary Efficacy Endpoints 
35 
10.5.3.1. 
Total postsurgical opioid consumption in oral morphine equivalents from 0 to 96 hours post-surgery35 
10.5.3.2. 
Opioid-free status through 96 hours Post-surgery 
36 
10.5.3.3. 
Time to first postsurgical opioid consumption 
36 
10.5.3.4. 
Worst and average NRS pain intensity scores at 24, 48, 72, and 96 hours post-surgery 
37 
10.5.3.5. 
Current pain intensity scores post-surgery through 96 hours 
37 
10.5.4. 
Subgroup Analysis 
37 
10.5.5. 
Exploratory Endpoints 
38 
 
 
 
 
 
 
 
 
 
10.6. 
Pharmacokinetic Analysis 
39 
10.6.1. 
Pharmacokinetic Parameter Calculation Methods 
39 
10.6.2. 
Pharmacokinetic Concentrations and Variables 
41 
10.7. 
Pharmacodynamic Analysis 
42 
10.7.1. 
Sensory Function 
42 
10.7.2. 
Motor Function 
42 
10.8. 
Safety Assessments 
42 
10.8.1. 
Adverse Events and Serious Adverse Events 
43 
10.8.2. 
Other Safety Assessments 
44 
10.9. 
Interim Analysis 
45 
11. 
SAMPLE SIZE CALCULATIONS 
45 
12. 
REFERENCES 
45 
 
 
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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical therapeutic class 
BMI 
Body mass index 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CP 
Conditional power 
CRF 
Case report form 
CSR 
Clinical study report 
CV 
Coefficient of Variation  
FDA 
Food and Drug Administration 
h 
Hour 
ICH 
International Conference on Harmonization 
IV 
Intravenous 
LN 
Natural Log  
LSM 
Least Squares Mean 
MedDRA 
Medical dictionary for regulatory affairs 
mg 
milligram 
min 
Minutes 
N, n 
Number of subjects 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OMED 
Oral morphine equivalent dose in mg 
PACU 
Postanesthesia care unit 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PO 
Per oral 
POD 
Postoperative Day 
PP 
Predictive Power 
PRN 
pro re nata, as needed 
PT  
Preferred Term  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TEAESI 
Treatment-emergent adverse event of special interest 
TLF 
Tables, listings and figures 
WHODD 
World Health Organization Drug Dictionary 
 
 


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2. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting for the 
clinical study 402-C-334 titled “A Phase 3, Randomized, Double-Blind, Active-Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL vs. 
Bupivacaine HCl Administered as a Sciatic (in the Popliteal Fossa) Nerve Block for Postsurgical 
Analgesia in Subjects Undergoing Bunionectomy”.  
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or manuscripts.  Post hoc exploratory analyses not identified in this SAP 
may be performed to further examine study data.  Any post hoc, unplanned, or exploratory analyses 
performed will be clearly identified as such in the final CSR. 
The following documents were reviewed in preparation of this SAP: 
• 
Protocol 402-C-334 issued on 23 September 2021 
• 
Protocol 402-C-334 Amendment 1 issued on 22 October 2021 
• 
Protocol 402-C-334 Amendment 2 issued on 24 February 2022 
• 
Electronic Case Report Form (eCRF) v5.0 dated 13 June 2022  
The reader of this SAP is encouraged to also read the clinical protocol and other identified documents 
for details on the planned conduct of this study.  Operational aspects related to collection and timing 
of planned clinical assessments are not repeated in this SAP unless relevant to the planned analyses. 
 
3. 
CHANGE TO THE PROTOCOL TERMINOLOGY OR SPECIFIED 
METHODS OR TO THE PREVIOUS SIGNED-OFF SAP 
The protocol uses the term “conditional power” to specify how the dose selection is made during the 
interim analysis.  This term is now replaced by “predictive power” to be precise when describing the 
dose selection method. There is no change in the protocol specified statistical methods. 
This version of the SAP removes “Time to offset of sensory block and motor block” from the list of 
Section 9.4 Pharmacodynamic (PD) Endpoints (Cohort 1 only)” and adds the word “Median” to read 
“Median time to onset …” and “Median duration of …” to the remaining two endpoints to be 
consistent with the protocol specified PD endpoints.  “Time to offset” was intended to be an 
intermediate variable for the calculation of duration.  It was not intended to be an endpoint. 
 


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4. 
STUDY OBJECTIVES 
4.1. Primary Objective  
• To compare the magnitude of the postsurgical analgesic effect following a single dose of 
EXPAREL vs. 0.25% bupivacaine hydrochloride (HCl) when administered as a sciatic nerve 
block in subjects undergoing bunionectomy. 
4.2. Secondary Objectives 
• To compare the total postsurgical opioid consumption (in oral morphine equivalents) from 0 
to 96 hours following a single dose of EXPAREL vs. 0.25% bupivacaine HCl 
• To compare the percentage of opioid-free subjects post-surgery through 96 hours following 
a single dose of EXPAREL vs. 0.25% bupivacaine HCl 
• To compare the time to first opioid consumption post-surgery, following a single dose of 
EXPAREL vs. 0.25% bupivacaine HCl 
• To characterize and compare the magnitude of the duration of motor and sensory block 
following a single dose of EXPAREL vs. 0.25% bupivacaine HCl 
• To assess the safety and pharmacokinetic (PK) profile of EXPAREL and 0.25% bupivacaine 
HCl 
 
5. 
STUDY OVERVIEW 
This is a Phase 3, multicenter, randomized, double-blind, active-controlled study in approximately 
180 subjects undergoing bunionectomy. Subjects will receive a combined sciatic (in the popliteal 
fossa) nerve block with a single dose of either EXPAREL 266 mg, EXPAREL 133 mg, or 0.25% 
bupivacaine HCl (50 mg).  The study will be conducted in two parts (Part A and Part B). Part A will 
be completed and analyzed before enrollment in Part B is initiated. 
Part A (PK, PD, Efficacy, and Safety) 
Part A is a 3-arm cohort. It will enroll approximately 60 subjects undergoing bunionectomy to obtain 
information on pharmacokinetic (PK) profile, pharmacodynamics (PD), efficacy, and safety. 
Subjects will be randomized (1:1:1) to receive either EXPAREL 266 mg, EXPAREL 133 mg, or 
0.25% bupivacaine HCl (50 mg). 
Part B (Efficacy and Safety) 
Part B is a 2-arm cohort. It will enroll approximately 120 subjects undergoing bunionectomy to 
evaluate the efficacy and safety of EXPAREL compared with bupivacaine HCl. The dose of the 
EXPAREL arm will be determined based on the interim analysis of the Part A cohort results. 


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Adaptive Study Design 
An unblinded interim analysis will be conducted by an independent party after completion of the 
Part A enrollment and assessment for the primary efficacy outcome. The predictive power (PP) of 
success at the end of the study for the primary efficacy outcomes comparing each of the two 
EXPAREL arms (EXPAREL 266 arm and EXPAREL 133 arm) to the bupivacaine HCl arm will be 
calculated: 
1. If the PP of one EXPAREL arm is less than 30% and the other EXPAREL arm is greater 
than or equal to 30%, then 
• The EXPAREL arm with PP less than 30% will be dropped in Part B. 
2. If both EXPAREL arms have a PP greater than or equal to 30%, then 
• If the PP of the 266 mg EXPAREL arm is more than 10% greater than the PP of the 133 
mg EXPAREL arm, then the 266 mg EXPAREL arm will be kept and the 133 mg 
EXPAREL arm will be dropped. Otherwise, the 133 mg EXPAREL arm will be kept and 
the 266 mg EXPAREL arm will be dropped in Part B. 
3. If the PPs of both treatment arms are less than 30%, then 
• The study will stop for futility. 
Final Analysis 
The final analysis will include subjects from both Part A and Part B cohorts. 
Block Procedure 
Subjects may be lightly sedated with 1 to 2 mg of midazolam intravenously (IV) before the nerve 
block procedure. The study drug, EXPAREL 266 mg, EXPAREL 133 mg, or 0.25% bupivacaine 
HCl (50 mg) will be administered under ultrasound guidance 90 min (±30 min) prior to surgery. A 
confirmatory ultrasound video will be taken during hydrodissection and infiltration of the study drug, 
with the needle in place to ensure accurate block placement. The video will be reviewed by an 
independent ultrasound adjudication committee to ensure accuracy of study drug administration. The 
designated study drug administrators (anesthesiologist) will not participate in any other study related 
assessments after randomization. 
Pre-Operative Medication 
• All subjects will receive celecoxib 200 mg orally (PO) within 4 hours prior to surgery. 
• Midazolam (versed) 1 to 2 mg and Ondansetron are allowed. 
• Gabapentinoids are not allowed. 
Anesthesia and Intraoperative Medication 


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• All subjects in Part A and Part B will receive a Mayo field block with 20 mL of 0.5% 
bupivacaine HCl after study drug administration (i.e., in the operating room immediately 
prior to surgical incision). The Mayo field block will be performed by the surgeon. 
• All subjects will receive a dose of 1000 mg of IV acetaminophen at the time of surgical 
incision.  
• IV fentanyl will be allowed for intraoperative pain control (at a dose not to exceed 1 µg/kg 
unless deemed medically necessary). 
Postsurgical Pain Management 
An unscheduled pain intensity assessment using the NRS (measured as “On a scale from 0 to 10, 
where 0 equals no pain and 10 equals the worst possible pain, how much pain are you experiencing 
in your operative foot right now?”) must be completed immediately prior to administration of any 
breakthrough pain medication up to 96 hours post-surgery. 
All subjects will receive a second postoperative dose of 1000 mg IV acetaminophen, administered 
approximately 8 hours after the first dose (approximately 8 hours after incision). The maximum total 
dose should not exceed 2000 mg. No additional acetaminophen is permitted after the second IV 
acetaminophen dose.  
Immediate-release PO oxycodone will be administered on an as needed (PRN) basis for 
breakthrough pain through 96 hours post-surgery in a stepwise approach:  
• Initial dose of 5 mg oxycodone may be offered.  
• If the initial opioid dose is insufficient for pain relief, an additional 5 mg oxycodone may be 
offered up to a maximum of 10 mg (total dose).  
• If a subject is unable to tolerate PO medication (or the PO oxycodone pain relief is 
insufficient), IV morphine (initiated at 2 mg) or IV hydromorphone (initiated at 0.2 mg) may 
be administered.  
No NSAIDs or other opioids (including tramadol) are allowed for the breakthrough pain 
management. No acetaminophen (other than the scheduled IV acetaminophen) should be used for 
breakthrough pain.  
Study design is presented as a schematic diagram in Figure 1. Protocol schedule of events and 
procedures are presented in Table 1. PK and PD assessment schedule are presented in Table 2. 
 


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Figure 1. Schematic Representation of Study Design 
 


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Table 1. Time and Events Schedule of Study Procedures (Screening Through POD 14) 
 


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Table 2. Pharmacokinetic and Pharmacodynamic Assessment (Part A Subjects only) 
 
 


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6. 
DEFINITIONS 
Start and End of the Nerve Block Procedure  
The start and end of study drug administration is indicative of the start and end of the nerve 
block procedure.  
Sensory and Motor block 
Sensory block is evaluated by subject’s light touch sensation at proximal and distal locations 
and comparing the sensation between the treated leg and untreated leg.  Motor block is 
evaluated by subject’s level of ankle movement.  See Sections 7.3.1 and 7.3.2 for detail. 
Study Day 
Study Day is calculated as the date of event minus the date of end of study drug administration 
plus one (1), if the date of event is on or after the date of end of study drug administration.  If 
the date of event is before the end of study drug administration, study day is the date of event 
minus the date of study drug administration.   
Time 0  
For PK, PD, and safety evaluations, Time 0 is defined as the date and time of the end of the 
study drug administration.   
For NRS pain collection, opioid consumption, vital signs, and EKG assessments, Time 0 is 
defined as the date and time of the end of the surgery. 
Baseline 
Baseline is defined as the last available measurement prior to the start of study drug 
administration. 
Treatment-Emergent Adverse Events (TEAEs) 
TEAEs are those with onset date and time on or after the start date and time of study drug 
administration. 
Beginning of Surgery 
The beginning of surgery is defined as the time of the first incision. 
End of Surgery 
The end of surgery is defined as the time recorded in the surgical record. 
Postsurgical  
Postsurgical is defined as after the end of surgery. Postsurgical Day 1 is the day of surgery. 


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Time Window for Numeric Rating Scale (NRS) for Scheduled Pain Score Collection 
Table 3 below provides the time windows for the NRS pain score for analysis by time point. If 
multiple scheduled or unscheduled assessments occur within the same window, the assessment 
closest to the scheduled time will be chosen. If the assessments are equidistant, the later 
assessment will be chosen. 
 
Table 3. Time Windows for NRS Pain Score Collected at Scheduled Time Points Post-
Surgery 
Scheduled Time of Collection 
Time Window for Acceptable Actual Time of Collection 
PACU 
First collection in PACU prior to the 6-hour time point  
6-hour 
From PACU arrival to 9-hour 
12-hour 
From >9-hour to 15-hour 
18-hour 
From >15-hour to 21-hour 
24-hour 
From >21-hour to 27-hour 
30-hour 
From >27-hour to 33-hour 
36-hour 
From >33-hour to 39-hour 
42-hour 
From >39-hour to 45-hour 
48-hour 
From >45-hour to 51-hour 
54-hour 
From >51-hour to 57-hour 
60-hour 
From >57-hour to 63-hour 
66-hour 
From >63-hour to 69-hour 
72-hour 
From >69-hour to 75-hour 
78-hour 
From >75-hour to 81-hour 
84-hour 
From >81-hour to 87-hour 
90-hour 
From >87-hour to 93-hour 
96-hour 
From >93-hour to 99-hour 
 
Time Windows for Sensory and Motor Block Tests 
Table 4 below provides the time windows for the sensory block and motor block summaries by 
timepoint (Sections 10.7). 
 


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Table 4. Time Windows for Sensory and Motor Block Tests at Scheduled Time Points 
Post-Study Drug Administration 
Scheduled Time of Collection 
Time Window for Acceptable Actual Time of Collection 
Predose 
Predose 
15-min 
From end of study drug administration to 22.5-min 
30-min 
From >22.5-min to 37.5-min 
45-min 
From >37.5-min to 52.5-min 
1-hour 
From >52.5-min to 1.5-hour 
2-hour 
From >1.5-hour to 5-hour 
8-hour 
From >5-hour to 10-hour 
12-hour 
From >10-hour to 18-hour 
24-hour 
From >18-hour to 27-hour 
30-hour 
From >27-hour to 39-hour 
48-hour 
From >39-hour to 54-hour 
60-hour 
From >54-hour to 66-hour 
72-hour 
From >66-hour to 78-hour 
84-hour 
From >78-hour to 90-hour 
96-hour 
From >90-hour to 108-hour 
120-hour 
From >108-hour to 132-hour 
144-hour 
From >132-hour to 156-hour 
168-hour 
From 156-hour to 180-hour 
 
Oral Morphine Equivalent Dose (OMED) 
This is an OMED converted from opioid dose subjects take during the study. This conversion 
enables the comparison of the analgesic effects of different opioid medications by the same 
route and in the same units. The conversion factors are listed in Section 10.2.2 Table 6. 
Time Window for Opioid Pain Medication  
This window (see Section 10.2.2 Table 8) captures the opioid analgesic effect from start of the 
opioid administration to the end of the opioid effect.  


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Time Windows for Vital Signs 
Table below provides the time window for vital signs for analysis by time point. If multiple 
scheduled or unscheduled assessments occur within the same window, the assessment closest 
to the scheduled time will be chosen. If the assessments are equidistant, the later assessment 
will be chosen. 
Table 5. Time Windows for Vital Signs Collected for Scheduled Time Points Post-Surgery 
Scheduled Time of Collection 
Time Window for Acceptable Actual Time of Collection 
Baseline 
Prior to study drug administration 
0.25-hour 
From 0-hour to 0.25-hour (inclusive) 
1-hour 
From 0.25-hour (exclusive) to 1.5-hour (inclusive) 
2-hour 
From 1.5-hour (exclusive) to 3-hour (inclusive) 
6-hour 
From 3-hour (exclusive) to 9-hour (inclusive) 
12, 18, …q6h, …, 96-hour 
From time point - 3 hour (exclusive) to time point + 3 hour 
(inclusive) 
120-hour (Cohort 1 only) 
From 99-hour (exclusive) to 132-hour (inclusive) 
144-hour (Cohort 1 only) 
From 132-hour (exclusive) to 156-hour (inclusive) 
168-hour (Cohort 1 only) 
From 156-hour (exclusive) to 180-hour (inclusive) 
 
7. 
STUDY ASSESSMENTS 
7.1. Efficacy Assessment 
7.1.1. Pain Intensity Assessment  
• Pain intensity scores measured using NRS as “On a scale from 0 to 10, where 0 equals 
no pain and 10 equals the worst possible pain, how much pain are you experiencing in 
your operative foot right now?” will be assessed as follows*:  
o Upon arrival in the Post-Anesthesia Care Unit (PACU)  
o Every 15 minutes interval in the PACU  
o At PACU discharge  
o Every 6 hours from the end of surgery to 96 hours post-surgery as follows: 6, 
12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 96 hours  
o Prior to administration of any pain medication until 96 hours post-surgery 
• Pain intensity using the NRS at 24, 48, 72, and 96 hours post-surgery measured as “What 
was your worst pain in your operative foot in the last 24 hours?” 


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• Pain intensity using the NRS at 24, 48, 72, and 96 hours post-surgery measured as “What 
was your average pain in your operative foot in the last 24 hours?” 
* If subject is asleep, the subject will not be awakened to assess pain. If the subject awakens within the time 
window, a pain score will be collected then.  
 
7.1.2. Opioid Dose Conversion 
Opioid dose will be converted to oral morphine equivalent dose (OMED mg) using the 
conversion factor in Table 6 for all summaries.  Total opioid dose is the sum of all opioids in 
OMED taken during the time interval of interest.   
 
Table 6. Conversion Factors to Oral Morphine Equivalent Dose from Other Opioids 
Medication 
Unit 
Route 
Oral Morphine Conversion 
(Multiplication) Factor 
Oxycodone, Oxycocet, Percocet, 
acetaminophen-oxycodone 
mg 
PO 
1.5 
Morphine 
mg 
IV, IM, SC 
3 
Morphine 
mg 
PO 
1 
Hydromorphone (Dilaudid) 
mg 
IV, IM, SC 
20 
Hydromorphone (Dilaudid) 
mg 
PO 
4 
Fentanyl 
mg 
IV, PO, IM 
300 
Hydrocodone combination product - Vicodin, 
Norco, Lorcet, Lortab, hydrocodone-
acetaminophen, Ketobemidone 
mg 
PO 
1 
Codeine combination product - Tylenol 3, 
acetaminophen-codeine, Paracetamol Forte, 
Tylenol 4 
mg 
PO 
0.15 
Ultram, Tramadol, Tramadol hydrochloride 
mg 
PO, IM 
0.25 
Demerol, Meperidine, Pethidine 
mg 
IV, SC 
0.3 
Demerol, Meperidine, Pethidine 
mg 
PO 
0.1 
Ketobemidone, Oxycodone 
mg 
IV 
 
3 
Nalbuphine (Nubain/Manfine) 
mg 
IV, IM, SC 
3 
PO = oral, IV = intravenous, IM = Intramuscular, SC = subcutaneous. 
 


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7.1.3. Subject Satisfaction with Pain Management 
The subject's satisfaction with pain management will be collected at 96 hours post-surgery using 
question from the International Pain Outcome (IPO). Subjects will be asked to circle a number 
that best describes how satisfied they are with the results of their pain treatment since surgery 
on an 11-point Likert scale from 0 (extremely dissatisfied) to 10 (extremely satisfied). 
 
7.2. Pharmacokinetic assessments (Part A only)  
Blood samples for PK assessment will be obtained from subjects enrolled in Part A. A total of 
17 PK samples will be collected for each subject. These samples will be obtained at pre-
dose/baseline (up to 15 min before block), 30 min, 45 min, and 1, 2, 8, 12, 24, 30, 48, 60, 72, 
84, 96, 120, 144, and 168 hours from end of block procedure.  
 
7.3. Pharmacodynamic Assessments (Part A only)  
PD assessments will be performed by a limited number of blinded, trained, licensed medical 
staff.   
7.3.1. Assessment of Sensory Block 
Sensory assessment for light touch will be performed at pre-dose, 15, 30, and 45 minutes, and 
1, 2, 8, 12, 24, 30, 48, 60, 72, 84, 96, 120, 144, and 168 hours from the end of the nerve block 
procedures, or until full sensory function has returned to baseline (pre-dose) levels. Each light 
touch area of assessment will be rated independently. Additional unscheduled assessments may 
be performed, particularly around the surgery, if no onset of block is noted on the last scheduled 
assessment prior to surgery.  
 
For each sensory assessment, both locations mentioned below will be assessed for light touch. 
If on the 168 hours assessment there is a sensory deficit, the incident will be recorded as an AE. 
The physician will assess the subject for other etiologies that may explain the persistent sensory 
deficit. If the sensory deficit persists at the 168 hour assessment, the subject is to return for 
unscheduled visit(s) at the Investigator's discretion until the sensory function has returned.  
 
Sensory function assessment will include the following two locations:  
1. Proximal – Lateral aspect of the lower leg (3-4 cm above ankle)  
2. Distal – Sole of the foot  
 
The intent of applying the tongue depressor to the contralateral foot is to establish a reference 
sensation to compare to the test area. The subject is to determine if the sensation on the 
contralateral foot is the same as the test area (“Yes” = the same = sensory not blocked) or if 


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there is a decreased sensation or not the same sensation (“No” = not the same = sensory 
blocked).  
 
The test may be repeated in case of ambiguous or inconsistent responses until the examiner is 
satisfied with the accuracy of the assessment. The assessments will be conducted single-blinded 
(i.e., the subject will be instructed to close their eyes). Once the offset of sensory block (return 
of light touch sensation in both test areas in a single assessment) is recorded, no further 
scheduled sensory assessments are required. 
Onset of sensory block is defined as the earliest timepoint with loss of light touch sensation in 
the distal test areas.  If onset time is not achieved, it will be considered censored at the last onset 
assessment time prior to surgery. 
Offset of sensory block is defined as the first timepoint of return of light touch sensation along 
the distribution of the target nerve distal to the site of the block. After offset of sensory 
assessments are noted (light touch sensation in BOTH proximal and distal test areas in a single 
assessment), no subsequent assessments will be conducted.  If offset time is not achieved, it 
will be considered censored at the last offset assessment time after surgery.  
Duration of sensory block is defined as the time between onset and offset of the sensory 
blocks.  If onset is not achieved, duration will be calculated from the surgery start time through 
the offset time, left censored. If both onset and offset are not achieved, duration will be 
calculated from the surgery start time through the last offset assessment time, interval censored.  
See Section 10.5.5.1 for how the censoring is handled in analysis.  If post-dose onset 
assessments are completely missing, time to onset will be set to missing.  If either onset or 
offset assessments are completely missing, duration of sensory block will be set to missing.  
7.3.2. Assessment of Motor Block 
Motor function (onset and offset of motor block) will be assessed by voluntary active movement 
of the foot. This will be used to determine the onset and duration of motor blockade.  
The motor function test will be performed at pre-dose, 15, 30, and 45 minutes, 1, 2, 8, 12, 24, 
30, 48, 60, 72, 84, 96, 120, 144, and 168 hours from the end of the nerve block procedure, or 
until full motor function has returned to baseline (pre-dose) levels. Additional unscheduled 
assessments may be performed, particularly around the surgery if no onset of block is noted on 
the last scheduled assessment prior to surgery. Once the offset of motor block is recorded, no 
further scheduled motor assessments are required. 
Onset of motor block is defined as the earliest timepoint with partial or no foot movement. If 
subject does not experience loss of motor function, their onset will be censored at their last 
available motor assessment time point prior to surgery.  


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Offset of motor block is defined as resolution of motor block with complete foot movement. 
If offset time is not achieved, it will be considered censored at the last offset assessment time 
after surgery. After offset of motor block is noted, no subsequent assessments will be required.  
Duration of motor block is defined as time between onset and offset of motor block. The 
censoring and missing data rule for the duration of sensory block also applies to the duration of 
motor block. 
 
7.4. Safety Assessments 
Adverse events and concomitant medications will be collected from signing the informed 
consent form (ICF) through end of study. In case an AE of special interest (AESI) or serious 
AE (SAE) occurs during the study, if the investigator or medical monitor considers that the 
event may be related to study treatment or suggests the possible occurrence of local anesthetic 
systemic toxicity (LAST; with or without the need for treatment [e.g., intralipids]), an 
unscheduled PK blood sample, 12-lead EKG, and vital signs will be collected. Unscheduled 
neurological assessments will be conducted according to the investigator site’s standard of care 
until resolution. 
Vital signs will be collected at baseline, upon arrival in PACU, at PACU discharge, and every 
6 hours post-surgery through 96 hours, and at hospital discharge for both Part A and Part B, 
and 120, 144, and 168 hours for Part A subjects.  
12-lead EKG assessments will be performed at screening and at 24, 48, 72, and 96 hours post-
surgery for subjects in both Part A and Part B, and additionally at 120, 144, and 168 hours post-
surgery for subjects in Part A. 
 
7.5. Change in the Study Design and Its Effect on the Statistical Analysis 
None. 
 
8. 
ANALYSIS SETS 
The following study analysis data sets are planned: 
Safety Analysis Set - The Safety Analysis Set will include all randomized subjects who receive 
study drug.  All analyses based on the Safety Analysis Set will be by actual treatment received. 
Efficacy Analysis Set - The Efficacy Analysis Set will include all subjects in the safety analysis 
set who undergo the planned surgery and have at least one post-study drug administration NRS 
pain assessment.  All analyses based on the Efficacy Analysis Set will be by randomized 


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treatment regardless of treatment actually received. This analysis set will be used for all efficacy 
analysis. 
Sensitivity Analysis Set – This is a subset of Efficacy Analysis Set.  This set will exclude 
Subject (xxx-xxxx) who received non-randomized study drug. 
Pharmacokinetic Concentration (PKC) Analysis Set – This set will include all subjects enrolled 
in Part A who receive study drug and have at least one post-dose plasma concentration sample.  
All analyses based on the PKC Analysis Set will be based on the actual treatment received. 
Pharmacokinetic Parameter (PKP) Analysis Set - The PK Analysis Set will include all subjects 
in Part A who receive study drug and provide sufficient samples to enable calculation of PK 
parameters. The final inclusion in the PK analysis set will be defined in the PK report. All 
analyses based on the PKP Analysis Set will be based on the actual treatment received.  
Pharmacodynamics (PD) Analysis Set - The PD Analysis Set will include all subjects in Part A 
and in the efficacy analysis set who provide sufficient data to allow for calculation of PD 
parameters required for analysis. All analyses based on the PD Analysis Set will be based on 
the randomized treatment group.   
 
9. 
STUDY ENDPOINTS 
9.1. Efficacy Endpoints 
9.1.1. Primary Endpoint 
The primary endpoint is the area under the curve (AUC) of the NRS pain intensity scores from 
0 to 96 hours post-surgery. 
9.1.2. Secondary Endpoints 
1. Total postsurgical opioid consumption in oral morphine equivalents dose (OMED) from 0 
to 96 hours post-surgery  
2. Opioid-free status from 0 to 96 hours post-surgery 
3. Time to first opioid consumption post-surgery  
4. Worst and average NRS pain intensity scores at 24, 48, 72, and 96 hours post-surgery 
9.1.3. Exploratory Endpoints 
 
 
 
 
 
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9.2. Safety Endpoints 
Safety endpoints will include the incidence of treatment-emergent AEs and SAEs from start of 
the nerve block procedure through POD14, change from baseline in vital signs over time, and 
abnormal post-baseline EKG findings.  
 
9.3. Pharmacokinetic (PK) Endpoints (Part A only)  
The following PK endpoints will be determined: 
• Area under the plasma concentration-versus-time curve (AUC), specifically AUC0-last 
and AUC0-∞ 
• Maximum plasma concentration (Cmax) and time of Cmax (Tmax) for subjects treated with 
bupivacaine HCl and Early and Late Cmax and Tmax for subjects treated with EXPAREL 
• Apparent terminal elimination half-life (t1/2el) 
• Apparent clearance (CL/F) 
• Apparent volume of distribution (Vd) 
 
9.4. Pharmacodynamic (PD) Endpoints (Part A only)  
• Median time to onset of sensory block and motor block 
• Median duration of the sensory block and motor block 
 
10. 
METHODS OF STATISTICAL ANALYSIS 
10.1. 
General Principles 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs).  All 
analyses and tabulations will be performed using SAS Version 9.4 or later.  Continuous 
variables will be summarized using descriptive statistics [sample size (n), mean, standard 
deviation (SD), minimum, median, and maximum].  Categorical variables will be tabulated with 
number (n) and percentage (%) of unique subjects. Unless otherwise noted, percentages will be 
calculated using the number of subjects in the respective treatment group and analysis set as the 
denominator and presented with only those categories appearing in the data. 
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Individual subject data will be provided in listings. All listings will be sorted by Part, treatment, 
site, subject, and, if applicable, collection date and time. 
The statistical methods presented in this document supersedes the statistical analysis methods 
described in the clinical protocol. Significant deviations/changes from the planned analyses 
described in this SAP will be identified, with justification, in the appropriate section of the 
clinical study report (CSR). 
This study is comprised of two parts. Part A will enroll subjects into 3 treatment groups 
(EXPAREL 133 mg, EXPAREL 266 mg, and bupivacaine).  Upon interim analysis when Part 
A is completed, one of the EXPAREL dose group will be dropped and the other EXPAREL 
dose group will be selected for the Part B cohort. The final CSR tables will pool subjects from 
both Part A and Part B cohorts.  The summary statistics will be presented for the bupivacaine, 
the EXPAREL 133 mg, and the EXPAREL 266 mg groups, as well as the EXPAREL 133 and 
266 mg combined group (for disposition, baseline characteristics and safety only). The 
statistical analysis for efficacy will only apply to the bupivacaine group and the selected 
EXPAREL dose group pooled from both parts. 
When investigator site is used as a stratification variable or as a categorical covariate, sites with 
fewer than 8 subjects in the efficacy analysis set will be pooled with other sites for analysis. US 
Census Bureau geographic regions (see Table 7) will be used for the pooling. Sites meeting the 
criteria for pooling will be pooled with other small sites within their states. If the resulting 
pooled site within the state still doesn’t have at least 8 subjects, it will be pooled with the site 
within the division with the smallest enrollment that doesn’t meet the pooling criteria. If all 
sites within a division are pooled and the resulting pooled site still doesn’t have at least 8 
subjects, the pooled divisional site will be pooled with other small sites within the region. If the 
pooled regional site still does not have at least 8 subjects, it will be pooled with the site with 
the smallest enrollment from the neighboring regions. 
 
Table 7. US Census Regions and Divisions  
Region  
Division  
State  
Midwest  
East North Central  
Illinois, Indiana, Michigan, Ohio, Wisconsin  
West North Central  
Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, South 
Dakota  
Northeast  
Middle Atlantic  
New Jersey, New York, Pennsylvania  
New England  
Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, 
Vermont  
South  
East South Central  
Alabama, Kentucky, Mississippi, Tennessee  
South Atlantic  
Delaware, District of Columbia, Florida, Georgia, Maryland, North 
Carolina, South Carolina, Virginia, West Virginia  
West South Central  
Arkansas, Louisiana, Oklahoma, Texas  
West  
Mountain  
Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, 
Wyoming  
Pacific  
Alaska, California, Hawaii, Oregon, Washington  
 


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10.2. 
Handling Missing Values 
10.2.1. Total Post-Surgical Opioid Consumption 
For the calculation of the total postsurgical opioid consumption from 0 to 96 hours, opioid pain 
medication recorded on the Breakthrough Pain Medication eCRF page will be used.  If an opioid 
is taken on the start of study drug administration day but the time is missing, the time will be 
imputed as end time of surgery plus (+1) 1 minute. If an opioid is taken after the day of study 
drug administration and time is missing, the time will be imputed as 00:00. 
For the calculation of the total dose through 96 hours, if a subject’s last follow-up time in the 
health care facility is 96-x hours, then the opioid taken between 96-2x hour to 96-x hour will be 
used to project the amount from the last follow-up time to 96 hours, where time of last follow-
up will be defined as the latter of (1) the last NRS pain assessment, (2) the start time of the last 
opioid pain medication, (3) time of the subject completion of the 96-hour satisfaction 
questionnaire, and (4) time of last sensory and motor block assessment. 
10.2.2. NRS Pain Intensity Scores  
Pain scores obtained during the opioid medication window will be replaced with the windowed-
worst observation carried forward (wWOCF).  For this study, the prescribed opioid pain 
medication for breakthrough pain is oxycodone. However, morphine, hydromorphone, or other 
opioids may be used if the subject is unable to tolerate oral oxycodone.  The durations of the 
analgesic effect for various opioids are listed in Table 8. 
 
Table 8. Opioid Pain Medication Window 
Medication 
Route 
Window Used to 
Replace NRS 
Oxycodone, Oxycocet, Percocet, acetaminophen-
oxycodone, Oxycontin 
PO, IM, IV, SC 
6 hours 
Morphine 
IV, PO, SC 
4 hours 
Hydromorphone (Dilaudid), Hydromorphone 
hydrochloride 
IV 
2 hours 
Hydromorphone (Dilaudid), Hydromorphone 
hydrochloride 
PO, IM, SC 
4 hours 
Hydrocodone 
PO 
6 hours 
Fentanyl 
IV, PO, IM 
6 hours 
Hydrocodone combination product - Vicodin, Norco, 
Lorcet, Lortab, hydrocodone-acetaminophen 
PO 
6 hours 
Codeine combination product - Tylenol 3, 
acetaminophen-codeine, Paracetamol Forte, Tylenol 4 
PO 
6 hours 
Ultram, Tramadol, Tramadol hydrochloride 
PO 
6 hours 
PO = oral, IV = intravenous, IM = Intramuscular, SC = subcutaneous. 


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If other opioid pain medications not listed above are given, the window will be determined prior 
to the database lock and unblinding.  If a combination opioid product is given, the window will 
be determined by the opioid part of the medication. 
For the primary efficacy endpoint of AUC of NRS pain intensity scores from 0 to  96 post-
surgery, after applying the visit windows (Section 6 Table 3) and wWOCF to all 
scheduled/unscheduled pain scores, remaining missing data at each scheduled time point (6, 12, 
18, 24, 30, 36, 42, 48, 54, 60, 66, 72 , 78, 84, 90, and 96 hours) will be interpolated by the two 
data points before and after the missing data points. (Note for Study 402-C-333, out of 3,738 data 
points collected or missing for 0-100 hours post-surgery, only 72 (1.9%) data points were actually 
missing [ref ADEF1] for Study 402-C-333). The procedures of wWOCF and interpolation are 
described as follows. 
A. For subjects who take an opioid pain medication, their NRS scores recorded within the 
window of opioid medication (see Table 8) will be replaced by the ‘worst’ observation.  
The ‘worst’ observation will be the highest NRS score from the end of previous opioid 
window (excluding the exact end of the window) or the end of surgery whichever is 
later, inclusive of the unscheduled NRS score taken at the time of opioid pain 
medication administration. If the scheduled NRS score taken in the window is higher 
than the ‘worst’ observation to be carried forward, the ‘worst’ observation will be 
replaced by this higher value which will be carried forward until the end of the window. 
If the scheduled NRS score within the window is missing, it will be imputed with the 
‘worst’ observation. 
B. After the wWOCF imputation described above, if there are still missing NRS scores at 
scheduled time points, they will be interpolated as follows, 
𝑝𝑝𝑖𝑖= (𝑝𝑝𝑖𝑖+1 −𝑝𝑝𝑖𝑖−1) 𝑡𝑡𝑖𝑖−𝑡𝑡𝑖𝑖−1
𝑡𝑡𝑖𝑖+1 −𝑡𝑡𝑖𝑖−1
+ 𝑝𝑝𝑖𝑖−1, 
where pi is the missing pain score at time point ti, pi-1 and pi+1 are the two collected or 
wWOCF imputed pain scores at time ti-1 and ti+1.  The interpolated value will retain one 
decimal place in the database. 
10.2.3. Adverse Event or Concomitant Medication Date or Time 
For AEs with missing or partially missing start date/time, the following imputation rules will 
be applied for the determination of treatment-emergent status: 
If an AE has a partial onset date and time, the collected or imputed start and stop dates and 
times will be used to determine treatment emergence (e.g., an AE with stop date and time before 
the start date and time of study treatment is not treatment-emergent).   
• If the year is unknown, then the onset date will be assigned the date and time of first 
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• If the year is known to be different from the year of the first dose, then missing month 
and day will be imputed as the first month and first day of the month. 
• If the year is known to be the year of the first dose, 
a) If the month is unknown or is the same as the month of the first dose, then the 
missing month and day will be imputed by the month and day of the first dose. 
b) If the month is known to be different from the month of the first dose, then the 
missing day is imputed as 01 (first day of the month). 
• If the time is unknown, then: 
a) If the date (day, month, and year) matches the date of the administration of study 
drug, then the time of the study treatment will be used to impute the missing 
time. 
b) Otherwise, ’00:00’ will be assigned. 
For medications with missing or partially missing dates, Section 10.4.5 provides rules for the 
determination of prior or concomitant status.   
10.2.4. Adverse Event Severity or Relationship to Study Drug 
If severity of an AE is not reported, then for tables of AEs by severity, the event will be 
classified as ‘Severe’ and will be footnoted for the table to indicate this imputation.  If 
relationship to study drug is not reported for an AE, then for tables of study-drug related AEs, 
the event will be assigned the relationship of ‘definite’.  Tables presenting related AEs will 
include all AEs with relationships of ‘possible,’ ‘probable,’ or ‘definite’ as assessed by the 
investigator. 
10.2.5. Time to Event  
For calculating time to an event when only the hour is reported, the minutes will be set to zero.  
The censoring method is described in Sections 7.3.1 and 7.3.2 when the onset time or the offset 
time of sensory or motor block is not captured. 
 
10.3. 
Subject Disposition 
Subject disposition summaries will include the number and percentage of subjects by treatment 
group for the following categories: 
• Screened 
o Screen failure 
o Enrolled (i.e., randomized) 
• Randomized  
o Randomized not treated 


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o Randomized treated 
• In the Safety Analysis Set 
• In the Efficacy Analysis Set 
• In the Pharmacokinetic Concentration and Parameter (PKC and PKP) Analysis Set 
• In the Pharmacodynamics (PD) Analysis Set 
• Protocol 
o Enrolled under each amendment 
• Completed the study as planned 
• Discontinued from the study 
o Reasons for discontinuation from the study 
The number and percentage of screen failures will be reported using the number of subjects 
screened as the denominator. Percentages based on the Efficacy Analysis Set will use the 
number of subjects randomized and treated as denominator with data grouped by randomized 
assignment. Percentages for the Safety, PKC, and PKP Analysis Sets (see Section 10.8) will be 
use the number of subjects treated as the denominator with data grouped by actual treatment 
received.  
In addition to the summary for the overall study, subject disposition will also be summarized 
by investigator site.  
 
10.4. 
Description of Demographics and Baseline Characteristics 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be provided for 
continuous variables. The number (n) and percentage (%) of subjects will be tabulated for 
categorical variables.  Subjects from Part A and Part B will be pooled and presented. 
10.4.1. Demographics  
The summary of demographic data will present: 
• Age (years) – continuous and categorical (<45, 45 to <65, and ≥65 years), n (%)  
• Sex – n (%) 
• Ethnicity – n (%) 
• Race – n (%)  
Age will be calculated based on the date the subject signed the informed consent form (ICF).   
The demographics will be summarized by treatment group and for all treatment groups 
combined. Summaries will be provided for each analysis set separately. The demographics will 
also be summarized by the pooled investigator site. 
10.4.2. Baseline Characteristics 
The summary of baseline characteristic data will present: 


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• American Society of Anesthesiologists (ASA) Classification – n (%) 
• Height (cm) – continuous 
• Weight (kg) – continuous 
• Body Mass Index (BMI) (kg/m2) – continuous and categorical (<25, 25 to <30, and 
≥30 kg/m2) 
• Average pain intensity scores on the NRS in the last 30 days of baseline 
• Worst pain intensity scores on the NRS in the last 30 days of baseline 
Weight in pounds will be converted to kilograms using the conversion factor of 2.2046 pounds 
to 1 kilogram. Height in inches will be converted to centimeters using the conversion factor of 
2.54 centimeters to 1 inch.  
Baseline characteristics will be summarized by treatment group and for all treatment groups 
combined. Summaries will be provided for each analysis set separately. The baseline 
characteristics will also be summarized by pooled investigator site. 
10.4.3. Medical and Surgical History 
The prevalence (frequency and percentage) of medical and surgical histories will be tabulated 
by MedDRA (v25.0) System Organ Class (SOC) and Preferred Term (PT) for each treatment 
group and for all groups combined.  All medical and surgical histories will be included in the 
data listing. 
10.4.4. Surgery Characteristics 
Surgery characteristics including duration of surgery, use of intraoperative medication (Y/N), 
and AE/SAE report during surgery (Y/N) will be summarized using descriptive statistics.  
Summaries will be provided for each (efficacy and safety) analysis set. 
The duration of surgery will be calculated as the difference between the end of surgery and start 
of surgery times. 
A listing of admission and discharge to the health care facility and PACU will be provided.   
10.4.5. Intraoperative, Prior, and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHO Drug Dictionary Global B3 March 2022 ) and will be classified according to the 
Anatomical Therapeutic Chemical classification term (ATC) and Preferred Term (PT). 
Intraoperative medications are defined as medications given as part of the surgical procedure. 
These may include anesthesia, local anesthetics, opioids, or other medications collected on the 
Intraoperative Medication CRF Page. 
Prior and concomitant medications are medications collected on the Prior/Concomitant 
Medication eCRF page. Prior medications are defined as medications with a stop date and time 
prior to the start of study drug administration. Concomitant medications are defined as 


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medications taken after the start of study drug administration (i.e., started prior to the start of 
study drug administration and continued after or started after the start of study drug 
administration). 
For the determination of the prior and concomitant status, these rules will be followed for 
incomplete dates. 
• If the medication stop date is partially missing,  
o If the year and month indicate the stop date is before study drug administration, 
it will be considered a prior medication.  
o Otherwise, it will be considered concomitant medication. 
• If the medication stop date is completely missing, it will be considered a concomitant 
medication. 
The frequency and percentage of subjects with prior medication use and concomitant 
medication use will be tabulated by WHODD ATC (Level 3) and PT for each treatment group 
and for all groups combined. 
All medications will be included in the data listing. 
10.4.6. Protocol Deviations 
Protocol deviations will be classified into, but not limited to, improper ICF procedure, 
ineligibility for inclusion/exclusion criteria, efficacy assessments, breakthrough pain 
medication dispensing procedure, study noncompliance, restricted medication, PK/PD 
assessments, and study drug error.  The frequency and percentage of subjects with important 
protocol deviations will be tabulated by treatment group. 
Additionally, the protocol deviations will also be summarized by investigator site. 
10.4.7. Measurements of Treatment Compliance 
Study drug is administered by a party other than the subject. However, any deviation from 
administration of study drug, as randomized, will be captured and summarized as a protocol 
deviation. 
 
10.5. 
Efficacy Analysis 
All efficacy analyses will be performed using the Efficacy Analysis Set Pooling Part A and Part 
B subjects.  Simple summary statistics (e.g., mean, standard deviation, median, minimum, and 
maximum) will be presented for all 3 treatment groups.  However, the statistical analysis (e.g., 
least square means, standard errors, the associated 95% confidence intervals, and the p-values) 
will be performed only for the select EXPAREL dose group for Part B and the bupivacaine 
group.  


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Unless specified otherwise, all confidence intervals will be 2-sided with 95% confidence. All 
hypothesis tests will be between the select EXPAREL dose group for Part B and the 
bupivacaine HCl group. All statistical comparisons will be 1-sided tests at an alpha level of 
0.025.   
10.5.1. Adjustments for 2-Stage Design and Multiplicity 
Adjustment due to interim dose selection and 2-stage design (Chaturvedi et al 2014): 
To control for the inflation in the overall Type-I error rate due to EXPAREL dose selection in 
the interim analysis, a closed testing procedure will be carried out for the hypotheses described 
below: 
𝐻𝐻𝑜𝑜
(1): 𝜃𝜃1 = 0 
𝐻𝐻𝑜𝑜
(2): 𝜃𝜃2 = 0 
 𝐻𝐻𝑜𝑜
(1,2): 𝜃𝜃1 = 𝜃𝜃2 = 0 
where 𝜃𝜃𝑖𝑖 is the mean difference between EXPAREL dose group i and the bupivacaine control 
group.  Without loss of generality, suppose dose group 1 is selected at the interim analysis. To 
declare statistical significance for dose group 1, both 𝐻𝐻𝑜𝑜
(1) and 𝐻𝐻𝑜𝑜
(1,2) will have to be rejected at 
level α.  Applying the Simes testing procedure, the intersection hypothesis p-value at the interim 
analysis is derived as 
𝑝𝑝(1,2) = 𝑚𝑚𝑚𝑚𝑚𝑚 (2𝑝𝑝(1), 𝑝𝑝(2)) 
where 𝑝𝑝(1) and 𝑝𝑝(2) are the p-values for EXPAREL dose group 1 and dose group 2 at the interim 
analysis. It is assumed 𝑝𝑝(1) < 𝑝𝑝(2) because 𝑝𝑝(1) is selected for Part B. 
The inverse normal combination function (also known as the method of inverse normal p-values 
[MINP]), 
𝐶𝐶(𝑝𝑝, 𝑞𝑞) = 1 −∅቎ඨ
𝑛𝑛1
𝑛𝑛1 + 𝑛𝑛2
∅−1(1 −𝑝𝑝) + ඨ
𝑛𝑛2
𝑛𝑛1 + 𝑛𝑛2
∅−1(1 −𝑞𝑞)቏ 
will be used to combine the p-value from Part A and Part B to derive the final p-value, where 
n1 = 20 and n2 = 60 are the sample sizes and p and q are the p-values of Part A and Part B. 
The final p-value, adjusting for multiplicity and 2-stage design, for the select EXPAREL dose 
group 1 is derived as follows 
p-value = 𝑚𝑚𝑚𝑚𝑚𝑚൛𝐶𝐶൫𝑝𝑝(1), 𝑞𝑞(1)൯, 𝐶𝐶൫𝑝𝑝(1,2), 𝑞𝑞(1)൯ൟ. 
Note this MINP method will only apply to the primary efficacy endpoint. 
Adjustment for multiplicity: 


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To control for the overall Type-I error rate for the multiple comparisons, the statistical tests will 
be conducted in the hierarchical order as follows.   
1. Primary endpoint (AUC of NRS pain 0-96 hours post-surgery) 
2. First secondary endpoint (Total postsurgical opioid consumption 0-96 hours post-
surgery) 
3. Second secondary endpoint (opioid-free through 96 hours) 
4. Third secondary endpoint (Time to first postsurgical opioid) 
At any step if the statistical test becomes non-significant, all the subsequent tests will be deemed 
non-significant. 
 
10.5.2. Primary Efficacy Endpoint 
The primary efficacy endpoint is AUC of the NRS pain intensity scores from 0 to 96 hours post-
surgery.  The NRS pain intensity score is collected from the assessment, “on a scale from 0 to 
10, where 0 equals no pain and 10 equals the worst possible pain, how much pain are you 
experiencing in your operative foot right now?” The worst and average daily pain scores are 
not included in the AUC calculation. 
For each subject, the AUC curve is derived using the trapezoidal rule (see formula below) on 
the pain scores adjusted for opioid pain medication using the observed and imputed values (see 
Section 10.2.2).  AUC will start with the first pain assessment obtained after surgery (arrival at 
PACU) and use all subsequent pain assessments up to 96 hours post-surgery. Pain scores 
collected prior to the opioid medication administration or unscheduled assessments are also 
included in the AUC calculation.  Exact assessment time will be used in deriving AUC. 
𝐴𝐴𝐴𝐴𝐴𝐴= ൝෍(
𝑛𝑛
𝑖𝑖=2
𝑝𝑝𝑖𝑖+ 𝑝𝑝(𝑖𝑖−1))(𝑡𝑡𝑖𝑖−𝑡𝑡(𝑖𝑖−1))ൡ/2 
where pi is the NRS pain score at time i and ti is the time, in hours, from end of surgery.  Note 
t1 is pain score collected upon PACU arrival.   
In calculating AUC0-96, if the exact 96-hour pain score is not collected, it will be interpolated 
using the two nearest before and after data points. If the last 96-hour assessment is before 
96.0 hours, then the exact 96-hour pain score for the AUC calculation will use this last 
observation carried forward. If the last assessment is after 96-hour but before 100-hour, then 
the exact 96-hour pain score will be interpolated using this last assessment and the assessment 
before 96-hour.  If the first assessment at PACU arrival time is not collected, the pain score at 
PACU arrival will use the first assessment after PACU arrival carried backward. The PACU 
arrival time will be imputed with the median arrival time of all subjects.  Generally, when the 
pain score is not collected at the exact time point for AUCx-y calculation, the pain score at the 


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exact time point will be interpolated by the two nearest data points before and after the exact 
time point. 
The AUC of NRS pain intensity scores from 0 to 96 hours will be summarized by treatment 
group.  
The primary analysis of the primary efficacy endpoint will compare the EXPAREL (at the dose 
selected for Part B) dose group and the bupivacaine HCl group. The superiority of EXPAREL 
to bupivacaine HCl will be evaluated based on the following null hypothesis and alternative 
hypothesis using the Efficacy Analysis Set with the wWOCF/interpolation method: 
H0: EXPAREL is not superior to bupivacaine HCl with respect to AUC of NRS pain 
intensity scores from 0 to 96 hours. 
Ha: EXPAREL is superior to bupivacaine HCl with respect to AUC of NRS pain 
intensity scores from 0 to 96 hours. 
A one-sided hypothesis test will be performed at α=0.025 level of significance comparing 
EXPAREL and bupivacaine HCl as follows: 
• If the one-sided p-value for the least square (LS) mean treatment difference in AUC 
NRS0-96 (EXPAREL – bupivacaine HCl only) is >0.025, then the superiority of 
EXPAREL admixed to bupivacaine HCl only is not achieved. 
• If the p-value for the LS mean treatment difference in AUC NRS0-96 (EXPAREL– 
bupivacaine HCl only) is ≤0.025, then the superiority of EXPAREL to bupivacaine HCl 
is achieved. 
To test for significant differences between the select EXPAREL dose group and the bupivacaine 
HCl group, an analysis of covariance (ANCOVA) model with main effect of treatment and 
covariate of age (continuous) will be used. The LS means for each treatment group, LS mean 
difference between the two treatment groups, two-sided 95% CI for the LS mean difference, 
and one-sided p-value will be presented. The primary analysis will be performed based on the 
Efficacy Analysis Set. 
Sample SAS code for ANCOVA follows.  
ods output Diffs=diff LSMEstimates=lsme; 
proc genmod data=auc; 
 
class trtpn; 
 
model aval=trtpn age / dist= normal link=identity; 
 
lsmestimate trtpn ‘Group x vs Group 3’ 1 -1  
/ cl lower alpha=0.025 ilink; 
run; 
In addition to the presentation for the between group difference, the percent reduction in AUC 
will also be presented. The % reduction is derived as follows, 
% Reduction = {LS MeansBup – LS MeansEXPAREL}/LS MeansBup ×100%. 


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Because this is a 2-stage design with dose selection after Part A is completed, to prevent the 
inflation in the Type-I error rate, the ANCOVA model will be performed for Part A and Part B 
separately. The Simes multiple comparison procedure will be applied to the comparisons of the 
two EXPAREL dose groups to the bupivacaine group for Part A, and the inverse normal p-
value method will be used to derive the final p-value for the select EXPAREL dose group 
compared to the bupivacaine group by combining the p-values from Part A and Part B (Section 
10.5.1).  
As a sensitivity analysis, the above-described procedure will be repeated using the Sensitivity 
Analysis Set.  A separate sensitivity analysis using the same ANCOVA model for Efficacy 
Analysis Set will be performed on the average NRS pain score derived from AUC/time span 
(“/” stands for “divided by”), where AUC is calculated using all NRS pain score collected 0 – 
96 hours without imputation, and the time span is last NRS time minus the first NRS time for 
the AUC calculation.  
Additional sensitivity analysis evaluating the consistency of the treatment effect will be carried 
out for AUC over various time intervals (0-24, 0-48, 0-72, 24-48, 24-72, 24-96, 48-72, 48-96, 
and 72-96 hours). 
10.5.3. Secondary Efficacy Endpoints 
10.5.3.1. Total postsurgical opioid consumption in oral morphine equivalents 
from 0 to 96 hours post-surgery  
Total postsurgical opioid consumption (OMED mg) will be summarized by treatment group.  
The summary will include the number of subjects receiving postsurgical opioids, geometric 
mean consumption, coefficient of variation (CV%), median, minimum and maximum.   
To test for a significant difference between the select EXPAREL and bupivacaine HCl groups, 
an ANCOVA model with treatment as main effect and pooled investigator site (categorical) 
and age (continuous) as covariates will be applied to the natural log-transformed total opioid 
consumption.  The LS means for the select EXPAREL and bupivacaine HCl groups, LS mean 
difference between the select EXPAREL and bupivacaine HCl groups, two-sided 95% CI for 
the LS mean difference, and the one-sided p-value will be reported.  LS means, the LS mean 
difference, and their associated CIs will be reported after back transformation (ie, taking 
exponential) to the original OMED scale.  If a subject does not have postsurgical opioid 
consumption, a 3.75 mg OMED will be assigned before the log transformation. The primary 
analysis will be performed based on the Efficacy Analysis Set. 
The percent reduction in total opioid consumption between groups will also be presented using 
the analogous calculations as outlined in Section 10.5.2.  
As sensitivity analysis, this endpoint will also be analyzed using the site-stratified Cochran-
Mantel-Haenszel (CMH) test for the row mean score difference with modified ridit scores.   
Sample SAS code follows. 


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PROC FREQ ; 
 
TABLES siteid*trtp*omed / CMH SCORE=modridit ; 
RUN ; 
Additional sensitivity analysis evaluating the consistency of the treatment effect will be carried 
out for opioid consumption over various time intervals (0-24, 0-48, 0-72, 24-48, 24-72, 24-96, 
48-72, 48-96, and 72-96 hours).  To facilitate the log-transformation analysis, 0 mg OMED for 
a time interval will be replaced with 3.75 mg / 96 hour * the length of the interval. 
10.5.3.2. Opioid-free status through 96 hours Post-surgery 
The percentage of opioid-free subjects through 96 hours post-surgery or PACU discharge, 
whichever is earlier, will be analyzed using the logistic regression model with treatment as main 
effect, and site and age as covariates. The percentage of opioid-free subjects from the model, 
odds ratio of select EXPAREL dose group over the bupivacaine HCl group and 95% CI for the 
odds ratio and p-value will be presented. The primary analysis will be performed based on the 
Efficacy Analysis Set. 
Sample SAS code for logistic regression model follows.  
ODS OUTPUT OddsRatios=or Diffs=diff(keep=probz) LSMeans=lsm ; 
PROC LOGISTIC ; 
  CLASS siteid trtpn / PARAM=glm ; 
  MODEL avalc(EVENT="Y")=trtpn siteid age ; 
  LSMEANS trtpn / DIFF ILINK ; 
  ODDSRATIO trtpn ; 
RUN ; 
10.5.3.3. Time to first postsurgical opioid consumption  
Time to first opioid consumption will be calculated in hours as the date and time of the first 
opioid medication taken post-surgery minus the date and time of end of surgery. If a subject 
does not use an opioid post-surgery, the time to first opioid consumption will be censored at the 
date of End of Study. For this derivation, the opioid consumption recorded on both 
Breakthrough Pain Medications and Prior/Concomitant Medications CRF pages will be 
considered. 
The primary analysis for time to first postsurgical opioid consumption will be a Cox 
proportional hazards regression with treatment as the factor and categorical pooled investigator 
site and continuous age as covariates.  The hazard ratio (risk ratio) of requiring opioid 
medication of the select EXPAREL group over the bupivacaine HCl group will be presented.  
Time to first opioid usage will also be analyzed by the Kaplan-Meier survival method for all 
treatment groups. Summary statistics for time to first postsurgical opioid consumption will be 
presented for all groups and the log-rank test comparing the select EXPAREL group and the 
bupivacaine HCl group will also be presented as a supportive analysis.  The log-rank test will 
be stratified by the pooled site.  In addition, the number (and %) of subjects with opioid pain 
medication post discharge as well as the number (and %) of subjects without opioid pain 


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medication post discharge will be presented for each treatment group.  One-sided p-value will 
be reported for the Cox regression and two-sided p-value will be reported for the log-rank test. 
Sample SAS code for the log-rank test and the proportional hazards regression follows. 
ODS OUTPUT HOMTESTS=lpval (WHERE=(TEST='Log-Rank')) ; 
PROC LIFETEST DATA=ef1 ; 
 
TIME aval*cnsr(1); 
 
STRATA siteid / GROUP=trtn; 
RUN; 
 
ODS OUTPUT DIFFS=hr LSMEstimates=pval ; 
PROC PHREG DATA=ef1 OUTEST=estim ; 
 
CLASS trtn(REF='2') siteid / PARAM=glm ; 
 
MODEL aval*cnsr(1) = trtn siteid age ; 
 
LSMEANS trtn / DIFF CL EXP ILINK ; 
 
LSMESTIMATE trtn ‘Grp X vs Grp 3’ 1 -1 / UPPER ; 
RUN ; 
10.5.3.4. Worst and average NRS pain intensity scores at 24, 48, 72, and 96 hours 
post-surgery 
“Worst” and “average” pain score over the last 24 hours will be summarized by treatment group 
daily at 24, 48, 72, and 96 hours.  For descriptive purposes, “worst” and “average” pain scores 
will be analyzed each day using ANCOVA with treatment as a factor, site as a categorical 
covariate and age as a continuous covariate (see Section 10.5.2). 
10.5.3.5. Current pain intensity scores post-surgery through 96 hours 
Current pain intensity collected 0 to 96 hours post-surgery will be summarized by treatment 
group in the Efficacy Analysis Set and analyzed for the treatment difference using ANCOVA 
at each scheduled time point. See Section 10.5.2 for model specification. This analysis will use 
the wWOCF-imputed pain intensity data set (see Section 10.2.2A). 
10.5.4. Subgroup Analysis  
The analysis of the primary and the first secondary endpoints will be repeated for the subgroups 
defined by the following variables using the Efficacy Analysis Set:  
• Pooled investigator site 
• Age (<45, 45 to <65, and ≥65 years) 
• Sex 
• Race (White and Non-White) 
• BMI (<25, 25 to <30, and ≥30 kg/m2)  
Because of the small sample sizes, no significance tests will be performed within subgroups. 


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10.5.5. Exploratory Endpoints 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
𝐴𝐴
  
 
  
 
  
 
 
𝑥𝑥
𝑥𝑥
 
 
   
 
 
 
CCI


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10.6. 
Pharmacokinetic Analysis 
PK samples are collected from Part A subjects.  Summary statistics for all 3 treatment gorups 
and analysis comparing the two EXPAREL groups against the bupivacaine HCl group will be 
presented. 
10.6.1. Pharmacokinetic Parameter Calculation Methods 
Pharmacokinetic parameters will be calculated by noncompartmental analysis (NCA) method 
from concentration-time data following these guidelines: 
• Actual sampling times relative to end of study drug administration will be used for all 
calculations of the PK parameters.  If there is any doubt as to the actual time a sample 
was taken, the scheduled time will be used. 
• Concentrations from unscheduled PK blood samples will be included in the calculation 
of the parameters. 
• There will be no imputation of missing concentration data. 
For the summaries of concentrations and for the NCA analysis of the bupivacaine plasma 
concentrations, concentrations below the limit of quantification (BLOQ) will be handled as 
follows: 
• Pre-dose BLOQ values will be set to zero. 
• BLOQ values between the dosing time and the first time point above lower limit of 
quantification (LLOQ) will be set to 0. 
• BLOQ values at time points between two measurable concentration values will be set 
to ½ of LLOQ (lower limit of quantification). 
• All remaining BLOQ values will be set to missing. 
The PK parameters will be estimated using the non-compartmental method according to the 
following guidelines: 
• The maximum observed plasma concentration (Cmax) for the bupivacaine HCl group 
will be obtained directly from the concentration-time data.  
• For the EXPAREL dose groups, a 2-peak PK profile is expected based on the previous 
study results.  Therefore, the following values will calcualted:  
o Early Cmax – occurring between dosing (0 hour) and x hours after dosing if 
appropriate based on the individual subject and treatment group mean 
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concentration-time plots, where x will be determined from the concentration-
time plot. 
o Late Cmax – occurring more than x hours after dosing if appropriate based on the 
individual subject and treatment group mean concentration-time plots. 
where x is a subject-specific local minimum turning point in the concentration-time 
curve.  
• Time to maximum concentration (Tmax) is the time at which Cmax is observed.  
o For EXPAREL 
 Early Tmax – the time corresponding to Early Cmax. 
 Late Tmax – the time corresponding to Late Cmax. 
o For bupivacaine HCl 
 Tmax – time corresponding to Cmax 
• The apparent terminal elimination rate constant (λz) will be estimated at terminal phase 
by linear regression after log-transformation of the concentrations: 
o Only those data points that are judged to describe the terminal log-linear decline 
will be used in the regression. 
o A minimum number of three data points in the terminal phase will be used in 
calculating λz with the line of regression starting post the late Cmax data point 
(Cmax will not be part of the regression slope) and including the last point above 
LLOQ value (Ct). 
o An appropriate number of decimal places will be used for λz to enable the 
reported value of terminal half-life (t1/2) to be calculated with more precision. 
• Rules for excluding subjects from the terminal phase-related parameter calculation: 
1. Adjusted R-square <80%, or 
2. Extrapolated AUC >30% of AUC0-∞ 
• Apparent terminal half-life (t1/2) will be calculated as ln(2)/λz. 
• The area under the plasma concentration-time curve from the time of dosing to the time 
of the last quantifiable concentration (AUC0-last) will be calculated using the linear-
up/log-down trapezoidal method. 
• The area under the plasma concentration-time curve from the time of dosing (zero) to 
infinity (AUC0-∞) will be calculated as the sum of AUC0-last and residual area Ct/λz. 


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• Extrapolated area under the curve from time of last point above LLOQ (tlast) to infinity 
(AUCextr), 
expressed 
as 
percentage 
of 
AUC0-∞ 
will 
be 
calculated 
as  
(Ct/λz)/AUC0-∞ 100%. 
• Apparent clearance CL/F will be estimated as Dose/AUC0-∞, where Dose = 221.7 mg 
(100 mg [Mayo field block] × 0.8867 [salt to free base conversion for bupivacaine HCl] 
+ 133 mg) and 354.7 mg (100 mg [Mayo field block] × 0.8867 + 266 mg) for subjects 
receiving EXPAREL 133 mg and 266 mg, respectively, and 44 mg (50 mg × 0.886) for 
subjects receiving 50 mg bupivacaine HCl. 
• Apparent volume of distribution (Vd/F) will be estimated as (CL/F)/λz. 
10.6.2. Pharmacokinetic Concentrations and Variables 
The analysis of the PK parameters will be based on the PKP analysis set. The analysis of the 
PK concentrations will be based on the PKC analysis set. 
Bupivacaine plasma concentrations will be listed by treatment, subject, nominal time, and 
actual time. Concentrations that are BLOQ will be indicated in this listing.  
Plasma concentrations will be summarized at each nominal time point seperately for each 
treatment. The following descriptive statistics will be presented: n, arithmetic mean, SD, 
geometric mean, %CV, median, minimum, and maximum.  
Pharmacokinetic parameters will be summarized by treatment. Descriptive statistics for PK 
parameters except for Tmax values will include: n, arithmetic mean, SD, geometric mean, %CV, 
median, minimum, and maximum values.  Descriptive statistics for Tmax  values will include n, 
median, minimum, and maximum values.  
Individual plasma concentration versus actual times will be plotted for each subject in linear 
and semi-logarithmic scales. Mean plasma concentration at the scheduled time points will be 
plotted for each treatment in linear and semi-logarithmic scale, with the associated standard 
errors (for linear scale only) at each scheduled time point. 
In the plot for individual subjects, concentrations that are below the limit of quantitation 
(BLOQ) will be assigned a value of ½ LLOQ if they are collected postdose.  
If there are detectable (non-BLOQ) concentration values at pre-dose that are >5% of Cmax for a 
bupivacaine HCl-treated subject and the higher of the Early and Late Cmax values for an 
EXPAREL-treated subject, these concentration values and PK parameters from such subjects 
with these values will be excluded from descriptive summaries. 
 


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10.7. 
Pharmacodynamic Analysis 
PD data are collected from Part A subjects.  Summary statistics for all three treatment gorups 
and analysis comparing the two EXPAREL groups against the bupivacaine HCl group will be 
presented. 
The time windows (Table 4) will be applied in the by-time point summaries and plots for the 
sensory function and motor function. 
10.7.1. Sensory Function 
Time to onset of sensory block from end of study drug administration and duration of sensory 
block will be summarized by the median and quartiles estimated using the Kaplan-Meier 
method similar to Section 10.5.3.2.  See Section 10.5.5.1 for how to handle censoring time. The 
Kaplan-Meier plot for time to onset and duration of sensory block will be presented.   
The number and percentage of subjects with normal sensation and no sensation will be tabulated 
by treatment group and timepoint.  Because subjects are not required to continue the onset or 
offset assessment after they have reached the onset or offset respectively, missing scheduled 
assessment after onset is achieved prior to surgery or after offset is achieved post-surgery will 
be imputed using the last observation carried forward (LOCF) method.   
Additionally, the mean PK concentrations and percentage of subjects with sensory block “on” 
will be overlaid and plotted over time to show the dynamic relationship between the two for 
each of the treatment groups. 
10.7.2. Motor Function 
Time to onset of motor block from end of study drug administration and duration of motor block 
will be summarized by the median and quartiles estimated using the Kaplan-Meier method 
similar to Section 10.5.3.2.  See Section 10.5.5.1 for how to handle censoring time.  The Kaplan-
Meier plot for time to onset and duration of motor block will be presented.   
The number and percentage of subjects with complete motor function and no motor function 
will be tabulated by treatment group and timepoint.  Missing assessment after onset is achieved 
prior to surgery or after offset is achieved post-surgery will be imputed by LOCF. 
Additionally, the mean PK concentrations and percentage of subjects with motor block “on” 
will be overlaid and plotted over time to show the dynamic relationship between the two for 
each of the treatment groups. 
 
10.8. 
Safety Assessments  
Safety data pooling from both Part A and Part B will be presented for all three treatment groups.   


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10.8.1. Adverse Events and Serious Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
version 25.0).  The summary tables will be based on the Safety Analysis Set. 
A treatment emergent adverse event (TEAE) is any adverse event with the onset date and time 
on or after the start date and time of study drug administration and ending with POD14. 
All AE summaries will present TEAEs only; AEs that are not treatment-emergent will be 
included in listings but not summarized. 
An overview of all TEAEs will present the number and percentage of unique subjects in the 
following categories: 
• Any TEAE 
o Maximum severity: Mild 
o Maximum severity: Moderate 
o Maximum severity: Severe 
• At least one related TEAE 
• At least one serious TEAE 
• Subjects discontinued due to a TEAE 
• Died on study 
Subjects may only be counted once in each of the above categories. 
The subject incidence of all TEAEs will be tabulated by the number and percentage of subjects 
reporting the TEAE. Incidence is defined as a subject reporting at least one TEAE within the 
summary level.  Summary levels are ‘at least one TEAE’, System Organ Class (SOC) and 
Preferred Term (PT).  Subjects will be counted only once within each reporting level in the 
table. For example if a subject reports a TEAE of headache on two separate occasions, the 
subject will be counted only once in the headache row of the table. Similarly if a subject reports 
two separate TEAEs within the same SOC the subject will only be counted once in the summary 
row for that SOC. For summary purposes, AE relationship to the study drug will be grouped 
into “Unrelated” for “unrelated” or “unlikely” and “Related” for “possible”, “probable”, or 
“definite”. For subjects with more than one event coded to the same PT, the subjects will be 
counted for the categories with the strongest relationship and the greatest severity.  Summaries 
will also be presented for the following categories of events: 
• TEAEs by PT sorted by the decreasing order of subject incidence in the group 
combining EXPAREL doses 
• TEAEs by SOC and PT sorted alphabetically  
• TEAEs by SOC and PT, and worst severity  
• TEAEs by SOC and PT and study drug-relationship 
• TEAE of special interest (TEAESI) by SOC and PT 
• Serious TEAE by SOC and PT 


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• Non-Serious TEAE by SOC and PT 
A subject data listing will be provided for all AEs. Included in the listing are the reported term, 
PT, SOC, TEAE flag, study day when AE starts, AE start/stop date and time, relationship to 
study drug, frequency, severity, action taken with subject, outcome, and seriousness criteria.  
Separate data listings will be provided for subject deaths, SAEs, TEAEs leading to study 
discontinuation, and AEs of special interest. A listing of the mapping of the SOC and PT to 
verbatim terms will be presented. 
AEs of special interest (AESIs) will be extracted based on the MedDRA terms below. 
• Falls 
• Persistent tingling   
• Persistent numbness   
• Persistent weakness   
• Hypersensitivity   
• Seizures   
• Tremors   
• Dizziness   
• Hematoma formation   
• Cardiovascular depression   
• Dyspnea 
• Cardiovascular arrest   
• Altered sensorium   
• Visual disturbances   
• Local anesthetic systemic toxicity 
10.8.2. Other Safety Assessments 
Vital signs and their change from baseline will be summarized with mean, median and SD at 
baseline and at each scheduled timepoint (see Table 5 for time windows and Section 7.4 for 
details). 
The frequency and percentage of EKG findings (normal, abnormal/not clinically significant, 
and abnormal/clinically significant) will be summarized at screening and each scheduled 
timepoint (Section 7.4).  
Both scheduled and unscheduled vital signs and EKG, and unscheduled neurological 
evaluations will be included in the by-subject data listing. 
 


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10.9. 
Interim Analysis 
An unblinded interim analysis will be performed by an independent party when all subjects 
enrolled in Part A (approximately 20 in each of the 3 treatment arms) have complete assessment 
data for the primary efficacy outcome. The efficacy will be evaluated and compared between 
study arms as per the procedures described in Section 5. The purpose of this interim analysis is 
to select one of the two EXPAREL arms for Part B of the study and evaluate futility. Full details 
on the planned interim analysis will be covered in a prospective interim analysis plan (IAP). 
 
11. 
SAMPLE SIZE CALCULATIONS 
Assuming one of the EXPAREL arm will continue from Part A into Part B for the final analysis, 
the total sample size for Part A and B was calculated based on the primary outcome measure of 
AUC of NRS pain intensity scores from 0 to 96 hours. A sample size of 80 subjects per study 
arm (1:1 random allocation, 80 select EXPAREL dose group, and 80 Bupivacaine HCl group) 
provides at least 85% power to detect a treatment difference of 110 units in the AUC (SD=230) 
comparing EXPAREL arm with Bupivacaine HCl arm at one sided 0.025 significance level. 
 
12. 
REFERENCES 
Chaturvedi PR, Antonijevic Z, and Mehta C (2014). “Chapter 20. Practical Considerations for 
a Two-Stage Confirmatory Adaptive Clinical Trial Design and Its Implementation: ADVENT 
Trial.” In: He W, Pinheiro J, Kuznestsova PM (eds) Practical Considerations for Adaptive Trial 
Design and Implementation. Springer.