Clinical trial NCT04518462
Conditions: Lower Extremity Surgery Bunion Metatarsophalangeal Fushion Midfoot Fusion Hindfoot Fushion Total Ankle Arthroplasty
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2020-10-20; Completion date: 2021-04-05
Enrollment: 121 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, multicenter, randomized, double blinded, active controlled study in approximately 120 subjects undergoing lower extremity surgeries.

Detailed description:

Arms: arm 1: Subjects randomized to this treatment arm will receive 20 mL (266 mg)EXPAREL mixed with 20 mL saline arm 2: subjects randomized to this treatment arm will receive 20 mL (266 mg)EXPAREL admixed with 20 mL (50 mg) 0.25% bupivacaine HCl. arm 3: subjects randomized to this treatment arm will receive 40 mL (100 mg)0.25% bupivacaine HCl.
Interventions: intervention 1: Exparel intervention 2: Bupivacaine Hydrochloride
Intervention descriptions: intervention 1: EXPAREL (bupivacaine liposome injectable suspension) intervention 2: 0.25% bupivacaine

Protocol documents:
Prot_000.pdf: 
Pacira Pharmaceuticals, Inc. 
402-C-333 
EXPAREL®
Clinical Study Protocol 
CONFIDENTIAL 
1 
Amendment 1 06 Nov2020
Clinical Study Protocol 
A Phase 3, Randomized, Double Blinded, Active Controlled, Multicenter 
Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL, 
EXPAREL admixed with Bupivacaine HCl vs. Bupivacaine HCl Administered 
as Combined Sciatic (in popliteal fossa) and Saphenous (in adductor canal) 
Nerve Blocks for Postsurgical Analgesia in Subjects Undergoing Lower 
Extremity Surgeries
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira Pharmaceuticals, a wholly 
owned subsidiary of Pacira Pharmaceuticals, Inc., (“Pacira”). 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 
Pharmaceuticals, Inc. 
Protocol No.: 402-C-333 
EudraCT No.: Not applicable 
IND No.: 069,198 
Study Phase: 3 
Study Drug: EXPAREL® (bupivacaine liposome injectable suspension) 
Original Protocol Date: 
Amendment 1: 
July 28, 2020 
November 06, 2020 
Study Sites: Multicenter study in USA 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
Tel: (973) 254-3560 


Pacira Pharmaceuticals, Inc. 
 
402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
2 
Amendment 1 06 Nov2020
 
 
1. 
SIGNATURE PAGE 
 
 
 
 
 
 
 
Donald C. Manning, MD, PhD 
Chief Medical Officer 
 
Date 
 
 
 
 
 
 
 
Gary Nevins, DC 
Executive Medical Director, Clinical Research 
 
Date 
 
 
 
 
 
Kimberly Hebert 
Executive Director, Clinical Operations 
 
Date 
 
 
 
 
 
Vincent Yu, PhD 
Vice President, Biometrics  
 
Date 
 
 
 
 
 
 
 
 
 
Michael Rozycki, PhD 
Senior Vice President, Regulatory Affairs 
 
Date 
 
 
 
06-Nov-2020
06-Nov-2020
06-Nov-2020
06-Nov-2020
06-Nov-2020


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
3 of 69  
Amendment 1 06 Nov2020 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
Title of Study: A Phase 3, Randomized, Double Blinded, Active Controlled, Multicenter Study to Evaluate 
the Efficacy, Safety, and Pharmacokinetics of EXPAREL, EXPAREL admixed with Bupivacaine HCl vs. 
Bupivacaine HCl Administered as Combined Sciatic (in popliteal fossa) and Saphenous (in adductor canal) 
Nerve Blocks for Postsurgical Analgesia in Subjects Undergoing Lower Extremity Surgeries 
Principal investigators: TBD 
Study Center(s): Multicenter study in the United States (US) 
Publications (Reference): None 
Objectives: The study objectives following the administration of study drug as a combined sciatic (in the 
popliteal fossa) and saphenous (in the adductor canal) nerve blocks in subjects undergoing lower extremity 
surgeries are listed below. 
Primary Objective:  
• 
To compare the magnitude of the analgesic effect following a single dose injection of EXPAREL 
vs. 0.25% bupivacaine hydrochloride (HCl)  
Secondary Objectives:  
• 
To compare the total opioid consumption (in oral morphine equivalents) from 0 to 96 hours 
following a single dose injection of EXPAREL vs. 0.25% bupivacaine HCl 
• 
To compare the time to first opioid consumption following a single dose injection of EXPAREL vs. 
0.25% bupivacaine HCl 
• 
To characterize and compare the magnitude of the analgesic effect following a single dose injection 
of EXPAREL vs. EXPAREL admixed with 0.25% bupivacaine HCl 
• 
To characterize and compare the magnitude of the duration of motor block following a single dose 
injection of EXPAREL vs. EXPAREL admixed with 0.25% bupivacaine HCl 
• 
To assess the efficacy, safety, and pharmacokinetic (PK) profile of EXPAREL; EXPAREL admixed 
with 0.25% bupivacaine HCl and/or 0.25% bupivacaine HCl 


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
4 of 69  
Amendment 1 06 Nov2020 
 
Methodology:  
This is a Phase 3, multicenter, randomized, double-blind, active controlled, 3-arm study in approximately 
120 subjects undergoing lower extremity surgeries. The study will have 2 cohorts. Both cohorts will enroll in 
parallel.  
 
Cohort 1 will enroll about 60 subjects undergoing bunionectomy to obtain information on PK profile, 
pharmacodynamics (PD), efficacy, and safety. Subjects in this cohort will be randomized (1:1:1) to receive 
combined sciatic (in the popliteal fossa) and saphenous (in the adductor canal) nerve blocks with EXPAREL, 
EXPAREL admixed with 0.25% bupivacaine HCl, or 0.25% bupivacaine HCl. Only select sites will enroll 
subjects for Cohort 1. 
 
Cohort 2 will enroll about 60 subjects to obtain information on efficacy and safety. Subjects in this cohort 
will receive combined sciatic (in the popliteal fossa) and saphenous (in the adductor canal) nerve blocks. 
Subjects will be randomized (1:1:1) to receive EXPAREL, EXPAREL admixed with 0.25% bupivacaine HCl, 
or 0.25% bupivacaine HCl, and will be stratified by each surgery grouping. 
  
Subjects in Cohort 1 and Cohort 2 will be discharged after the completion of the 168 h and 96 h assessments, 
respectively.  
 
An adaptive study design will be used in this study. For efficacy, an interim analysis will occur when a total 
of approximately 60 subjects combined from either Cohort 1 or Cohort 2 have enrolled and provided complete 
assessment data for their primary efficacy outcome. 
 
Obtaining Informed Consent 
Potential subjects undergoing one of the eligible surgeries will be approached by the investigator and/or the 
study staff for informed consent up to 30 days before the surgery. Subject 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 informed consent 
form (ICF) and have all the questions answered by the investigator/study staff prior to providing informed 
consent.  
 
Screening 
Subjects may be screened up to 30 days prior to day of surgery but eligibility should be re-confirmed on 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 30-day time window. Any screening procedures that are not 
standard of care, must be completed after written informed consent is provided and prior to surgery. 
 
The following screening procedures should be performed after the ICF is signed: explain study purpose and 
procedures, assess eligibility, record medical/surgical history, record prior and concomitant medications, 
record demographics and baseline characteristics including Pain Catastrophizing Scale (PCS), 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, record adverse events (AEs)/serious 
adverse events (SAEs) starting when the ICF is signed and record concomitant medications for treatment of 
AEs.  
 
Day of Surgery 
On the day of surgery, before administration of the block, the subject must record responses to the following 
pain assessments:  
• 
Pain intensity scores on the numeric rating scale (NRS) as “What was your worst pain in the last 
30 days?”  
• 
Pain intensity scores (using the NRS) “What was your average pain in the last 30 days?” 
In addition, the following procedures will be conducted: conduct urine pregnancy test for women of 
childbearing potential, record changes to concomitant medications since screening, confirm eligibility and 


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
5 of 69  
Amendment 1 06 Nov2020 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
randomize subject, record AEs/ SAEs and any treatment(s) for the events, and provide e-diary and instruct 
the subjects on duties and responsibilities for assessment completion. For Cohort 1 only, the following 
procedures are conducted: perform sensory function assessment, perform motor function assessment and 
obtain PK samples. 
Cohort 1: PK, PD, Efficacy, and Safety 
The participants enrolled in Cohort 1 will provide blood samples for PK and measures for efficacy and safety. 
About 60 subjects undergoing bunionectomy will be enrolled in this cohort. On the day of surgery, eligible 
subjects will be randomized (1:1:1) to receive EXPAREL (n=20), EXPAREL admixed with 
0.25% bupivacaine HCl (n=20), or bupivacaine HCl (n=20) as a combined sciatic (in the popliteal fossa) and 
saphenous (in the adductor canal) nerve blocks.  
Cohort 2: Efficacy and Safety 
The participants enrolled in Cohort 2 will provide measures for efficacy and safety. About 60 subjects will 
be enrolled in this cohort. On day of surgery, eligible subjects will be randomized 1:1:1 to receive EXPAREL 
(n=20), EXPAREL admixed with 0.25% bupivacaine HCl (n=20), or bupivacaine HCl (n=20). All subjects 
will receive combined sciatic (in the popliteal fossa) and saphenous (in the adductor canal) nerve blocks, by 
stratifying by each surgery grouping. 
Treatments for Cohort 1 and Cohort 2 
On the day of surgery, Cohort 1 and 2 subjects will receive ultrasound-guided combined sciatic (in popliteal 
fossa) and adductor canal nerve block with one of the following treatments: 
• 
EXPAREL arm: subjects randomized to this treatment arm will receive 20 mL (266 mg) 
EXPAREL mixed with 20 mL saline 
• 
EXPAREL admix arm: subjects randomized to this treatment arm will receive 20 mL (266 mg) 
EXPAREL admixed with 20 mL (50 mg) 0.25% bupivacaine HCl 
• 
Bupivacaine HCl arm:  subjects randomized to this treatment arm will receive 40 mL (100 mg) 
0.25% bupivacaine HCl 
Block procedure:  
Subjects may be lightly sedated with 1 to 2 mg of midazolam intravenously (IV) before the block procedure. 
The study drug (EXPAREL, EXPAREL admixed with 0.25% bupivacaine HCl, or bupivacaine HCl) will be 
administered under ultrasound guidance 90 min (±30 min) prior to surgery.  
For all arms, the total volume (40 mL) will be split such that 20 mL will be administered as the sciatic nerve 
block (in popliteal fossa) and 20 mL will be administered as the saphenous nerve block (in the adductor canal). 
 


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
6 of 69  
Amendment 1 06 Nov2020 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
Study Schema:   
 
Note: Cohort 1 will enroll bunionectomy subjects only. 
Breakthrough Pain Medication: 
All opioid and other analgesics (pain medications) administered post-surgery through Post-operative Day 
(POD) 14 should be recorded.  
Medications will be provided on an as needed (PRN) basis in relation to the breakthrough pain intensity. The 
intent is to use the guide below in a step-wise approach; acetaminophen or nonsteroidal anti-inflammatory 
drugs (NSAIDs) should be used for the initial treatment of post-surgical pain and escalation to opioids (and 
subsequent increased dose of opioids) should be implemented if the initial pain treatment (and initial opioid 
dose) is insufficient for pain relief. Opioids should not be the first choice for pain relief unless clinically 
indicated in the opinion of the investigator and should not be given on a schedule. 
• 
For the initial treatment of post-surgical pain, subjects may receive either acetaminophen or 
NSAIDs without exceeding the maximum daily dose.  


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
7 of 69  
Amendment 1 06 Nov2020 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
• 
If the initial pain treatment (acetaminophen or NSAIDs) is insufficient for pain relief, immediate 
release oral (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, 10 mg oxycodone may be offered. 
• 
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. 
 
Post discharge, the subject may be provided with a prescription for oxycodone 5 mg. The subject may take 
acetaminophen, NSAIDs, or the prescribed oxycodone and will be given instructions on which medication to 
take PRN based on their pain intensity. 
Post-surgical Assessments: 
The post-surgical assessments are as follows: record pain intensity scores (NRS) (see Appendix 1, 
Section 18.1) measured as “How much pain are you experiencing right now?” from the end of surgery to 96 
hours post-surgery at the designated timepoints. Additional assessments include: record pain intensity scores 
(NRS) measured as “What was your worst pain in the last 24 hours?” and “What was your average pain in 
the last 24 hours?” and subject to record satisfaction with pain management questionnaire. For Cohort 1 only, 
assessments include: collect scheduled PK blood samples, perform sensory and motor function assessments, 
record AEs/ SAEs and record concomitant medications.  
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. 
 
Health Care Facility Discharge: 
Subjects in Cohort 1 and Cohort 2 will be discharged after the completion of the 168 h and 96 h assessments, 
respectively. Record date and time of health care facility discharge. Re-instruct on duties and responsibilities 
with the e-diary and for breakthrough medications.  
Number of Subjects (Planned): Approximately 120 adult subjects undergoing lower extremity surgeries 
will be enrolled for the study. The surgeries that can be included in the study are: bunionectomy, 
1st metatarsophalangeal fusion, specific forefoot surgeries (Weil osteotomy, Clayton-Hoffman procedures 
only), midfoot fusion, hindfoot fusion, and total ankle arthroplasty.  
Eligibility Criteria: 
At screening, the subject should satisfy the following inclusion and exclusion criteria: 
 
Inclusion Criteria:   
1. Healthy adult male or female volunteers ages 18 or older 
2. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3 (see Appendix 6, 
Section 18.6) 
3. Able to provide informed consent, adhere to the study schedule, and complete all study assessments 
4. Body Mass Index (BMI) ≥18 and ≤40 kg/m2 


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
8 of 69  
Amendment 1 06 Nov2020 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
Exclusion Criteria: 
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) 
2. Concurrent painful physical condition that may require analgesic treatment (such as long-term, 
consistent use of opioids) in the post dosing period for pain and which, in the investigator’s opinion, 
may confound the post dosing assessments 
3. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or 
alcohol within the past 2 years 
4. 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 
5. Previous participation in an EXPAREL study 
6. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the 
investigator, could interfere with study assessments or compliance 
7. Currently pregnant, nursing, or planning to become pregnant during the study  
8. 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 
9. Currently on a neuromodulating agent (e.g., gabapentin, pregabalin [Lyrica], duloxetine [Cymbalta], 
etc.)] 
10. Inadequate sensory function on the foot (monofilament test) 
11. Chronic opioid use within 30 days prior to randomization (average ≥30 oral morphine 
equivalents/day) 
Test Product, Dose, Mode of Administration, and Lot Number: Name: EXPAREL (bupivacaine 
liposome injectable suspension)  
Active ingredient: Bupivacaine 
Dosage:  
• 
EXPAREL arm: single administration of 20 mL (266 mg) EXPAREL mixed with 20 mL saline 
• 
EXPAREL admix arm: single administration of 20 mL (266 mg) EXPAREL admixed with 
20 mL (50 mg) 0.25% bupivacaine HCl 
Lot number: To be determined. 
Mode of administration: Combined sciatic (in popliteal fossa) and saphenous (adductor canal) nerve blocks 
Reference Product, Dose, Mode of Administration, and Lot Number:  
Name: 0.25% bupivacaine HCl  
Active ingredient: Bupivacaine 
Dosage: Single administration of 40 mL (100 mg) 0.25% bupivacaine HCl 
Lot number: To be determined 
Mode of administration: Combined sciatic (in popliteal fossa) and saphenous (in adductor canal) nerve blocks 


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
9 of 69  
Amendment 1 06 Nov2020 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
Duration of Subject Participation in Study: 
Participation will begin upon signing of the ICF. No more than 30 days should pass between signing the ICF 
and study drug administration. Study drug administration will be on the same day of surgery. A follow-up 
phone call will occur on POD 14 (±3 days). Therefore, each subject may participate in the study for up to a 
maximum of 47 days. 
Efficacy Assessments: 
• 
Pain intensity measured using the NRS as “How much pain are you experiencing right now?” will 
be assessed: 
o 
Upon arrival in the Post-anesthesia Care Unit (PACU) (±5 min) 
o 
Every 15 minutes in the PACU (±5 min) 
o 
At PACU discharge (±5 min) 
o 
Every 6 hours from the end of surgery until 96 hours post-surgery: 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) 
o 
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 21:00 (±3 h) from POD 1 to POD 14 measured as “What 
was your worst pain in the last 24 hours?”  
• 
Pain intensity using the NRS once daily at 21:00 (±3 h) from POD 1 to POD 14 measured as “What 
was your average pain in the last 24 hours?”  
Subjects will be instructed to focus all NRS pain intensity ratings on the operative ankle/foot, and not 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 (±3 h) post-surgery. 
Efficacy endpoints: 
Primary Endpoint: 
• 
The area under the curve (AUC) of the NRS pain intensity scores from 0 to 96 hours post-surgery 
comparing EXPAREL to 0.25% bupivacaine HCl 
Secondary Endpoints:  
• 
Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 0 to 96 hours 
post-surgery comparing EXPAREL to 0.25% bupivacaine HCl 
• 
Time to first opioid consumption comparing EXPAREL to 0.25% bupivacaine HCl 
• 
The AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery comparing EXPAREL to 
EXPAREL admixed with 0.25% bupivacaine HCl 
• 
The duration of the motor block EXPAREL to EXPAREL admixed with 0.25% bupivacaine HCl 
Safety Assessments: 
• 
Adverse events (AEs) and SAEs will be recorded from the time of informed consent through POD 14 
Safety Endpoint:  
• 
Incidence of treatment-emergent AEs and SAEs from the start of block procedure through POD 14  


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
10 of 69  
Amendment 1 06 Nov2020 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
Pharmacokinetic and Pharmacodynamic Assessments (Cohort 1 bunionectomy subjects only):  
Blood samples for PK assessment and the sensory/motor function assessments will be assessed at scheduled 
timepoints in Cohort 1 subjects only (See Table 2). 
Pharmacokinetic Endpoint:  
The following model-predicted 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) 
Pharmacodynamic Endpoint: 
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  
Statistical Methods:  
A comprehensive statistical analysis plan (SAP) will be finalized for this study prior to database lock. 
Demographic and baseline characteristics will be summarized descriptively by treatment group for all subjects 
who receive study drug. Efficacy and safety endpoint analyses will be described in the SAP.  
 
Efficacy data will be analyzed by randomized treatment group. Superiority of treatment with EXPAREL 
compared with bupivacaine HCl will be determined using analysis of variance (ANOVA) with treatment as 
main effect for the primary efficacy endpoint of AUC of the NRS pain intensity scores from 0 to 96 hours 
post-surgery. Additional factors such as site or surgery type may be included to adjust the model if deemed 
necessary. Other efficacy endpoints will be analyzed using ANOVA, logistic regression model, chi-square 
tests, and Kaplan-Meier and log-rank tests, as appropriate.  
 
Safety and pharmacokinetic endpoints will be summarized descriptively by actual treatment received 
 
Determination of Sample Size:   
The sample size was calculated based on the primary efficacy endpoint of the AUC of the NRS pain intensity 
scores from 0 through 96 hours post-surgery comparing EXPAREL to bupivacaine HCl.  
 
The sample size for Cohort 1 was based on the number of subjects necessary to characterize the PK following 
administration. 
 
Cohort 1 and Cohort 2 subjects will be combined within treatment groups for the efficacy and safety analyses; 
therefore, the overall sample size was based on the primary efficacy endpoint of the AUC of the NRS pain 
intensity scores from 0 through 96 hours post-surgery. Assuming a 2-sided 0.05 alpha, common standard 
deviation (SD) of 170 a sample size of 40 subjects for EXPAREL and 40 subjects for bupivacaine HCl should 


Pacira Pharmaceuticals, Inc. 
 
    402-C-333 
EXPAREL® 
 
Clinical Study Protocol 
CONFIDENTIAL 
11 of 69  
Amendment 1 06 Nov2020 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For 
National 
Authority Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension)  
 
 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
 
have at least 90% power to detect a true difference of 150-units in the AUCs. Therefore, since Cohort 1 will 
have 60 subjects (20 EXAPREL, 20 EXPAREL admixed with bupivacaine HCl and 20 bupivacaine HCl), 
Cohort 2 will need to enroll 60 subjects (20 EXAPREL, 20 EXPAREL admixed with bupivacaine HCl and 
20 bupivacaine HCl) to meet the total requirements.  
 
An efficacy interim analysis will occur when approximately 60 subjects have enrolled and provided complete 
data for the primary efficacy outcome.  
 


Pacira Pharmaceuticals, Inc. 
 
    
 402-C-333 
EXPAREL® 
 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
12 of 69  
Amendment 1 06 Nov2020 
 
Table 1: 
Time and Events Schedule of Study Procedures (Screening through Day 14) 
 
Screen-
ing 
Visit1 
Day of 
Surgery 
Prior to 
Nerve 
Block  
O
R 
P
A
C
U 
Time from End of Surgery (h) 
Health 
Care 
Facility
Dis-
charge2 
PO
D 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 
Obtain ICF* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm 
eligibility * 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record medical/ 
surgical history* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect height/weight 
for BMI calculation* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
baseline 
characteristics* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Pain 
Catastrophizing Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record prior and 
concomitant 
medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Provide e-diary and 
explain expectations 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
for WOCBP4 
X 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record worst and 
average pain (NRS) 
in the last 30 days 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize subject; 
prepare study drug. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record block 
start/end times5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record surgery start 
and end times 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record intra-op 
medication 
administered 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record PACU time 
in and out 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record scheduled 
NRS scores6,7 
 
 
 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: AE=adverse event; BMI=Body Mass Index; D=day; ED=Emergency Department; 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 30 days before scheduled surgery day 
1. Subjects may be screened on the same day as health care facility admission/surgery or up to 30 days prior to surgery but eligibility should be re-confirmed on day of surgery and 
ample time must be allowed for the informed consent process. 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. Subjects in Cohort 1 and Cohort 2 will be discharged after 168 h and 96 h assessments, respectively. At discharge, subject should be re-instructed on duties with the e-diary.  
3. Provision of e-diary to subject, urine pregnancy test, and score of worst and average pain score over the previous 30 days to be assessed prior to study drug administration. The 
diary may be activated during the screening period in order to perform set-up and training, but no data entry may occur in the e-diary before the day of surgery. 
4.  Pregnancy test should be re-confirmed on the day of surgery prior to study drug administration. 
5. Block to be administered 90 min (±30 min) prior to surgery.  
6.  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. This assessment should not be completed immediately following physical activity.  
 
 
 
O
R 
P
A
C
U 
Time from End of Surgery (h) 
 
 
 
Screen-
ing 
Visit1 
Day of 
Surgery 
Prior to 
Nerve 
Block  
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 
Health 
Care 
Facility
Dis-
charge2 
PO
D 14 
Call 
±3 
days 
Subject records worst 
and average NRS 
scores daily at 21:00 
(±3 h) POD 1-146,7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record unscheduled 
NRS immediately 
prior to breakthrough 
pain medication7,8,9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record date, time, 
dose of breakthrough 
pain medication8,9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record day and time 
of HCF admission 
and discharge1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Record AEs/SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remind subject to 
return e-diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Subject to record 
subject satisfaction 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


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7. Pain scores (24 h recall) once daily (i.e., worst/average pain) will be collected at 21:00 (±3 hours) from POD 1 to POD 14. Pain scores (current pain) will be collected 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.  
8. Breakthrough pain medication will be provided on a PRN basis in relation to the breakthrough pain intensity. Opioids should not be the first choice for pain relief, unless clinically 
indicated in the opinion of the Investigator, and should not be given on a schedule. 
9. For the initial treatment of post-surgical pain, subjects may receive acetaminophen or NSAIDs without exceeding the maximum daily dose. If the initial pain treatment 
(acetaminophen or NSAIDs) is insufficient for pain relief, immediate release PO oxycodone may be offered in a stepwise approach: initial dose of 5 mg oxycodone will be 
offered; if the initial opioid dose is insufficient for pain relief, 10 mg oxycodone may be offered. 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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Table 2: 
Pharmacokinetic and Pharmacodynamic Assessments (Cohort 1 bunionectomy 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 sample 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess and record 
sensory and 
motor functionb,c 
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. 
Once offset of sensory and motor block are determined (in two consecutive evaluations), no subsequent assessments will be conducted. Sensory and motor are assessed 
independently.  
c. 
When subject is in surgery, no sensory or motor block assessments be conducted. 


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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ....................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS ...........................................................................................16 
4. 
LIST OF ACRONYMS/ABBREVIATIONS .............................................................21 
5. 
ETHICS ......................................................................................................................23 
5.1. 
Institutional Review Board/Independent Ethics Committee ......................................23 
5.2. 
Ethical Conduct of the Study ......................................................................................23 
5.3. 
Subject Information and Consent ...............................................................................23 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE .................23 
7. 
INTRODUCTION ......................................................................................................24 
7.1. 
Indication ....................................................................................................................24 
7.2. 
Current Therapies/Treatments ....................................................................................24 
7.3. 
EXPAREL (Bupivacaine Liposome Injectable Suspension) ......................................25 
7.4. 
Summary of Human Experience with EXPAREL ......................................................25 
7.5. 
Rationale for the Study ...............................................................................................26 
8. 
OBJECTIVES .............................................................................................................26 
8.1. 
Primary Objective .......................................................................................................26 
8.2. 
Secondary Objectives .................................................................................................26 
9. 
OVERALL STUDY DESIGN AND PLAN ...............................................................26 
9.1. 
Study Design ...............................................................................................................26 
9.2. 
Duration of the Study and Subject Participation ........................................................28 
9.2.1. 
Study Stopping Rules .................................................................................................29 
9.3. 
Discussion of Study Design ........................................................................................29 
10. 
STUDY POPULATION .............................................................................................30 
10.1. 
Inclusion Criteria ........................................................................................................30 
10.2. 
Exclusion Criteria .......................................................................................................30 
10.3. 
Removal of Subjects from Therapy or Assessment ....................................................31 
10.3.1. 
Withdrawal Secondary to Adverse Events .................................................................31 
10.3.2. 
Voluntary or Study Investigator Withdrawal .............................................................32 


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10.3.3. 
Early Termination Assessments .................................................................................32 
11. 
TREATMENTS ..........................................................................................................33 
11.1. 
Treatments to be Administered ...................................................................................33 
11.1.1. 
Study Drug Administration Considerations ................................................................33 
11.1.2. 
Bupivacaine HCl Administration Considerations ......................................................34 
11.2. 
Identity of the Investigational Products ......................................................................34 
11.2.1. 
Description of EXPAREL ..........................................................................................34 
11.2.2. 
Description of Reference Product ...............................................................................34 
11.3. 
Method of Assigning Subjects to Treatment ..............................................................34 
11.3.1. 
Randomization Scheme ..............................................................................................34 
11.3.2. 
Randomization Procedures .........................................................................................35 
11.3.3. 
Replacement of Subjects .............................................................................................35 
11.4. 
Selection of Doses in the Study ..................................................................................35 
11.5. 
Blinding ......................................................................................................................36 
11.5.1. 
Unblinding Procedures ...............................................................................................36 
11.5.2. 
Blinding Procedure .....................................................................................................36 
11.6. 
Prior and Concomitant Therapy and Medications ......................................................37 
11.6.1. 
Prior to Study Drug Administration ...........................................................................37 
11.6.2. 
Perioperative ...............................................................................................................37 
11.6.3. 
Post-surgery ................................................................................................................38 
11.7. 
Postsurgical Pain Medication for Breakthrough Pain .................................................38 
11.8. 
Treatment Compliance ................................................................................................39 
11.9. 
Accountability of Study Drug .....................................................................................39 
12. 
STUDY ENDPOINTS AND MEASUREMENTS ....................................................39 
12.1. 
Efficacy Assessments .................................................................................................39 
12.2. 
Efficacy Endpoints ......................................................................................................40 
12.3. 
Safety Assessments .....................................................................................................41 
12.4. 
Safety Endpoints .........................................................................................................41 
12.5. 
Pharmacokinetic Assessments (Cohort 1 only) ..........................................................41 
12.6. 
Pharmacokinetic Endpoints (Cohort 1 only) ..............................................................41 
12.7. 
Pharmacodynamic Assessments (Cohort 1 only) .......................................................41 


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12.8. 
Pharmacodynamic Endpoints (Cohort 1 only) ...........................................................42 
12.9. 
Appropriateness of Measures .....................................................................................43 
13. 
STUDY PROCEDURES ............................................................................................43 
13.1. 
Instructions for Conducting Procedures and Measures ..............................................43 
13.1.1. 
Pain Intensity Assessment ..........................................................................................43 
13.1.2. 
Subject Satisfaction with Postsurgical Pain Control ..................................................44 
13.1.3. 
Pharmacokinetic Assessments (Cohort 1 only) ..........................................................44 
13.1.4. 
Pharmacodynamic assessment (Cohort 1 only) ..........................................................44 
13.2. 
Study Procedures ........................................................................................................45 
13.2.1. 
Obtaining Informed Consent ......................................................................................45 
13.2.2. 
Screening ....................................................................................................................45 
13.2.3. 
Baseline Procedures (Prior to Study Drug Administration) .......................................46 
13.3. 
Nerve Block Procedure ...............................................................................................46 
13.3.1. 
Procedures for Sciatic Nerve Block ............................................................................46 
13.3.2. 
Procedures for Adductor Canal Nerve Block .............................................................47 
13.4. 
Post-Block Assessments .............................................................................................47 
13.5. 
Intraoperative Procedures ...........................................................................................48 
13.6. 
Post-Anesthesia Care Unit Procedures .......................................................................48 
13.7. 
Postsurgical Assessments from End of Surgery through Discharge ..........................49 
13.8. 
Health Care Facility Discharge ...................................................................................50 
13.9. 
Postsurgical Assessments from Discharge through POD 14 ......................................50 
13.10. 
Unscheduled Visits .....................................................................................................50 
13.11. 
Postsurgical Day 14 Phone Call .................................................................................50 
14. 
ADVERSE EVENT REPORTING ............................................................................50 
14.1. 
Adverse Events ...........................................................................................................51 
14.1.1. 
Definitions ..................................................................................................................51 
14.1.2. 
Recording Adverse Events .........................................................................................51 
14.1.3. 
Severity of Adverse Events ........................................................................................52 
14.1.4. 
Relationship of Adverse Events to Study Drug ..........................................................52 
14.1.5. 
Outcome of Adverse Events .......................................................................................53 
14.1.6. 
Action Taken with Subject Due to an Adverse Event ................................................53 


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14.1.7. 
Adverse Events of Special Interest .............................................................................53 
14.2. 
Serious Adverse Events ..............................................................................................54 
14.2.1. 
Definition of a Serious Adverse Event .......................................................................54 
14.2.2. 
Reporting Serious Adverse Events .............................................................................55 
15. 
STATISTICAL METHODS .......................................................................................56 
15.1. 
Study Hypothesis ........................................................................................................56 
15.2. 
Study Endpoints ..........................................................................................................56 
15.3. 
Determination of Sample Size ....................................................................................56 
15.4. 
Analysis Populations ..................................................................................................57 
15.5. 
Handling Subject Dropouts and Discontinuations ......................................................57 
15.6. 
Statistical Analyses .....................................................................................................57 
15.6.1. 
Baseline Characteristics ..............................................................................................57 
15.6.2. 
Study Procedure Compliance .....................................................................................57 
15.6.3. 
Efficacy Analyses .......................................................................................................57 
15.6.3.1. 
Primary Efficacy Measure ..........................................................................................58 
15.6.3.2. 
Secondary Efficacy Measures .....................................................................................58 
15.6.3.3. 
Pharmacokinetic Analyses ..........................................................................................59 
15.6.4. 
Safety Analyses ..........................................................................................................59 
15.6.4.1. 
Adverse Events ...........................................................................................................59 
15.7. 
Significance Testing ...................................................................................................59 
15.8. 
Interim Analyses .........................................................................................................59 
16. 
REFERENCES ...........................................................................................................60 
17. 
INVESTIGATOR AGREEMENT .............................................................................61 
18. 
APPENDICES ............................................................................................................62 
18.1. 
Appendix 1: Pain Intensity Scores using the Numeric Rating Scale (NRS) ..............62 
18.2. 
Appendix 2: Subject Satisfaction Questionnaire ........................................................64 
18.3. 
Appendix 3: Motor Function Test (Cohort 1 only) ....................................................65 
18.4. 
Appendix 4: Light Touch Assessment and Cold Sensation Assessment 
(Cohort 1 only) ...........................................................................................................66 
18.5. 
Appendix 5: Pain Catastrophizing Scale ....................................................................68 
18.6. 
Appendix 6: ASA Physical Status Classification System ..........................................69 
 


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LIST OF TABLES 
Table 1: 
Time and Events Schedule of Study Procedures (Screening through Day 14) ..........12 
Table 2: 
Pharmacokinetic and Pharmacodynamic Assessments (Cohort 1 
bunionectomy subjects only) ......................................................................................15 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................28 
 
 
 


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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 
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 
HCl 
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 
PCS 
Pain catastrophizing scale 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PO 
Oral 
POD 
Post-operative day 
PRN 
As needed 
PTAE 
Pretreatment Adverse Event 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
t1/2el 
Apparent terminal elimination half-life 
Tmax 
Time to maximum plasma concentration 


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TEAE 
Treatment-emergent adverse event 
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, and other service providers is available upon 
request to the IRB/IECs and regulatory agencies. 


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7. 
INTRODUCTION 
7.1. 
Indication 
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.  
EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia 
and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. 
Effective postsurgical pain control is a critical element in subject recovery following surgery, as 
the majority of subjects may experience significant pain, particularly in the first few days. 
Improved postsurgical pain management contributes to better healing, faster subject mobilization, 
shortened hospital stays, and reduced healthcare costs (American Society of Anesthesiologists 
Task Force on Pain Management 1995). 
7.2. 
Current Therapies/Treatments 
Current modalities of postsurgical analgesia include wound infiltration with local anesthetics 
combined with the systemic administration of analgesics (multimodal therapy). Multimodal 
therapy usually includes opioid medications, which have considerable drawbacks, including time 
and resources required for monitoring opioid-related side effects. A reduction in the use of 
postsurgical opioids is desirable to decrease the incidence and severity of opioid induced adverse 
events (AEs), such as respiratory depression, nausea, vomiting, constipation, somnolence, pruritus, 
and urinary retention. 
With over 70 million surgeries performed annually in the US, postsurgical pain is a ubiquitous 
condition among the US population. While it is a predictable component of the postsurgical 
process, such pain 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 subject 
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 [PO] intake, etc.), and conserve healthcare resources. As 
such, the Joint Commission on Accreditation of Healthcare Organizations requires that all 
healthcare facilities practice adequate pain management and monitor opioid-related AEs 
(Apfelbaum 2003). 
Opioid analgesics have long been established to be the most effective agents used for the 
management of moderate to severe postsurgical pain and are currently considered the mainstay of 
treatment. Opioid-only regimens are common and intravenous (IV) subject-controlled analgesia is 
a widely used delivery system for morphine sulfate. However, AEs related to opioid administration 
(e.g., nausea, vomiting, ileus, confusion) represent one important reason that there is a need to 
develop opioid-sparing strategies. Indeed, fear of gastrointestinal AEs, such as nausea and 
vomiting, as well as respiratory depression, present major limitations for the widespread use of 
opioid analgesics (Chernin 2001, Viscusi 2009). Furthermore, management of opioid-related AEs 
often requires medical attention (e.g., opioid antagonists, antiemetic agents) and increased 
pharmacy/nursing time, which may raise healthcare expenses (Carroll 1994). 


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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. 
7.4. 
Summary of Human Experience with EXPAREL 
Pacira has conducted more than 36 clinical studies and one observational follow-up study to 
investigate EXPAREL. Across these studies, over 1800 human subjects received EXPAREL at 
doses ranging from 2 mg to 665 mg (equivalent to 2 mg to 750 mg bupivacaine HCl) administered 
by various routes: local infiltration into the surgical site, subcutaneous, perineural (or nerve block), 
and epidural. EXPAREL has been generally well tolerated and, in active comparator studies, AEs 
occurred at a similar rate as the corresponding bupivacaine HCl controls. 
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.” Since its approval, EXPAREL has been administered to approximately 
5 million subjects in the US (January 2019). 
Following the initial approval of EXPAREL, numerous clinical studies were conducted in which 
EXPAREL was administered via various routes of administration, including interscalene nerve 
block (Sternlicht 2014, Feierman 2014).  
Please see the EXPAREL Full Prescribing Information (November 2018) for complete safety 
information 
regarding 
EXPAREL 
(liposome 
bupivacaine 
injectable 
suspension): 
https://www.exparel.com/hcp/prescriptioninformation.pdf.  


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7.5. 
Rationale for the Study 
Pacira is investigating the pharmacokinetics (PK), efficacy, and safety of EXPAREL administered 
as combined sciatic (in the popliteal fossa) and saphenous (in the adductor canal) nerve block in 
healthy adult subjects undergoing lower extremity surgeries.  
A dose of 20 mL (266 mg) EXPAREL with 20 mL of saline or EXPAREL admixed with 20 mL 
(50 mg) 0.25% bupivacaine HCl is expected to provide prolonged pain relief after these painful 
procedures compared with 40 mL (100mg) 0.25% bupivacaine HCl when injected in 20 mL 
volumes in sciatic nerve (in the popliteal fossa) and the saphenous nerve (in the adductor canal). 
8. 
OBJECTIVES 
The study objectives following the administration of study drug as a combined sciatic (in the 
popliteal fossa) and saphenous (in the adductor canal) nerve blocks in subjects undergoing lower 
extremity surgeries are listed below. 
8.1. 
Primary Objective 
To compare the magnitude of the analgesic effect following a single dose injection of EXPAREL 
vs. 0.25% bupivacaine HCl. 
8.2. 
Secondary Objectives 
• To compare the total opioid consumption (in oral morphine equivalents) from 0 to 
96 hours following a single dose injection of EXPAREL vs. 0.25% bupivacaine HCl 
• To compare the time to first opioid consumption following a single dose injection of 
EXPAREL vs. 0.25% bupivacaine HCl 
• To characterize and compare the magnitude of the analgesic effect following a single 
dose injection of EXPAREL vs. EXPAREL admixed with 0.25% bupivacaine HCl 
• To characterize and compare the magnitude of the duration of motor block following 
a single dose injection of EXPAREL vs. EXPAREL admixed with 
0.25% bupivacaine HCl 
• To assess the efficacy, safety, and pharmacokinetic (PK) profile of EXPAREL; 
EXPAREL admixed with 0.25% bupivacaine HCl and/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, 3-arm study in 
approximately 120 subjects undergoing lower extremity surgeries. The study will have 2 cohorts. 
Both cohorts will enroll in parallel.  


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Cohort 1 will enroll about 60 subjects undergoing bunionectomy to obtain information on PK 
profile, pharmacodynamics (PD), efficacy, and safety. Subjects in this cohort will be randomized 
(1:1:1) to receive combined sciatic (in the popliteal fossa) and saphenous (in the adductor canal) 
nerve blocks with EXPAREL, EXPAREL admixed with 0.25% bupivacaine HCl, or 
0.25% bupivacaine HCl. Only select sites will enroll subjects for Cohort 1. 
Cohort 2 will enroll about 60 subjects to obtain information on efficacy and safety. Subjects in this 
cohort will receive combined sciatic (in the popliteal fossa) and saphenous (in the adductor canal) 
nerve blocks. Subjects will be randomized (1:1:1) to receive EXPAREL, EXPAREL admixed with 
0.25% bupivacaine HCl, or 0.25% bupivacaine HCl, and will be stratified by each surgery 
grouping.  
Subjects in Cohort 1 and Cohort 2 will be discharged after the completion of the 168 h and 96 h 
assessments, respectively.  
An adaptive study design will be used in this study. For efficacy, an interim analysis will occur 
when a total of approximately 60 subjects combined from either Cohort 1 or Cohort 2 have enrolled 
and provided complete assessment data for their primary efficacy outcome.  


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Figure 1: 
Study Schema 
 
Note: Cohort 1 will enroll bunionectomy subjects only. 
9.2. 
Duration of the Study and Subject Participation 
Participation will begin upon signing of the ICF. No more than 30 days should pass between 
signing the ICF and study drug administration. Study drug administration will be on the same day 
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 47 days. 


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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 review all serious adverse events 
(SAEs) 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. 
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, double-blinded, randomized, active controlled study will enroll 
approximately 120 subjects to evaluate the efficacy and safety of EXPAREL, EXPAREL admixed 
with 0.25% bupivacaine HCl and 0.25% bupivacaine HCl when administered as a combined sciatic 
(in the popliteal fossa) and saphenous (in the adductor canal) nerve blocks, in subjects undergoing 
lower extremity surgeries. 
Only Cohort 1 subjects, 60 subjects all undergoing bunionectomy surgery, will provide blood 
samples for PK assessments. Subjects in this cohort will provide information on efficacy and safety 
of EXPAREL, EXPAREL admixed with 0.25% bupivacaine HCl, and 0.25% bupivacaine HCl.  
Cohort 2 will assess the efficacy and safety of EXPAREL, EXPAREL admixed with 
0.25% bupivacaine HCl, and 0.25% bupivacaine HCl in 60 subjects undergoing lower extremity 
surgery.  
The three treatment arms of the study for Cohort 1 and 2 are as follows: 
• EXPAREL arm: subjects randomized to this treatment arm will receive 20 mL 
(266 mg) EXPAREL mixed with 20 mL saline. 
• EXPAREL admix arm: subjects randomized to this treatment arm will receive 
20 mL (266 mg) EXPAREL admixed with 20 mL (50 mg) 0.25% bupivacaine HCl. 
• Bupivacaine HCl arm: subjects randomized to this treatment arm will receive 40 mL 
(100 mg) 0.25% bupivacaine HCl. 


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For all arms, the total volume (40 mL) will be split such that 20 mL will be administered as the 
sciatic nerve block (in popliteal fossa) and 20 mL will be administered as the saphenous nerve 
block (in the adductor canal). 
10. 
STUDY POPULATION 
Approximately 120 adult subjects undergoing lower extremity surgeries will be enrolled for the 
study. The surgeries that can be included in the study are:  
1. Bunionectomy  
2. 1st metatarsophalangeal fusion  
3. Specific forefoot surgeries (Weil osteotomy, Clayton-Hoffman procedures only) 
4. Midfoot fusion  
5. Hindfoot fusion  
6. Total ankle arthroplasty 
10.1. 
Inclusion Criteria 
At screening, the subject should satisfy the following criteria: 
1. 
Healthy adult male or female volunteers ages 18 or older 
2. 
American Society of Anesthesiologists (ASA) physical status 1, 2, or 3 (see Appendix 6, 
Section 18.6) 
3. 
Able to provide informed consent, adhere to the study schedule, and complete all study 
assessments 
4. 
Body Mass Index (BMI) ≥18 and ≤40 kg/m2 
10.2. 
Exclusion Criteria 
At screening, the subject must not meet any of the following criteria: 
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, nonsteroidal anti-inflammatory drugs [NSAIDs]) 
2. 
Concurrent painful physical condition that may require analgesic treatment (such as long-
term, consistent use of opioids) in the post dosing period for pain and which, in the 
investigator’s opinion, may confound the post dosing assessments 
3. 
History of, suspected, or known addiction to or abuse of illicit drug(s), prescription 
medicine(s), or alcohol within the past 2 years 
4. 
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 


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planned administration of another investigational product or procedure during the 
subject’s participation in this study 
5. 
Previous participation in an EXPAREL study 
6. 
Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of 
the investigator, could interfere with study assessments or compliance 
7. 
Currently pregnant, nursing, or planning to become pregnant during the study  
8. 
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 
9. 
Currently on a neuromodulating agent (e.g., gabapentin, pregabalin [Lyrica], duloxetine 
[Cymbalta], etc.) 
10. Inadequate sensory function on the foot (monofilament test) 
11. Chronic opioid use within 30 days prior to randomization (average ≥30 oral morphine 
equivalents/day) 
Given the COVID-19 pandemic, 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, the subject must be excluded per Exclusion criterion #8. 
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. 
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 End of Study 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 


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urgency of the situation permits. Any subject exhibiting AEs will receive appropriate treatment at 
the discretion of the investigator until resolution of the AE.  
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., combined 
sciatic [in the popliteal fossa] and saphenous [in the adductor canal] nerve blocks) 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. 
10.3.3. 
Early Termination Assessments 
In case of early termination, the following assessments shall be performed:  
• Record date and time of withdrawal 
• Record responses to pain assessment:  
− Pain intensity scores on the Numeric Rating Scale (NRS) measured as “How 
much pain are you experiencing right now?” 
− Pain intensity scores (using the NRS) measured as “What was your worst pain in 
the last 24 hours?” 
− Pain intensity scores (using the NRS) measured as “What was your average pain 
in the last 24 hours?” 
• Remind to return the e-diary (if applicable) 
• Final phone call for safety 


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11. 
TREATMENTS 
11.1. 
Treatments to be Administered 
Cohort 1: PK, PD, Efficacy, and Safety 
The participants enrolled in Cohort 1 will provide blood samples for PK and measures for efficacy 
and safety. About 60 subjects undergoing bunionectomy will be enrolled in this cohort. On the day 
of surgery, eligible subjects will be randomized (1:1:1) to receive EXPAREL (n=20), EXPAREL 
admixed with 0.25% bupivacaine HCl (n=20), or 0.25% bupivacaine HCl (n=20) as a combined 
sciatic (in the popliteal fossa) and saphenous (in the adductor canal) nerve blocks.  
Cohort 2: Efficacy and Safety 
The participants enrolled in Cohort 2 will provide measures for efficacy and safety. About 
60 subjects will be enrolled in this cohort. On day of surgery, eligible subjects will be randomized 
1:1:1 to receive EXPAREL (n=20), EXPAREL admixed with 0.25% bupivacaine HCl (n=20), or 
bupivacaine HCl (n=20). All subjects will receive combined sciatic (in the popliteal fossa) and 
saphenous (in the adductor canal) nerve blocks, by stratifying by each surgery grouping. 
Treatments for Cohort 1 and Cohort 2 
On the day of surgery, Cohort 1 and 2 subjects will receive ultrasound-guided combined sciatic 
(in popliteal fossa) and adductor canal nerve block with one of the following treatments: 
• EXPAREL arm: subjects randomized to this treatment arm will receive 20 mL 
(266 mg) EXPAREL mixed with 20 mL saline 
• EXPAREL admix arm: subjects randomized to this treatment arm will receive 20 mL 
(266 mg) EXPAREL admixed with 20 mL (50 mg) 0.25% bupivacaine HCl 
• Bupivacaine HCl arm:  subjects randomized to this treatment arm will receive 40 mL 
(100 mg) 0.25% bupivacaine HCl 
Block Procedure:  
Subjects may be lightly sedated with 1 to 2 mg of midazolam IV before the block procedure. The 
study drug (EXPAREL, EXPAREL admixed with 0.25% bupivacaine HCl, or 0.25% bupivacaine 
HCl) will be administered under ultrasound guidance 90 min (±30 min) prior to surgery.  
For all arms, the total volume (40 mL) will be split such that 20 mL will be administered as the 
sciatic nerve block (in popliteal fossa) and 20 mL will be administered as the saphenous nerve 
block (in the adductor canal).  
11.1.1. 
Study Drug Administration Considerations 
As described in the EXPAREL Full Prescribing Information (November 2018), 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 


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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, 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 known hypersensitivity to amide-like local 
anesthetics. Caution must be exercised to prevent incidental intravenous administration of 
bupivacaine during block placement. 
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 combined sciatic (in popliteal 
fossa) and adductor canal nerve block. 
11.3. 
Method of Assigning Subjects to Treatment 
11.3.1. 
Randomization Scheme 
This is a randomized study. Cohort 1 will enroll approximately 60 total subjects undergoing 
bunionectomy surgery randomized 1:1:1 in the EXPAREL arm, EXPAREL admixed with 
0.25% bupivacaine HCl arm (“admix” arm), and bupivacaine HCl arm.   
Cohort 2 will enroll approximately 60 total subjects undergoing distal lower extremity surgery, 
20 subjects in each treatment arm; EXPAREL arm, EXPAREL admix arm, and bupivacaine HCl 
arm. Subjects will be randomized 1:1:1 to treatment groups, by stratifying by surgery grouping. 
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 


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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. In rare cases, if a subject has an early morning 
surgery and there would not be enough time to obtain study drug from the pharmacy, sites will be 
permitted to randomize the subject the day before the surgery (after contacting the subject the day 
before surgery to confirm eligibility details). The e-diary may be activated during the screening 
period in order to perform set-up and training, but no data entry may occur in the e-diary before 
the day of surgery. The subject will be considered randomized into the study once the study 
treatment assignment 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 study drug or do not undergo the surgical procedure may be replaced. Additionally, 
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 developmental program, a pilot dose-escalation study (402-C-122) 
evaluating the PK, PD, and safety of EXPAREL as a sciatic nerve block in the popliteal fossa in 
subjects undergoing bunionectomy was conducted. The preliminary results for this study showed 
that compared to the EXPAREL 266 mg or 133 mg admixed groups, EXPAREL 266 mg had 
similar NRS pain scores, opioid consumption, and onset and duration of block, but produced lower 
PK concentrations of bupivacaine HCl. Thus, a total dose of 266 mg was deemed appropriate for 
the current study population administered in two halves as 133 mg EXPAREL in each of the sciatic 
and saphenous nerve blocks. 


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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, EXPAREL admixed with 0.25% bupivacaine HCl, 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 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 blocks.  
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 pharmacist will receive unblinded randomization 
assignments; the designated unblinded pharmacist or administrator will be responsible for 
preparing 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 


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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 group by Anatomic Therapeutic Chemical class and preferred terms. 
11.6.1. 
Prior to Study Drug Administration 
Permitted Prior Medications and Therapy: 
• Low-dose aspirin for cardioprotection 
• 1 to 2 mg of midazolam (Versed) 
Restricted Prior Medications and Therapy: 
• 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 cardioprotection) are not permitted within 3 days of study drug 
administration.  
• Dexmedetomidine HCl (Precedex) use is not permitted within 3 days of study drug 
administration. 
• 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 
Permitted Medications:  


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• Acceptable anesthetic techniques include general anesthesia or non-opioid sedation 
(except fentanyl, not to exceed 1 ug/kg unless deemed medically necessary). 
Neuroaxial or regional anesthesia technique (except the investigational related blocks) 
are not permitted.  
• Single-dose administration of ondansetron or metoclopramide may be used intra-
operatively for nausea/vomiting prevention.  
Restricted Medications: 
• 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.  
• 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 
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.  
• Patient Controlled Analgesia is not permitted.  
• Dexmedetomidine HCl (Precedex) use is prohibited.  
• Lidocaine and other local anesthetics will not be permitted to be locally administered 
in the area of the nerve block administration through POD 7. 
11.7. 
Postsurgical Pain Medication for Breakthrough Pain 
An unscheduled pain intensity assessment using the NRS (measured as “How much pain are you 
experiencing right now?”) must be completed immediately prior to administration of any 
breakthrough pain medication up to 96 hours post-surgery. All opioid and other analgesics (pain 
medications) administered post-surgery through POD 14 must be recorded.  
Medications will be provided on an as needed (PRN) basis in relation to the breakthrough pain 
intensity. The intent is to use the guide below in a step-wise approach; acetaminophen or NSAIDs 
should be used for the initial treatment of post-surgical pain and escalation to opioids (and 
subsequent increased dose of opioids) should be implemented if the initial pain treatment (and 
initial opioid dose) is insufficient for pain relief. Opioids should not be the first choice for pain 
relief unless clinically indicated in the opinion of the investigator and should not be given on a 
schedule.  


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• For the initial treatment of post-surgical pain, subjects may receive either 
acetaminophen or NSAIDs without exceeding the maximum daily dose.  
• If the initial pain treatment (acetaminophen or NSAIDs) is insufficient for pain relief, 
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, 10 mg oxycodone may be 
offered. 
• 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. 
Post discharge, the subject may be provided with a prescription for oxycodone 5 mg. The subject 
may take acetaminophen, NSAIDs, or the prescribed oxycodone and will be given instructions on 
which medication to take PRN based on their pain intensity. 
11.8. 
Treatment Compliance 
Not applicable, since study drug (EXPAREL, EXPAREL admix, or bupivacaine HCl) will be 
administered preoperatively by the study staff. 
11.9. 
Accountability of Study Drug 
Any shipment of EXPAREL for the study will contain an investigational drug transmittal and 
receipt form to assist the Investigator or designee (e.g., pharmacist) in 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 “How much pain are you experiencing right 
now?” will be assessed: 
− Upon arrival in the Post-anesthesia Care Unit (PACU) (±5 min) 


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− 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: 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) 
• 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 21:00 (±3 h) from POD 1 to POD 14 
measured as “What was your worst pain in the last 24 hours?”  
• Pain intensity using the NRS once daily at 21:00 (±3 h) from POD 1 to POD 14 
measured as “What was your average pain in the last 24 hours?”  
• In addition, 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.  
Subjects will be instructed to focus all NRS pain intensity ratings on the operative ankle/foot, and 
not other locations where they may be experiencing pain. 
The following information shall be captured for data management purposes: 
• Start and end time of block 
• Start and stop time of surgery 
• Start and stop of PACU admission and discharge 
• Date and time of health care facility admission and discharge 
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 comparing EXPAREL to 0.25% bupivacaine HCl 
Secondary Endpoints:  
• Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 
0 to 96 hours post-surgery comparing EXPAREL to 0.25% bupivacaine HCl 
• Time to first opioid consumption comparing EXPAREL to 0.25% bupivacaine HCl 
• The AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery 
comparing EXPAREL to EXPAREL admixed with 0.25% bupivacaine HCl 
• The duration of the motor block EXPAREL to EXPAREL admixed with 0.25% 
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12.3. 
Safety Assessments 
• Adverse events (AEs) and SAEs will be recorded from the time of informed consent 
through POD 14   
12.4. 
Safety Endpoints 
• Incidence of treatment-emergent AEs and SAEs from the start of block procedure 
through POD 14 
12.5. 
Pharmacokinetic Assessments (Cohort 1 only) 
Blood samples for PK assessment will be obtained from the Cohort 1 subjects. A total of 17 PK 
samples will be collected for each subject. These samples will be obtained at predose (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), 
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) hours from end of block procedure. (See 
Table 2). 
12.6. 
Pharmacokinetic Endpoints (Cohort 1 only) 
The following model-predicted 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 (Cohort 1 only) 
Pharmacodynamic assessments must be performed by 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 functions (Light Touch Assessment and Cold Sensation Assessment): 
• Sensory functions will be assessed using a wooden tongue depressor and ice. These 
assessments will evaluate light touch and cold sensation. The light touch assessment 
will be done first, followed by the cold sensation assessment. The tongue depressor 
application and ice application will be performed at predose (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 procedures, or until full sensory function 
has returned to predose levels in two consecutive evaluations. Each light touch 


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assessment will be rated independently. Each cold sensation 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 performed, all 4 locations (as described in 
Appendix 4, Section 18.4) will be assessed for both light touch and cold (e.g., total of 
8 independent ratings will be performed for each sensory assessment).  
Onset of sensory block (sciatic and saphenous nerve tracked independently) will be 
defined as the earliest timepoint with loss of light touch sensation and/or cold sensation 
along the distribution of the target nerve distal to the site of the block. 
Offset of sensory block (sciatic and saphenous nerve tracked independently) will be 
defined as recovery of light touch sensation and/or cold sensation along the distribution of 
the target nerve distal to the site of the block on 2 consecutive assessments. After offset of 
all sensory assessments are noted (on 2 consecutive assessments for all 4 areas for both 
touch and cold sensation), no subsequent assessments will be conducted. 
Duration of sensory block will be defined as the time between onset and offset of light 
touch sensory and/or cold sensation block for each nerve individually (see Appendix 4, 
Section 18.4). 
Assessment of motor function (onset and offset 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 predose (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 end of block procedure, or until full motor function has returned to predose 
levels in two consecutive evaluations. 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 (sciatic) will be defined as the earliest timepoint with partial or no 
foot movement.  
Offset of motor block (sciatic) will be defined as resolution of the motor block with 
complete foot movement on two consecutive assessments. After offset of motor block is 
noted (on 2 consecutive assessments), no subsequent assessments will be conducted. 
Duration of motor block will be defined as time between onset and offset of motor block 
(see Appendix  3, Section 18.3). 
12.8. 
Pharmacodynamic Endpoints (Cohort 1 only) 
The following pharmacodynamics endpoints will be determined: 
• Median time to onset of sensory block and motor block 


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• 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. 
13.1. 
Instructions for Conducting Procedures and Measures 
All PK, sensory/motor function assessments, and safety assessments conducted after baseline 
(predose) 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 combined sciatic (in popliteal fossa) and 
saphenous (in the adductor canal) nerve blocks. 
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.  
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 through the primary endpoint will take place 
under the supervision of study staff at the site. 
Subjects will be provided an e-diary on the day of surgery and instructed on duties and 
responsibilities with the e-diary. 
13.1.1. 
Pain Intensity Assessment 
Pain intensity will be assessed using an 11-point NRS (0-10) as follows: 
• Pain intensity scores (using the NRS) measured as “How much pain are you 
experiencing 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)  


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− 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 
− Subjects 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. 
• Pain intensity scores (NRS) once daily at 21:00 (±3 h) from POD 1 to POD 14 
measured as “What was your worst pain in the last 24 hours?”  
• Pain intensity scores (NRS) once daily at 21:00 (±3 h) from POD 1 to POD 14 
measured as “What was your average pain in the last 24 hours?”  
Subjects will be instructed to focus all NRS pain intensity ratings on the operative ankle/foot, and 
not 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 (Cohort 1 only) 
Blood samples for PK assessment will be obtained from the Cohort 1 subjects. A total of 17 PK 
samples will be collected for each subject. These samples will be obtained at predose (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), 
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 end of block procedure. (See Table 2). 
13.1.4. 
Pharmacodynamic assessment (Cohort 1 only) 
Onset and duration of sensory block will be assessed using the light touch assessment and/or cold 
sensation to characterize the sensory block (see Appendix 4, Section 18.4).  
Onset and duration of motor block will be assessed using the movement of the foot to characterize 
the motor block (see Appendix 3, Section 18.3). 
Pharmacodynamic assessments must be performed by 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. 


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13.2. 
Study Procedures 
13.2.1. 
Obtaining Informed Consent 
Potential subjects undergoing one of the eligible surgeries will be approached by the investigator 
and/or the study staff for informed consent up to 30 days before the surgery. Subject 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 the questions answered by the investigator/study staff prior 
to providing informed consent. 
13.2.2. 
Screening 
Subjects may be screened up to 30 days prior to day of surgery but eligibility should be re-
confirmed on 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 30-day time window. 
Any screening procedures that are not standard of care must be completed after written informed 
consent is provided and prior to surgery. 
The following screening procedures should be performed after the ICF is signed:  
• Explain study purpose and procedures, including responsibilities regarding the e-diary  
• 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 lower 
extremity surgery, 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 and concomitant medications  
• Record demographics and baseline characteristics including Pain Catastrophizing Scale 
(PCS) (see Appendix 5, Section 18.5). 
• Record subject height and weight for BMI calculation  
• Assess chronic opioid use in the past 30 days  
• Conduct urine pregnancy test for women of childbearing potential 
• Record AEs/SAEs from the time the ICF is signed  
• Record concomitant medications for treatment of AEs 


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13.2.3. 
Baseline Procedures (Prior to Study Drug Administration) 
• On the day of surgery, before administration of the block, the subject must record 
responses to the following pain assessments:  
− Pain intensity scores on the NRS as “What was your worst pain in the last 30 days?”  
− Pain intensity scores (using the NRS) “What was your average pain in the last 
30 days? 
• Conduct urine pregnancy test for women of childbearing potential 
• Record changes to concomitant medications since screening  
• Confirm eligibility and randomize subject 
• Record AEs/ SAEs and any treatment(s) for the events 
• Provide e-diary and instruct the subjects on duties and responsibilities for assessment 
completion 
• For Cohort 1 only:  
− Perform sensory function assessment 
− Perform motor function assessment 
− 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. 
• Administer study drug as combined sciatic (in popliteal fossa) and saphenous (in the 
adductor canal) nerve blocks using ultrasound 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 and any treatment(s) for the events 
13.3.1. 
Procedures for Sciatic Nerve Block 
A: Placement of ultrasound probe: 
• Position the patient supine (with the leg placed on an elevated footrest) or lateral 
(operative side up). Place ultrasound probe in the popliteal fossa, 3 to 5 cm above the 
popliteal crease in the transverse orientation. 
• Identify the sciatic nerve where it splits into the peroneal and tibial nerves but still 
enclosed in the connective tissue sheath (paraneural sheath). 
B: Insertion of needle into paraneural sheath: 


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• Use a 100 mm, 21-gauge insulated needle 
• Needle approach is from the lateral side 
• The needle should be advanced in plane until the needle tip has pierced the sciatic 
nerve sheath (paraneural sheath), (i.e., advance needle underneath the peroneal nerve, 
and pop through the sheath that surrounds the tibial and peroneal nerves). 
C: Hydrodissection of sciatic nerve block: 
• Never advance the needle tip directly at either nerve, but rather use small aliquots of 
saline (1-2 ml) to hydrodissect and outline the nerves. 
D: Study drug administration: 
• Switch syringes and inject 20 mL of the study drug admixture in the sheath, between 
the two nerves. 
13.3.2. 
Procedures for Adductor Canal Nerve Block 
A: Placement of ultrasound probe: 
• With the patient in the supine position, place ultrasound transducer at the midpoint 
between the inguinal crease and the superior pole of the patella. The femoral artery 
should be visible directly beneath the sartorius muscle. 
• The saphenous nerve is frequently visible as a hyperechoic structure immediately 
lateral to the femoral artery. 
B: Insertion of needle into adductor canal: 
• From a lateral approach in plane using a 100 mm 21-gauge insulated needle, insert 
the needle until the tip is just lateral to the femoral artery and under the saphenous 
nerve. 
• The injection will occur immediately lateral to the femoral artery, below the sartorius 
muscle. 
C: Saline injection of adductor canal nerve block: 
• Slowly start the saline injection to visualize the saphenous nerve so as not to injure it. 
The goal is to confirm needle tip position, and no more than 1-2 mL of saline should 
be required. 
D: Study drug administration: 
• Switch syringes and slowly start injecting the remaining 20 mL of study drug around 
the saphenous nerve as visualized during saline injection. 
13.4. 
Post-Block Assessments 
The following assessments will be conducted in Cohort 1 subjects only: 
• Assess sensory and motor function (onset and offset of block) 


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− Perform sensory/motor function assessments at 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 block procedure, or until full sensory/motor function has returned to predose 
levels in two consecutive evaluations. The light touch, cold sensation, and motor 
function tests will be rated independently from each other. For sensory function, 
the light touch assessment will be done first, followed by the cold sensation 
assessment. 
• Collect scheduled PK blood samples. These samples will be obtained at predose (up to 
15 min before block), and at 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 end of block procedure. (See Table 2). 
In both Cohort 1 and Cohort 2 subjects:  
• Record AEs/ SAEs 
• Record any concomitant medications for treatment(s) for the events. 
13.5. 
Intraoperative Procedures 
• Record type of general anesthesia or sedation 
• Record intraoperative drugs administered and doses  
• Record date and start/end times of surgery  
• Record AEs/ SAEs  
• Record concomitant medications for treatment of AEs/ SAEs (if any) 
13.6. 
  Post-Anesthesia Care Unit Procedures 
• Record date/time of admission to and discharge from the PACU 
• For Cohort 1 only  
− Collect scheduled PK blood sample(s)  
− Perform sensory and motor function assessments 
• Record AEs/ SAEs  
• Record concomitant medications for treatment of AEs/ SAEs 
• Subject to record NRS score (“How much pain are you experiencing now?”) upon 
arrival in the PACU (±5 min); every 15 minutes while in the PACU (±5 min); and at 
PACU discharge (±5 min) 


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• Subject to record NRS score (“How much pain are you experiencing now?”) before 
administration of breakthrough pain medication 
• Record date, time, and dosage of any breakthrough pain medication         
13.7. 
 Postsurgical Assessments from End of Surgery through Discharge 
•  
• Record pain intensity scores (NRS) (see Appendix 1, Section 18.1) measured as “How 
much pain are you experiencing 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.,  
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. 
− Subjects 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. 
− An unscheduled NRS assessment will be obtained immediately prior to 
administration of any breakthrough pain medication until 96 hours post-surgery. 
• Record pain intensity scores (NRS) measured as “What was your worst pain in the last 
24 hours?” and “What was your average pain in the last 24 hours?”  
− Once daily at 21:00 (±3 h) starting on POD 1. 
• Subject to record satisfaction with pain management using 1 question from the 
International Pain Outcome (IPO) questionnaire at 96 hours (±3 h) post-surgery.  
• For Cohort 1 only:  
− Collect scheduled PK blood sample(s).  
− Perform sensory and motor function assessments. 
• Record AEs/ SAEs.  
• Record concomitant medications for treatment of AEs/ SAEs. 
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. 


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13.8. 
   Health Care Facility Discharge 
• Subjects in Cohort 1 and Cohort 2 will be discharged after the completion of the 168 h 
and 96 h assessments, respectively. 
• Record date and time of health care facility discharge.  
• Re-instruct on duties and responsibilities with the e-diary and for breakthrough 
medications.  
13.9. 
Postsurgical Assessments from Discharge through POD 14   
• Record pain intensity scores (NRS) measured as “What was your worst pain in the last 
24 hours?” and “What was your average pain in the last 24 hours?” once daily at 
21:00 (±3 h) from the day after discharge (daily continuation from POD 1 to POD 14). 
13.10. 
Unscheduled Visits 
• If a sensory or motor function deficit persists on POD 7 (168 h 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 and any treatment(s) for the events. 
13.11. 
Postsurgical Day 14 Phone Call 
• Remind subject to complete and return the e-diary, if applicable, after POD 14 
assessment. 
• Ask the subject about any new AE(s) and the resolution of any ongoing adverse 
event(s) since discharge. Record any adverse event information. 
• Ask the subject about any medication(s) taken, that were not reported in the e-diary, 
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 14.1.2, 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. 


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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 ICF is signed and before the start of the study drug administration is 
identified as a pretreatment AE (PTAE). An AE that occurs after the administration of the study 
treatment is considered a treatment-emergent adverse event (TEAE).  
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 (i.e., PTAEs and TEAEs) 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 line 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 collapsed (removed; i.e., lined through and initialed). 
Whenever possible, abnormal laboratory results must be reported as their clinical corollary (e.g., 
low potassium should be recorded as hypokalemia).  


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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 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 study drug administration, 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 
The severity of an AE must 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 
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);  


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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 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 last assessment, the event was decreasing in 
frequency, severity, etc., and a resolution was expected  
Fatal:  
The AE directly caused death  
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: 


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• 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 
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 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 


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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.  
4Persistent or significant incapacity: A substantial disruption of a person’s ability to conduct 
normal life functions.  
5Congenital anomaly/birth defect: Report if you suspect that exposure to a medical product prior 
to conception or during pregnancy may have resulted in an adverse outcome in the child. 
6Medically significant: Important medical events that may not result in death, be life-threatening, 
or require hospitalization, may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medically significant events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
14.2.2. 
Reporting Serious Adverse Events 
Any SAE or death that occurs at any time after the subject signs the ICF through POD 14, whether 
or not related to EXPAREL, must be reported by the Investigator or designee to Pacira Drug Safety 
within 24 hours of discovery by either email (drugsafety@pacira.com) or fax (858-408-3588). In 
addition, the Investigator or designee is encouraged to contact the Medical Monitor to discuss the 
case, as needed.  
Investigators should not wait to receive additional information to fully document the event before 
notifying Pacira Drug Safety or designee of the SAE. The fax or email report must be followed by 
a full written summary using the SAE Form detailing relevant aspects of the SAE in question. 
Where applicable, information from relevant hospital records and autopsy reports must be obtained 
and all subject-identifying information redacted prior to forwarding to Pacira. In the event of a 
fatal or life-threatening SAE, any required follow-up must be provided to Pacira Drug Safety or 
designee immediately. The Investigator will follow all SAEs until resolved or the condition 
stabilizes, and further follow-up is not warranted.  
If the Investigator is made aware of any SAEs after Postsurgical Day 14, these must also be 
reported to Pacira Drug Safety or designee provided the SAE is considered related to EXPAREL. 
The site would then provide a completed SAE form within 1 business day and the event would be 
followed until resolution, or until adequate stabilization is met. 


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15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be finalized for this study prior to database 
lock. Demographic and baseline characteristics will be summarized descriptively by treatment 
group for all subjects who receive study drug. Efficacy and safety endpoint analyses will be 
described in the SAP.  
Efficacy data will be analyzed by randomized treatment group. Superiority of treatment with 
EXPAREL compared with bupivacaine HCl will be determined using analysis of variance 
(ANOVA) with treatment as main effect for the primary efficacy endpoint of AUC of the NRS 
pain intensity scores from 0 to 96 hours post-surgery. Additional factors such as site or surgery 
type may be included to adjust the model if deemed necessary. Other efficacy endpoints will be 
analyzed using ANOVA, logistic regression model, chi-square tests, and Kaplan-Meier and log-
rank tests, as appropriate.  
Safety and pharmacokinetic endpoints will be summarized descriptively by actual treatment 
received. 
15.1. 
Study Hypothesis 
The primary null hypothesis is: 
H0: The AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery are not different 
between the EXPAREL and bupivacaine HCl treatment group. 
The alternative hypothesis is:  
HA: The AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery for the EXPAREL 
treatment group is less than that of the bupivacaine HCl treatment group. 
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 sample size was calculated based on the primary efficacy endpoint of the AUC of the NRS 
pain intensity scores from 0 through 96 hours post-surgery comparing EXPAREL to bupivacaine 
HCl.  
The sample size for Cohort 1 was based on the number of subjects necessary to characterize the 
PK following administration. 
Cohort 1 and Cohort 2 subjects will be combined within treatment groups for the efficacy and 
safety analyses; therefore, the overall sample size was based on the primary efficacy endpoint of 
the AUC of the NRS pain intensity scores from 0 through 96 hours post-surgery. Assuming a 
2-sided 0.05 alpha, common standard deviation (SD) of 170 a sample size of 40 subjects for 
EXPAREL and 40 subjects for bupivacaine HCl should have at least 90% power to detect a true 
difference of 150-units in the AUCs. Therefore, since Cohort 1 will have 60 subjects 


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(20 EXAPREL, 20 EXPAREL admixed with bupivacaine HCl and 20 bupivacaine HCl), Cohort 
2 will need to enroll 60 subjects (20 EXAPREL, 20 EXPAREL admixed with bupivacaine HCl 
and 20 bupivacaine HCl) to meet the total requirements.  
An efficacy interim analysis will occur when approximately 60 subjects have enrolled and 
provided complete data for the primary efficacy outcome. 
15.4. 
Analysis Populations 
The following analysis sets are planned: 
Safety: The safety analysis set will include all 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 undergo the planned 
surgery. All analyses will be based on randomized treatment regardless of actual treatment 
received. 
Pharmacokinetic: The pharmacokinetic analysis set will include all subjects 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 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 group. 
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 group. 
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 endpoint will be additionally analyzed by 
stratifying by surgery on the efficacy analysis set as a sensitivity analysis. 
For continuous measures of efficacy, summary statistics (n, mean, median, standard deviation, 
minimum, and maximum) will be shown by treatment group. For categorical measures of efficacy, 
number and percentage of subjects in each category will be shown by treatment group. For time to 


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event measures of efficacy, medians and Kaplan-Meier estimates will be shown by treatment 
group. 
Baseline is defined as the last non-missing assessment of a given assessment prior to first dose of 
trial drug unless otherwise specified. 
All assessments will be presented in by-subject data listings. 
15.6.3.1. Primary Efficacy Measure 
The primary efficacy measure is the AUC of the NRS pain intensity scores from 0 to 96 hours 
post-surgery.  
For the AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery, EXPAREL will be 
compared to bupivacaine HCl using ANOVA with treatment as a main effect. Additional 
covariates may be included. Based on the model, the difference between treatment groups will be 
estimated along with the 2-sided 95% confidence intervals. The stratified sensitivity analysis will 
report similar statistics. 
15.6.3.2. Secondary Efficacy Measures 
The secondary efficacy measures are: 
• Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 0 to 
96 hours post-surgery comparing EXPAREL to bupivacaine HCl 
• Time to first opioid consumption comparing EXPAREL to bupivacaine HCl 
• The AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery comparing 
EXPAREL to EXPAREL admixed with bupivacaine HCl 
• The duration of the motor block EXPAREL to EXPAREL admixed with bupivacaine 
HCl 
For the total postsurgical opioid consumption endpoint, opioid medications will be converted to 
the oral morphine equivalents in mg amount. All opioids administered from 0 hours to 96 hours 
post-surgery will be included in the analysis. Prior to analysis, the natural logarithm transformation 
may be applied to the total amount. A minimal set value will be used for subjects that do not report 
opioid use. To test for a significant difference between EXPAREL and bupivacaine HCl, an 
ANOVA with treatment as a main effect will be used. Additional covariates may be included. 
Based on the model, the difference between treatment groups will be estimated along with the 2-
sided 95% confidence intervals. 
The time to event endpoints will be summarized with medians and Kaplan-Meier estimates. A log-
rank test will be used to compare EXPAREL to bupivacaine HCl. Subjects that do not report any 
event will be censored at their last valid assessment respective to the endpoint. 
For the endpoint AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery, 
EXPAREL will be compared to EXPAREL admixed with bupivacaine HCl.  
For the endpoint duration of the motor block, EXPAREL will be compared to EXPAREL admixed 
with bupivacaine HCl. 


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15.6.3.3. 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. 
Safety Analyses 
All safety analyses will be based on actual treatment received. 
15.6.4.1. 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 group. Incidence rates will also be displayed for each treatment group 
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 group. All incidence rates will be categorized 
and displayed by system organ class and preferred term. 
15.7. 
Significance Testing 
All tests will be two-sided and based on a significance level of 0.05 unless otherwise specified. 
15.8. 
Interim Analyses 
An unblinded efficacy interim analysis conducted by an independent committee will occur when 
approximately 60 subjects (20 in each arm) have been randomized, treated and provided their 
primary efficacy outcome. An interim analysis will be conducted to evaluate and compare the 
clinical efficacy between EXAPREL only and bupivacaine HCl only. Primary purpose of this 
interim analysis is to evaluate the sample size assumptions and evaluate futility. Full details on the 
planned or additional interim analysis will be covered in a prospective interim analysis plan. 


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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. 
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. 
EXPAREL Full Prescribing Information, November 2018.  
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. 
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. 
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.  
Sternlicht A, Shapiro M, Robelen G, et al. Infiltration of liposome bupivacaine into the transversus 
abdominis plane for postsurgical analgesia in robotic laparoscopic prostatectomy: a pilot study. 
Local Reg Anesth. 2014;7:69-74. 
Viscusi ER. New and emerging treatment options for acute postoperative pain in the inpatient 
setting: Barriers to effective pain management. Medscape Pharmacists. 


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17. 
INVESTIGATOR AGREEMENT  
Printed Name of Investigator:   
 
Printed Title/Position: 
 
Printed Institution Address: 
 
 
 
 
 
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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18. 
APPENDICES 
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). Subjects will be instructed 
to focus all NRS pain intensity ratings on the operative ankle/foot, and not other locations where 
they may be experiencing pain. 
• Pain intensity using the NRS measured as “What was your worst pain in the last 30 days?” 
and “What was your average pain in the last 30 days?” will be assessed at Baseline/Day of 
surgery 
• Pain intensity using the NRS measured as “How much pain are you experiencing 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: 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 
− Subjects 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  
• Pain intensity using the NRS measured as “What was your worst pain in the last 
24 hours?” and “What was your average pain in the last 24 hours?” will be assessed: 
− Once daily at 21:00 (±3 h) from POD 1 to POD 14  
 
 
 
 


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Numeric Rating Scale (NRS) 
 
 
 
 
 


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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) shall 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: Motor Function Test (Cohort 1 only) 
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 predose (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 block procedures, or until full motor function has returned to the baseline 
(pre-block) level in two consecutive evaluations. 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. 
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 
 
 
 


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18.4. 
Appendix 4: Light Touch Assessment and Cold Sensation 
Assessment (Cohort 1 only) 
Sensory function for light touch will be assessed using a wooden tongue depressor. Sensory 
function for cold sensation will be assessed using ice. The light touch assessment will be done 
first, followed by the cold sensation assessment.  
• The wooden tongue depressor light touch assessment and the cold sensation assessment 
will be performed at predose (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 
procedures, or until full sensory function has returned to baseline (pre-block) levels in two 
consecutive evaluations. Each light touch area of assessment will be rated independently. 
Each cold sensation 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 
performed, all 4 locations below will be assessed for both light touch and cold (e.g., total 
of 8 independent ratings will be performed for each sensory assessment). 
Sensory function assessment will include the following four locations:  
1. Saphenous proximal - Medial aspect of the lower leg (3-4 cm below the knee)   
2. Saphenous distal - Medial aspect of the lower leg (3-4 cm above ankle) 
3. Sciatic proximal - Lateral aspect of the lower leg (3-4 cm above ankle) 
4. Sciatic distal - Sole of the foot 
The intent of applying the tongue depressor or ice 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). 
Tongue Depressor Assessment 
The tongue depressor assessment procedures are as follows: 
• The subject should 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. 
• 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. 


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EXPAREL® 
 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
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Amendment 1 06 Nov2020 
 
  
 
 
• 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 three areas as above.  
Ice Assessment 
The ice assessment procedures are as follows: 
• The subject should be instructed to close their eyes before the application of the ice 
(place ice in a small plastic bag to avoid any wet sensation). 
• Instruct the subject you will be touching the subject on both legs and they will be asked 
if the cold sensation is the same (YES) or not the same (NO) when comparing each 
side. 
• For the subject’s reference, the ice is placed on the contralateral assessment area. 
• The ice is then placed on the corresponding test assessment area. 
• The subject will be asked if the cold sensation is the same (YES) or not the same (NO) 
when comparing each side.  
• Record the subject’s response (YES or NO) to the cold sensation in the assessment 
area.  
• Proceed to test the other three areas as above. 
 
 
 
 
 
 


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EXPAREL® 
 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
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Amendment 1 06 Nov2020 
 
  
 
 
18.5. 
Appendix 5: Pain Catastrophizing Scale 
The Pain Catastrophizing Scale (PCS) is provided below. 
 
 
 
The PCS contact information and permission to use: Mapi Research Trust, Lyon, France. Internet: 
https://eprovide.mapi-trust.org  
 
SAMPLE COPY – DO NOT 
USE WITHOUT PERMISSION 


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EXPAREL® 
 
Clinical Study Protocol 
 
 
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Amendment 1 06 Nov2020 
 
  
 
 
18.6. 
Appendix 6: 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: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A Phase 3, Randomized, Double Blinded, Active Controlled, Multicenter 
Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL, 
EXPAREL admixed with Bupivacaine HCl vs. Bupivacaine HCl Administered 
as Combined Sciatic (in popliteal fossa) and Saphenous (in adductor canal) 
Nerve Blocks for Postsurgical Analgesia in Subjects Undergoing Lower 
Extremity Surgeries 
 
 
Protocol No.: 402-C-333 
IND No.: 069,198  
Study Phase: 3 
Study Drug: EXPAREL (bupivacaine liposome injectable suspension) 
Original Protocol Date 28 July 2020 
Procotol Ammendent 1 Date  6 November 2020 
SAP Date/Version 27 April 2021 / Version 1.0 
Prepared by: Chao Wang, PhD 
Sponsor: Pacira BioSciences, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 973-254-3560 
 
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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Statistical Analysis Plan 
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CONFIDENTIAL 
Page 2 of 39 
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SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
Chao Wang, PhD 
Principal Statistician 
Pharma Data Asociates, LLC 
 
Date 
 
 
 
 
 
 
 
 
Don Manning, MD, PhD  
Chief Medical Office  
Pacira BioSciences, Inc. 
 
 
Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
Vincent Yu, PhD 
Vice President, Biometrics 
Pacira BioSciences, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
Gary Nevins, DC 
Executive Medical Director, Medical Strategy 
Pacira BioSiences, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
Michael Rozycki, PhD 
Sr. Vice President, Regulatory Affair 
Pacira BioSciences, Inc. 
Date 
 
 
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Pacira Biosciences, Inc. 
Statistical Analysis Plan 
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402-C-333 
 
 
CONFIDENTIAL 
Page 3 of 39 
27 April 2021 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS 
5 
2. 
INTRODUCTION 
6 
3. 
STUDY OBJECTIVES 
6 
3.1. 
Primary Objective 
6 
3.2. 
Secondary Objectives 
6 
4. 
STUDY OVERVIEW 
7 
5. 
DEFINITIONS 
12 
6. 
STUDY ASSESSMENTS 
15 
6.1. 
Efficacy Assessment 
15 
6.1.1. 
Pain Intensity Assessment 
15 
6.1.2. 
Opioid Dose Conversion 
15 
6.1.3. 
Subject Satisfaction with Pain Management 
16 
6.1.4. 
Postsurgical Breakthrough Pain Medication 
16 
6.2. 
Pharmacokinetic assessments (Cohort 1 only) 
17 
6.3. 
Pharmacodynamic Assessments (Cohort 1 only) 
17 
6.3.1. 
Assessment of Sensory Block: 
17 
6.3.2. 
Assessment of Motor Block: 
18 
6.4. 
Change in the Study Design and Its Effect on the Statistical Analysis 
19 
7. 
ANALYSIS SETS 
19 
8. 
STUDY ENDPOINTS 
19 
8.1. 
Efficacy Endpoints 
19 
8.1.1. 
Primary Endpoint 
20 
8.1.2. 
Secondary Endpoints 
20 
8.1.3. 
Exploratory Endpoints 
20 
8.2. 
Safety Endpoints 
20 
8.3. 
Pharmacokinetic (PK) Endpoints (Cohort 1 only) 
20 
8.4. 
Pharmacodynamic (PD) Endpoints (Cohort 1 only) 
20 
9. 
METHODS OF STATISTICAL ANALYSIS 
21 
9.1. 
General Principles 
21 
9.2. 
Handling Missing Values 
21 
9.2.1. 
Total Post-Surgical Opioid Consumption 
21 
9.2.2. 
NRS Pain Intensity Scores 
21 
9.2.3. 
Adverse Event or Concomitant Medications Dates or Times 
24 
9.2.4. 
Adverse Event Severity or Relationship to Study Drug 
25 
9.2.5. 
Time to Event 
25 
9.3. 
Subject Disposition 
25 
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9.4. 
Description of Demographics and Baseline Characteristics 
26 
9.4.1. 
Demographics 
26 
9.4.2. 
Baseline Characteristics 
26 
9.4.3. 
Medical and Surgical History 
27 
9.4.4. 
Surgery Characteristics 
27 
9.4.5. 
Intraoperative, Prior, and Concomitant Medications 
27 
9.4.6. 
Measurements of Treatment Compliance 
28 
9.5. 
Efficacy Analysis 
28 
9.5.1. 
Primary Efficacy Endpoint 
29 
9.5.2. 
Secondary Efficacy Endpoints 
30 
9.5.2.1. 
Total postsurgical opioid consumption in oral morphine equivalents from 0 to 96 hours post-
surgery comparing EXPAREL to 0.25% bupivacaine HCl 
30 
9.5.2.2. 
Time to first postsurgical opioid consumption comparing EXPAREL to 0.25% bupivacaine 
HCl 
31 
9.5.2.3. 
AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery comparing 
EXPAREL to EXPAREL admixed with 0.25% bupivacaine HCl 
31 
9.5.2.4. 
Duration of the motor block comparing EXPAREL to EXPAREL admixed with 0.25% 
bupivacaine HCl (Cohort 1 only) 
32 
9.5.3. 
Subgroup Analysis for the Primary and First Secondary Efficacy Endpoints 
32 
9.5.4. 
Exploratory Endpoints 
32 
9.6. 
Pharmacokinetic Analysis 
33 
9.6.1. 
Pharmacokinetic Parameter Calculation Methods 
33 
9.6.2. 
Pharmacokinetic Concentrations and Variables 
35 
9.7. 
Pharmacodynamic Analysis 
36 
9.7.1. 
Sensory Function 
36 
9.7.2. 
Motor Function 
36 
9.8. 
Safety Assessments 
36 
9.9. 
Interim Analysis 
38 
10. 
SAMPLE SIZE CALCULATIONS 
39 
11. 
REFERENCES 
39 
 
 
 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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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 
CRF 
Case report form 
CSR 
Clinical study report 
CV 
Coefficient of Variation  
EMA 
European Medicines Agency 
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 durg 
OMED 
Oral morphine equivalent dose in mg 
PACU 
Postanesthesia care unit 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PO 
Per oral 
POD 
Postoperative Day 
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 
Table, listings and figures 
NRS 
Numerical rating scale 
WHO-DD 
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-333 titled “A Phase 3, Randomized, Double Blinded, Active Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of EXPAREL, 
EXPAREL admixed with 0.25% Bupivacaine HCl vs. 0.25% Bupivacaine HCl Administered as 
Combined Sciatic (in popliteal fossa) and Saphenous (in adductor canal) Nerve Blocks for 
Postsurgical Analgesia in Subjects Undergoing Lower Extremity Surgeries”.  
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: 
x 
Protocol 402-C-333 issued on 28 July 2020 
x 
Protocol 402-C-333 Amendment 1 issued on 06 November 2020  
x 
Electronic Case Report Form (eCRF) dated 11 November 2020  
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. 
STUDY OBJECTIVES 
3.1. 
Primary Objective  
To compare the magnitude of the analgesic effect following a single dose injection of EXPAREL 
vs. 0.25% bupivacaine hydrochloride (HCl). 
3.2. 
Secondary Objectives 
x To compare the total opioid consumption (in oral morphine equivalents) from 0 to 96 hours 
following a single dose injection of EXPAREL vs. 0.25% bupivacaine HCl  
x To compare the time to first opioid consumption following a single dose injection of 
EXPAREL vs. 0.25% bupivacaine HCl. 
x To characterize and compare the magnitude of the duration of motor block following a 
single dose injection of EXPAREL vs. EXPAREL admixed with 0.25% bupivacaine HCl. 
x To further assess the efficacy, safety, and pharmacokinetic (PK) profile of EXPAREL; 
EXPAREL admixed with 0.25% bupivacaine HCl and/or 0.25% bupivacaine HCl. 
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4. 
STUDY OVERVIEW 
This is a Phase 3, multicenter, randomized, double blind, active controlled study in approximately 
120 subjects undergoing lower extremity surgeries. This study will have 2 cohorts. Both cohorts 
will enroll in parallel.  
Randomization 
Cohort 1 will enroll about 60 subjects undergoing bunionectomy to obtain information on PK 
profile, PD, efficacy and safety. Subjects in this cohort will be randomized (1:1:1) to receive 
combined sciatic (in popliteal fossa) and saphenous (in the adductor canal) nerve block with 
EXPAREL, EXPAREL admixed with 0.25% bupivacaine HCl, or 0.25% bupivacaine HCl.  
Cohort 2 will enroll about 60 subjects to obtain information on efficacy and safety. Subjects in this 
cohort will receive combined sciatic (in popliteal fossa) and saphenous (in the adductor canal) 
nerve block. Subjects will be randomized (1:1:1) to receive EXPAREL, EXPAREL admixed with 
0.25% bupivacaine HCl, or 0.25% bupivacaine HCl, by stratifying by each surgery grouping.  
Treatment 
For both Cohorts 1 and 2, subjects randomized to the EXPAREL arm will receive 20 mL (266 mg) 
EXPAREL mixed with 20 mL saline; subjects randomized to EXPAREL admix arm will receive 
20 mL (266 mg) EXPAREL admixed with 20 mL (50 mg) 0.25% bupivacaine HCl;  subjects 
randomized to the 0.25% bupivacaine HCl arm will receive 40 mL (100 mg) 0.25% bupivacaine 
HCl. 
Block Procedure 
Subjects may be lightly sedated with 1 to 2 mg of midazolam intravenously (IV) before the block 
procedure. The study drug (EXPAREL, EXPAREL admixed with 0.25% bupivacaine HCl, or 
0.25% bupivacaine HCl) will be administered under ultrasound guidance 90 min (±30 min) prior 
to surgery.  
Breakthrough Pain Medication 
All opioid and other analgesics administered post-surgery through post-operative day 14 (POD14) 
will be recorded.  
For the initial treatment of breakthrough pain, subjects may receive acetaminophen or NSAIDs. 
If the initial pain treatment (acetaminophen or NSAIDs) is insufficient for pain relief, immediate 
release PO oxycodone may be administered in a stepwise approach: 
x Initial dose of 5 mg oxycodone may be offered. 
x If the initial opioid dose is insufficient for pain relief, 10 mg oxycodone may be offered. 
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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. 
Figure 1 presents a schematic diagram of the study design. Protocol Time and Events schedule for 
study procedures are presented in Table 1 and for PK and PD Assessment Schedule are presented 
in Table 2. 
 
Figure 1: Schematic Representation of Study Design 
 
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CONFIDENTIAL 
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Table 1: Time and Events Schedule of Study Procedures (Screening Through Day 14) 
 
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Table 2: Pharmacokinetic and Pharmacodynamic Assessment Schedule (Cohort 1 bunionectomy subjects only) 
 
 
 
 
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5. 
DEFINITIONS 
Start and End of Block  
See Sections 6.3.1 and 6.3.2 for onset and offset of sensory block and motor block, respectively. 
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 evaluation, Time 0 is defined as the date and time of the end of the study 
drug administration.  For NRS pain collection and opioid consumption, 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 start of study drug administration. 
Surgical Type 
It is expected this study will enroll patients for bunionectomy, 1st metatarsophalangeal fusion, 
specific forefoot surgeries, midfoot fusion, hindfoot fusion, and total ankle arthroplasty. Due to 
overwhelmingly large number of bunionectomy patients enrolled as of this date, patients will 
be subgrouped into bunionectomy and non-bunionectomy for the purpose of by-subgroup 
summaries. 
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. 
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Time Window for Numeric Rating Scale (NRS) for Scheduled Pain Score Collection 
Table below provides the time window for the NRS pain score for analysis. 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 equidistance the later will be chosen. 
 
Table 3. Time Window for the NRS Pain Score Collected at Scheduled Time Points Post-
Surgery 
Scheduled Time of Collection 
Time Window for Acceptable Actual Time of Collection 
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 Window for Sensory and Motor Block Tests 
Table below provides the time window for the sensory block and motor block summaries by 
timepoint (Sections 9.7.1 and 9.7.1). 
 
 
 
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Table 4. Time Window for the 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 on the same 
route and unit. The conversion factor is listed in Table 5. 
Time Window for Opioid Pain Medication  
This window (see Section 9.2.2 Table 6) captures the opioid analgesic effect from start of the 
opioid administration to the end of the opioid effect.  
 
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6. 
STUDY ASSESSMENTS 
6.1. 
Efficacy Assessment 
6.1.1. Pain Intensity Assessment  
x Pain intensity scores measured using NRS as “How much pain are you experiencing 
right now?” * will be assessed as follows:  
o Upon arrival in the Post-Anesthesia Care Unit (PACU)  
o At 15-minute intervals in the PACU  
o At to PACU discharge  
o Every 6 hours from the end of surgery to 96 hours postsurgery as follows: 6 h, 
12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h, 66 h, 72 h, 78 h, 84 h, 90 h, 
and 96 h.  
o Prior to administration of any pain medication until 96 hours post-surgery 
x Pain intensity using the NRS once daily at 21:00 (±3 h) from POD 1 to POD 14 
measured as “What was your worst pain in the last 24 hours?” 
x Pain intensity using the NRS once daily at 21:00 (±3 h) from POD 1 to POD 14 
measured as “What was your average pain 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.  
 
6.1.2. Opioid Dose Conversion 
Opioids dose will be converted to oral morphine equivalent dose (OMED mg) using the 
conversion factor in Table 5 for all summaries.  Total opioid dose is the sum of all opioids in 
OMED taken during the time interval of interest.   
 
Table 5. Conversion Factors to IV and 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 
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Table 5. Conversion Factors to IV and Oral Morphine Equivalent Dose from Other Opioids 
Medication 
Unit 
Route 
Oral Morphine Conversion 
(Multiplication) Factor 
Hydrocodone combination product - Vicodin, 
Norco, Lorcet, Lortab, hydrocodone-
acetaminophen, Ketobemidone 
mg 
PO 
1 
Codeine combination product - Tylenol 3, 
acetaminophen-coedine, Paracetamol Forte, 
Tylenol 4 
mg 
PO 
0.15 
Ultram, Tramadol, Tramacol 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/Nallouphine (Nubain/Manfine) 
mg 
IV, IM, SC 
3 
PO = oral, IV = intravenous, IM = Intramuscular, SC = subcutaneous. 
 
6.1.3. 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 eleven-point Likert scale from zero (extremely dissatisfied) to 10 (extremely satisfied). 
6.1.4. Postsurgical Breakthrough Pain Medication 
All opioid and other analgesics (pain medications) administered post-surgery through POD 14 
will be recorded. Analgesics will be administered based on the pain assessment as outlined 
below. 
x For the initial treatment of post-surgical pain, subjects may receive either 
acetaminophen or NSAIDs without exceeding the maximum daily dose.  
x If the initial pain treatment (acetaminophen or NSAIDs) is insufficient for pain 
relief, 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, 10 mg oxycodone may be 
offered. 
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x 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. 
Post discharge, the subject will be provided with a prescription for oxycodone 5 mg. The subject 
may take acetaminophen, NSAIDs, or the prescribed oxycodone and will be given instructions 
on which medication to take PRN based on their pain intensity. 
 
6.2. 
Pharmacokinetic assessments (Cohort 1 only)  
Blood samples for PK assessment will be obtained from the Cohort 1 subjects. A total of 17 PK 
samples will be collected for each subject. These samples will be obtained at predose/baseline 
(up to 15 min before block), 30 min, 45 min, and 1 h, 2 h, 8 h, 12 h, 24 h, 30 h, 48 h, 60 h, 72 
h, 84 h, 96 h, 120 h, 144 h, and 168 h from end of block procedure.  
 
6.3. 
Pharmacodynamic Assessments (Cohort 1 only)  
Time of onset/offset is collected on the corresponding “PD Assessment – Onset/Offset 
Sensory/Motor Block” eCRF. 
6.3.1. Assessment of Sensory Block: 
Sensory function for the sciatic and saphenous nerve will be assessed independently using a 
wooden tongue depressor and ice. This assessment will evaluate light touch and cold sensation.  
 
Sensory function assessment will include the following four locations:  
1. Saphenous proximal - Medial aspect of the lower leg (3-4 cm below the knee)  
2. Saphenous distal - Medial aspect of the lower leg (3-4 cm above ankle)  
3. Sciatic proximal - Lateral aspect of the lower leg (3-4 cm above ankle)  
4. Sciatic distal - Sole of the foot  
 
The tongue depressor application and ice will be performed at predose, 15 min, 30 min, 45 min, 
1 h, 2 h, 8 h, 12 h, 24 h, 30 h, 48 h, 60 h, 72 h, 84 h, 96 h, 120 h, 144 h, and 168 h hours from 
the end of the nerve block procedure, or until full sensory function has returned to baseline (pre-
block) levels in two consecutive evaluations. 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 sensory block (sciatic and saphenous nerve tracked independently) will be defined as 
the earliest timepoint with loss of EITHER light touch sensation OR cold sensation in EITHER 
proximal OR distal locations at any time.  If onset time is not achieved, it will be considered 
censored at the last onset assessment time prior to surgery.  Offset of sensory block (sciatic 
and saphenous nerve tracked independently) will be defined as recovery of BOTH light touch 
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sensation AND cold sensation in BOTH proximal and distal locations on two consecutive 
recovery assessments (excluding Not Done assessment). After offset of all sensory assessments 
are noted (on 2 consecutive assessments for all 4 locations), 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.  If the patient’s sensory block is recovered at the last assessment 
time (scheduled at 168 h or unscheduled post-168 h) without the second consecutive assessment 
to confirm, the sensory block is considered recovered at this last time point.  Duration of 
sensory block will be defined as the time between onset and offset of the sensory blocks for 
each nerve individually.  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 9.5.2.4 for how the censoring is handled in the 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.  
6.3.2. Assessment of Motor Block:  
Motor function (onset and offset of motor block) will be assessed using the 2-point scale on the 
side of the block. This will be used to determine the onset and duration of motor blockade.  
Motor function will be assessed using a 2-point scale. The motor function test will be performed 
at predose, 15 min, 30 min, 45 min, 1 h, 2 h, 8 h, 12 h, 24 h, 30 h, 48 h, 60 h, 72 h, 84 h, 96 h, 
120 h, 144 h, and 168 h from end of block procedure, or until full motor function has returned 
to pre-dose levels in two consecutive evaluations. 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 2-point score of 1- Partial 
or no foot movement as opposed to 0- Complete foot movement. If subject does not experience 
loss of motor, their onset will be censored at their last available motor assessment time point 
prior to surgery. Offset of motor block will be defined as resolution of motor block at foot, 
first time point of the two consecutive recovery assessments (score 0- complete foot movement) 
(excluding Not Done assessment). 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 (on 2 
consecutive assessments), no subsequent assessments will be required. If the patient’s motor 
block is recovered at the last assessment time (scheduled at 168 h or unscheduled post-168 h) 
without the second consecutive assessment to confirm, the motor block is considered recovered 
at this last time point. Duration of motor block will be 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. 
 
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6.4. 
Change in the Study Design and Its Effect on the Statistical Analysis 
Protocol version 1.0 (dated 28 July 2020) specified sensory function assessment by light 
touch. Six subjects enrolled under this version.  Protocol Amendment 1 (dated 6 November 
2020) adds cold sensation in the sensory function assessment.  As such, six (6) subjects 
enrolled under Protocol v1.0 did not have cold sensation assessment.  These 6 subjects will be 
excluded from the sensory block evaluation. 
7. 
ANALYSIS SETS 
The following study analysis sets are planned: 
Safety Analysis Set - The safety analysis set will include all subjects who receive study drug.  
All analyses based on the safety 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.  All analyses based on the efficacy analysis set will be by 
randomized 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 excludes Subject 
(101-1013) who received non-randomized study drug and Subject (101-1167) who passed the 
screening, completed the study but later discovered the subject actually failed the screening (ie, 
met the screening exclusion criteria). 
Pharmacokinetic Concentration (PKC) Analysis Set – This set will include all subjects in 
Cohort 1 who received study drug and have at least one post dose plasma concentration sample.  
PK concentration analysis will be based on the actual treatment subject received. 
Pharmacokinetic Parameter (PKP) Analysis Set - The PK analysis set will include all subjects 
in Cohort 1 who receive study drug and provide sufficient samples to enable calculation of PK 
parameters. For example, Subjects 104-1020 and 103-1076 discontinued the PK sampling after 
30-hour and 48-hour time points, respectively.  They will be excluded from the PK Parameter 
analysis set. The final inclusion in the PK analysis set will be defined in the PK report.  PK 
analysis will be based on the actual treatment subject received.  
Pharmacodynamics (PD) Analysis Set - The PD analysis set will include all subjects in Cohort 
1 who receive study drug and provide sufficient data to allow for calculation of PD parameters 
required for analysis.  For example, the first 6 enrolled subjects who had light touch but no cold 
test will be excluded from the sensory block analysis.  PD analysis will be based on the 
randomized treatment group.   
 
8. 
STUDY ENDPOINTS 
8.1. 
Efficacy Endpoints 
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8.1.1. 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 comparing EXPAREL to 0.25% bupivacaine HCl. 
8.1.2. Secondary Endpoints 
1. Total postsurgical opioid consumption in oral morphine equivalents from 0 to 96 hours post-
surgery comparing EXPAREL to 0.25% bupivacaine HCl 
2. Time to first postsurgical opioid consumption comparing EXPAREL to 0.25% bupivacaine 
HCl 
3. AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery comparing 
EXPAREL to EXPAREL admixed with 0.25% bupivacaine HCl 
4. Duration of the motor block comparing EXPAREL to EXPAREL admixed with 0.25% 
bupivacaine HCl (Cohort 1 only) 
5. Proportion of opioid-free subjects through 24, 48, 72, and 96 hours from end of surgery 
8.1.3. Exploratory Endpoints 
1. Subject satisfaction as measured by International Pain Outcome (IPO) at 96 hours 
2. AUC of “average” pain scores from POD1 through POD4 and POD1 through POD14 
3. AUC of “worst” pain scores from POD1 through POD4 and POD1 through POD14 
4. Current pain intensity scores post-surgery through 96 hours 
8.2. 
Safety Endpoints 
Safety endpoints will include the incidence of treatment-emergent AEs and SAEs from the start 
of block procedure through POD14. 
8.3. 
Pharmacokinetic (PK) Endpoints (Cohort 1 only)  
The following model-predicted PK endpoints will be determined. 
x Area under the plasma concentration-versus-time curve (AUC). Specifically AUC0-last 
and AUC0-∞ 
x Maximum plasma concentration (Cmax) and time of Cmax (Tmax). Specifically Early and 
Late Cmax and Tmax 
x The apparent terminal elimination half-life (t1/2) 
x Apparent clearance (CL/F) 
x Apparent volume of distribution (Vd/F) 
8.4. 
Pharmacodynamic (PD) Endpoints (Cohort 1 only)  
x Time to onset of sensory block and motor block 
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x Duration of the sensory block and motor block 
 
9. 
METHODS OF STATISTICAL ANALYSIS 
9.1. 
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 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. 
Individual subject data will be provided in listings.  All listings will be sorted by 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). 
 
9.2. 
Handling Missing Values 
9.2.1. Total Post-Surgical Opioid Consumption 
For the calculation of the total postsurgical opioid consumption 0-96 hours, both opioid pain 
medication before hospital discharge and opioid pain medication in the daily diary after 
discharge will be included.  If opioid is taken on the start of study drug administration day but 
time is missing, time will be imputed as end time of surgery plus (+1) 1 minute. If opioid is 
taken after the day of study drug administration and time is missing, it will be imputed as 00:00. 
For the calculation of the total dose through 96 hours, if a subject’s last follow-up time is 96-x 
hours, then the opioid that was 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. 
9.2.2. NRS Pain Intensity Scores  
Pain scores obtained during the opioid medication window will be replaced with the worst 
observation carried forward (wWOCF).  For this study, the prescribed opioid pain medication 
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is oxycodone. However, morphine, hydromorphone, or other opioids may be used.  The 
durations of the analgesic effect for various opioids are listed in Table 6. 
 
Table 6: 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-coedine, Paracetamol Forte, Tylenol 4 
PO 
6 hours 
Ultram, Tramadol, Tramacol hydrochloride 
PO 
6 hours 
PO = oral, IV = intravenous, IM = Intramuscular, SC = subcutaneous. 
 
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 score 0-96 post-surgery, after applying 
the visit windows (Section 5 Table 3) and wWOCF to all scheduled/unscheduled pain scores, 
remaining missing data at each scheduled time point (6 h, 12 h , 18 h, 24 h, 30 h, 36 h, 42 h, 
48 h, 54 h, 60 h, 66 h, 72 h , 78 h, 84 h, 90 h, and 96 h) will be imputed using the Rubin’s (1987) 
multiple imputation procedure.  This procedure replaces each missing value with a set of 
plausible values that represent the uncertainty about the right value to impute.  The procedures 
of wWOCF and multiple imputation are described in the order as follows.   
A. For subjects who take an opioid pain medication, their NRS scores recorded within the 
window of controlled type of opioid medication (see Table 6) 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. The NRS score at the time of opioid pain medication 
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administration will be included in this calculation. Note (1) the NRS score in the 
window that is higher than the worst value to be carried forward, this “higher” value 
will not be overwritten.  Instead, the worst value will be replaced by this “higher” value 
and continue carrying forward until the end of the window. (2) if the scheduled NRS 
score within the window is missing, it will be imputed with this worst value. 
B. After the wWOCF imputation described above, if there are still missing NRS scores at 
scheduled time points, they will be imputed using the multiple imputation procedures 
using the Markov Chain Monte Carlo (MCMC) method (Schafer 1997).  This 
imputation will be carried out within each treatment group using SAS PROC MI. Thirty 
imputations will be conducted.  To minimize the effect of data skewness on the 
imputation result, the NRS score is log-transformed [y=log(x+0.5), where y is the 
transformed score, x is the raw NRS score, and constant 0.5 is added to avoid log(0)] 
prior to the imputation and back-transformed after the imputation.  In order to achieve 
the stationary distribution and to avoid dependency within samples generated by 
MCMC method, the number of iterations for the burn-in period will be set to 2000 and 
the number of iterations between two consecutive samples will be set to 1000.   
For the imputed NRS scores, the associated time will be assigned with the exact 
scheduled time, eg, 48.0 h. 
To better simulate the observed NRS pain score, all imputed scores will be rounded to 
become a number between 0.0 and 10.0 with 1 decimal place. 
C. The AUC at various time intervals will be derived as described in Section 9.5.1 from 
the imputed NRS scores.  For each subject, there will be 50 sets of AUC from the 50 
imputed data sets.  
D. The endpoints derived in Step C will be analyzed as described in Section 9.5.1 for each 
imputed data set. 
E. Rubin’s (1987) synthesizing procedure will be applied to synthesize analysis results 
from the 50 imputed data sets.  SAS PROC MIANALYZE will be used for this analysis.  
The least squares mean (LSM) and standard error (SE) for each treatment group, and 
the LSM, SE, 95% CI and p-value for the between treatment difference in AUC will be 
computed from this analysis.  
The SAS pseudo-code for multiple imputations and analysis is as follows. 
** Step (b) uses MCMC method to create fully imputed data sets  
** Note the value for the random seed is fixed to be 156799 so that the results are 
reproducible, MIN=0 and MAX=10 are to bound the imputed VAS score within 0-10, 
ROUND=0.1 is to round the imputed NRS score with 1 decimal place. The Box-Cox 
transformation is to reduce the skewness of the data distribution ** 
 
proc mi data=adef seed=156799 nimpute=50 out=output_step1 min=0 
max=10 round=0.1 minmaxiter=10000; 
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by treatment; 
 
mcmc chain=multiple impute=full initial=em prior=jeffreys 
nbiter=2000 niter=1000; 
 
var t6 t12 t18 t24 t30 t36 t42 t48 t54 t60 t66 t72 t78 t84 t90 
t96 ; 
 
transform boxcox (t6 t12 t18 t24 t30 t36 t42 t48 t54 t60 t66 
t72 t78 t84 t90 t96 / c=0.5 lambda=0) ;* this is log(t+0.5) 
transformation ; 
run; 
 
** Step (c) calculates AUC for each subject in the imputed data set (with _IMPUTATION_ =1 
to 50) **; 
 
** Step (d) analyzes AUC using ANCOVA model for each imputed data set and derives LSM, 
SE for each treatment group and LSM, SE, and 95% CI for the between treatment difference 
**;  
ods output Diffs=diff LSMeans=lsm ; 
proc genmod data=auc1; 
 
by _imputation_; 
 
class trtpn siteid; 
 
model aval=trtpn siteid age height / dist= normal 
link=identity; 
 
lsmeans trtpn / diff cl alpha=0.05 ilink; 
 
ods output LSMeans=lsm; 
 
ods output Diffs=diff; 
run; 
 
** Step (e) synthesizes LSMs and SEs derived from the 50 imputed data sets ** ; 
ods output ParameterEstimates=lsmdif ; 
proc mianalyze data=diff alpha=0.05 ; 
modeleffects estimate ; 
stderr stderr ; 
run ; 
 
ods output ParameterEstimates=lsmeans ; 
proc mianalyze data=lsm alpha=0.05 ; 
by trtpn ; 
modeleffects estimate ; 
stderr stderr ; 
run ; 
 
9.2.3. Adverse Event or Concomitant Medications Dates or Times 
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).   
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x If the year is unknown, then the date will be assigned the date and time of first dose of 
study treatment. 
x 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. 
x 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). 
x 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 9.2.3 provides rules for the 
determination of prior or concomitant status.   
9.2.4. 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. 
9.2.5. 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 6.3.1 and 6.3.2 when the onset time or the offset 
time of sensory or motor block is not captured. 
 
9.3. 
Subject Disposition 
Subject disposition summaries will include the number (and %) of subjects by treatment group. 
x Screened, 
o Screen failure 
o Enrolled (ie, randomized) 
x Randomized  
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o Randomized not treated 
o Randomized treated 
x In the Safety analysis set 
x In the Efficacy analysis set 
x In the Pharmacokinetic analysis set 
x In the Pharmacodynamics analysis set 
x Protocol 
o Enrolled under each amendment 
x Completed the study as planned 
x Discontinued from the study 
o Reasons for discontinuation from the study 
Percentages will be reported for the screen failures and enrolled using the number of subjects 
screened as the denominator; other percentages will use the number of subjects randomized and 
treated as denominator.  All data will be presented as randomized, although analysis for Safety 
set (see Section 9.8) will be based on the actual treatment patients received.  
 
9.4. 
Description of Demographics and Baseline Characteristics  
9.4.1. Demographics  
The summary of demographic data will present: 
x Age (years) – descriptive statistics 
x Sex – n (%) 
x Ethnicity – n (%) 
x Race – n (%) 
Age is calculated at the date the subject signed the informed consent form.  It is presented as 
the number of years rounding down to the nearest integer.   
The demographic summary will present the data for each treatment group.  Summaries will be 
provided for each (efficacy, safety, PK and PD) analysis set separately.   
9.4.2. Baseline Characteristics 
The summary of baseline characteristic data will present: 
x American Society of Anesthesiologists (ASA) Classification – n (%) 
x Height (cm) 
x Weight (kg) 
x Body Mass Index (BMI) (kg/m2) 
x Average and Worst pain intensity scores on the numeric rating scale (NRS) in the last 30 
days  
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x Pain Catastrophizing Scale Total Score 
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.  
The Pain Catastrophizing Scale Total Score is the summation of the 13 questions.  
Baseline characteristics summaries will present the data for each treatment group.  Summaries 
will be provided for each (efficacy, safety, PK and PD) analysis set separately.   
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be provided for 
continuous variables.  The number and percent of subjects will be tabulated for the categorical 
variables. 
9.4.3. Medical and Surgical History 
Subject medical and surgical history will be provided in a by treatment group and subject data 
listing. 
9.4.4. Surgery Characteristics 
Surgery characteristics including duration of surgery will be summarized using descriptive 
statistics.  Summaries will be provided for each (efficacy and safety) analysis set. 
Duration of surgery is calculated as the difference between the end of surgery and start of 
surgery times and reported in hours. 
9.4.5. Intraoperative, Prior, and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHO Drug Dictionary Global September 2020 C3 Format) 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, 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 
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. 
x If the medication stop date is partially missing,  
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o If the year and month indicate the stop date is before study drug administration, 
it is Prior medication.  
o Otherwise, it is concomitant medication. 
x If the medication stop date is completely missing, it is concomitant medication. 
All medications will be summarized separately by category using n (%) of subjects for each 
treatment group and across treatment groups by ATC3 term and PT for the safety analysis set.  
Subjects may have more than one medication per ATC3 and PT.  At each level of subject 
summarization, a subject will be counted once if one or more medications are reported by the 
same subject at that level.  
All medications will be included in the data listing. 
9.4.6. Measurements of Treatment Compliance 
Study drug is administered by the site personnel; therefore, compliance is assumed.   
 
9.5. 
Efficacy Analysis 
For Primary and Secondary Efficacy Analyses, descriptive statistics that are appropriate for the 
efficacy variable will also be shown by surgical type, but no statistical analyses will be 
performed within a surgery type.  All efficacy analyses will be performed using the Efficacy 
analysis set.   
Unless specified otherwise, all confidence interval will be 2-sided with 95% confidence. All 
statistical comparison will be 2-sided at alpha=0.05 level.  The leading statistical comparison 
is between EXPAREL and 0.25% bupivacaine HCl for the primary and first two secondary 
endpoints and between EXPAREL and EXPAREL admixed with 0.25% bupivacaine HCl for 
the third and fourth secondary endpoints, though all 3 pairwise comparisons (EXPAREL vs 
0.25% bupivacaine HCl, EXPAREL vs EXPAREL admixed with 0.25% bupivacaine HCl, and 
EXPAREL admixed with 0.25% bupivacaine HCl vs 0.25% bupivacaine HCl) will be 
presented. 
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.  See also Section 8.1 for detail. 
1. Primary endpoint: EXPAREL vs 0.25% bupivacaine HCl 
2. First secondary endpoint: EXPAREL vs 0.25% bupivacaine HCl 
3. Second secondary endpoint: EXPAREL vs 0.25% bupivacaine HCl 
4. Third secondary endpoint: EXPAREL vs EXPAREL admixed with 0.25% bupivacaine 
HCl 
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5. Fourth secondary endpoint: EXPAREL vs EXPAREL admixed with 0.25% bupivacaine 
HCl 
9.5.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is AUC of the NRS pain intensity scores from 0 to 96 hours post-
operation using Efficacy Analysis Set.  The NRS pain intensity score is collected from the 
assessment “How much pain are you experiencing right now?”  The worst and average daily 
pain scores are not included in the AUC calculation. 
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 9.2.2).  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 are also included in the AUC calculation.  
Exact assessment time will be used in deriving AUC. 
ܣܷܥൌ൝෍ሺ
௡
௜ୀଶ
݌௜൅݌ሺ௜ିଵሻሻሺݐ௜െݐሺ௜ିଵሻሻൡȀʹ 
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.  It is the first time NRS score is collected.  
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.  
AUC0-96 for pain intensity from 0 to 96 hours will be summarized by treatment group, by 
surgery type and overall.  
Tests for the superiority of treatment effect of EXPAREL versus 0.25% bupivacaine HCl will 
be based on the following null hypotheses and alternative hypotheses using the Efficacy 
analysis set and multiple imputation method: 
Ho: EXPAREL is not different from 0.25% bupivacaine HCl with respect to AUC for 
pain intensity 
HA: EXPAREL is superior to 0.25% bupivacaine HCl with respect to AUC for pain 
intensity 
A two-sided hypothesis test will be performed at 5% level of significance comparing 
EXPAREL and 0.25% bupivacaine HCl as follows: 
x If the upper bound of the 2-sided 95% confidence interval for the least square (LS) 
means for the difference of AUC0-96 (EXPAREL) – AUC0-96 (0.25% bupivacaine HCl) 
is ≥0, then superiority of EXPAREL to 0.25% bupivacaine HCl is not achieved. 
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x If the upper bound is <0 then declare that the superiority of EXPAREL to 0.25% 
bupivacaine HCl is achieved. 
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 Means_Bup – LS Means_EXPAREL}/LS Means_Bup. 
To test for significant differences between EXPAREL and 0.25% bupivacaine HCl, an analysis 
of covariance (ANCOVA) model with main effects of treatment (EXPAREL, 
EXPAREL+0.25% bupivacaine HCl, and 0.25% bupivacaine HCl), and covariates of 
investigator site (categorical), age and height 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 p-value will be presented.  
Due to multiple imputations for the missing pain scores (Section 9.2.2), 50 sets of AUC0-96 will 
be generated for each subject.  The average of these 50 sets of AUCs are the basis of the 
summary statistics.  No Rubin’s synthesizing method will be applied for the computations of 
these statistics.  For the hypothesis tests and the least square mean computations, the 
synthesizing method will be used to account for the between imputation variability. 
In addition to the above-described primary efficacy analysis, a 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, where AUC is calculated using all NRS pain score collected 
0 – 96 h without imputation, and the time span is last NRS time minus the first NRS time for 
the AUC calculation.  
Another sensitivity analysis will be carried out in the same way as the primary analysis but 
excluding the subject (101-1013) who received non-randomized study drug and the subject 
(101-1167) who passed the screening, completed the study but later discovered the subject 
actually met the exclusion criteria at the screening time. 
9.5.2. Secondary Efficacy Endpoints 
9.5.2.1. 
Total postsurgical opioid consumption in oral morphine equivalents from 0 to 96 
hours post-surgery comparing EXPAREL to 0.25% bupivacaine HCl 
Total postsurgical opioid consumption (OMED mg) will be summarized by treatment group 
and surgery type using Efficacy Analysis Set.  The summary will include number of subjects 
receiving postsurgical opioids, geometric mean and coefficient of variation (CV%), median, 
minimum and maximum.   
To test for significant difference between EXPAREL and 0.25% bupivacaine HCl, an analysis 
of covariance (ANCOVA) model with treatment as main effect and investigator site 
(categorical), age, and height as covariates will be applied to the natural log-transformed total 
dose.  The LS means for EXPAREL and 0.25% bupivacaine HCl, LS mean difference between 
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EXPAREL and 0.25% bupivacaine HCl, two-sided 95% CI for the LS mean difference, and the 
two-sided p-value 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 for the ANCOVA analysis using log-transformation. 
In addition to the presentation for the between group difference, the percent reduction in total 
opioid consumption will also be presented similar to Section 9.5.1.  
As sensitivity analysis, this endpoint will also be analyzed using the non-stratified Cochran-
Mantel-Haenszel test for the row mean score difference with modified ridit scores.   
A sample SAS code is as follows. 
PROC FREQ ; 
 
TABLES trtp*omed / CMH SCORE=modridit ; 
RUN ; 
Another sensitivity analysis will be carried out in the same way as for the primary analysis 
using ANCOVA but excluding two subjects described in Section 9.5.1. 
9.5.2.2. 
Time to first postsurgical opioid consumption comparing EXPAREL to 0.25% 
bupivacaine HCl 
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 have an opioid usage 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. 
Time to first opioid usage will be analyzed by the Kaplan-Meier survival analysis.  Median time 
and the log-rank test comparing EXPAREL and 0.25% bupivacaine HCl will be presented. The 
log-rank test will be stratified by the age and height group (Section 9.5.3).  Cox proportional 
hazards regression with treatment (EXPAREL, EXPAREL admixed with 0.25% bupivacaine, 
and 0.25% bupivacaine HCl) as factors and categorical investigator site, continuous age and 
height as covariates will also be performed. The number (and %) of subjects with opioid pain 
medication post discharge as well as the number (and %) of subjects without opioid pain 
medication post discharge will be presented for each treatment group.  
9.5.2.3. 
AUC of the NRS pain intensity scores from 0 to 96 hours post-surgery comparing 
EXPAREL to EXPAREL admixed with 0.25% bupivacaine HCl 
To examine differences between EXPAREL and EXPAREL admixed with 0.25% bupivacaine 
HCl, the same ANCOVA model as for the primary efficacy endpoint will be used. The LS mean 
difference between EXPAREL and EXPAREL admixed with 0.25% bupivacaine HCl groups, 
and two-sided 95% CI for the LS mean difference will be presented.  
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In addition to the presentation of the difference, the percent reduction in AUC will also be 
presented. The % reduction is derived as follows, 
% Reduction = {LS Means_EXP+Bup – LS Means_EXPAREL}/LS Means_EXP+Bup. 
9.5.2.4. 
Duration of the motor block comparing EXPAREL to EXPAREL admixed with 
0.25% bupivacaine HCl (Cohort 1 only) 
Duration of motor block will be analyzed by the Kaplan-Meier survival analysis.  Although 
duration can be captured as left, right, or interval censored (Section 6.3.1), all these censored 
durations will be considered right censored for the programming purpose, because all these 
censoring implies that the actual duration is longer than the observed censored duration.  
Median time and the stratified log-rank test comparing EXPAREL and EXPAREL admixed 
with 0.25% bupivacaine HCl will be presented.  
In addition to the presentation of the median, the ratio of EXPAREL to 0.25% bupivacaine HCl 
in motor duration median will be presented. The ratio is derived as follows, 
Ratio = (Median_EXPAREL/Median_EXP+Bup) 
9.5.3. Subgroup Analysis for the Primary and First Secondary Efficacy Endpoints 
The analysis of the primary and the first secondary endpoints will be repeated for select 
subgroups such as  
x Age (<45, and ≥45),  
x Sex 
x Race (White and Non-White),  
x BMI (<25, 25 to <30, and ≥30+ kg/m2)  
x Height (<165 cm, and ≥165 cm) 
x Site 
x Surgical Type 
9.5.4. Exploratory Endpoints 
Assessment of subject satisfaction with pain control using International Pain Outcome (IPO) at 
96 hours will be summarized by treatment group. 
Current pain intensity collected 0 to 96 hours post surgery will be summarized by treatment 
group and analyzed for between treatment difference using ANCOVA at each scheduled time 
point.  See Section 9.5.1 for model specification.  This analysis will use wWOCF-imputed pain 
intensity data set (see Section 9.2.2A). 
“Average” and “worst” pain score over the last 24 hours will be summarized by treatment group 
daily from POD1 through POD14.  They will also be analyzed each day using ANCOVA (see 
Section 9.5.1). 
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AUC of “average” and “worst” pain scores will be calculated for each subject from POD1 
through POD4 and through POD14 using the ranctangular area method as follows. 
ܣܷܥ଴ିସൌ
෍
݌௜
௉ை஽ସ
௜ୀ୔୓ୈଵ
ܣܷܥ଴ିଵସൌ
෍
݌௜
௉ை஽ଵସ
௜ୀ୔୓ୈଵ
 
The ranctangular method is chosen because the pain score here is already a summary of the last 
24 hours pain by the patient.  
For patients with monotone missing, (ie, once missing, all the following days are missing), the 
last observation carried forward (LOCF) will be applied to impute the missing daily scores.  For 
patients with intermittent missing, the missing daily scores are imputed as follows. 
݌௫ൌ൫݌௬൅݌௭൯ݔെݕ
ݖെݕǡ 
where x is the day with missing pain score, y and z are the days with non-missing pain scores 
closest to but before and after Day x, respectively.  As an example, suppose Day 2 and Day 3 
are missing, but Day 1 and Day 4 are collected, Day 2 and Day 3 pain scores are imputed as 
follows. 
݌ଶൌሺ݌ଵ൅݌ସሻʹ െͳ
Ͷ െͳ ൌͳȀ͵ሺ݌ଵ൅݌ସሻǡ ݌ଷൌሺ݌ଵ൅݌ସሻ͵ െͳ
Ͷ െͳ ൌʹȀ͵ሺ݌ଵ൅݌ସሻǤ 
For subjects with missing score for the first a few days, the first observation will be carried 
backward for the missing daily scores.  AUC of “average” and “worst” pain scores will be 
summarized by treatment group.  The between group difference will be analyzed using 
ANCOVA similar to the sensitivity analysis for the primary efficacy endpoint (Section 9.5.1).  
A listing of admission and discharge to the surgical facilitate and PACU, postsurgical and pain 
medications will be provided.   
 
9.6. 
Pharmacokinetic Analysis 
9.6.1. Pharmacokinetic Parameter Calculation Methods 
Pharmacokinetic parameters will be calculated by noncompartmental analysis (NCA) method 
from concentration-time data following these guidelines: 
x 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. 
x Concentrations from unscheduled PK blood samples will be included in the analysis of 
the parameters. 
x There will be no imputation of missing concentration data. 
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For the summaries of concentrations and for the NCA analysis of the 0.25% bupivacaine plasma 
concentrations, concentrations below the limit of quantification (BLOQ) will be handled as 
follows: 
x Pre-dose BLOQ values will be set to zero. 
x BLOQ values between the dosing time and the first time point above lower limit of 
quantification (LLOQ) will be set to 0. 
x BLOQ values at time points between two measurable concentration values will be set 
to ½ of LLOQ (lower limit of quantification). 
x 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: 
x The maximum observed plasma concentration (Cmax) will be obtained directly from the 
concentration-time data.  
o Early Cmax – occurring between dosing (0 h) and X hours after dosing if 
appropriate based on the individual subject and treatment group mean 
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.  
x Time to maximum concentration (Tmax) is the time at which Cmax is observed.  
o Early Tmax – the time corresponding to Early Cmax. 
o Late Tmax – the time corresponding to Late Cmax. 
x 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. 
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x Rules for excluding subjects from the terminal phase-related parameter calculation: 
1. Adjusted R-square <80%, or 
2. %extrapolated AUC >30% of AUC0-∞ 
x Apparent terminal half-life (t1/2) will be calculated as ln(2)/λz. 
x 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. 
x 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. 
x 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%. 
x Apparent clearance CL/F will be estimated as Dose/AUC0-∞, where Dose = 266 mg for 
subjects receiving EXPAREL, 44 mg (50 mg × 0.886 [salt to free base conversion]) for 
subjects receiving 50 mg 0.25% bupivacaine, and 87 mg for subjects receive 100 mg 
0.25% bupivacaine. 
x Apparent volume of distribution (Vd/F) will be estimated as (CL/F)/λz. 
9.6.2. Pharmacokinetic Concentrations and Variables 
The analysis of the PK parameter will be based on the PK analysis set. The analysis of the PK 
concentration will be based on the Safety 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 will include: n, arithmetic mean, SD, geometric mean, %CV, 
median, minimum and maximum values.  Descriptive statistics for Tmax (early and late) 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, placed on the same page.  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. 
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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 global 
Cmax for the respective subjects, these concentration values and PK parameters from subjects 
with these values will be excluded from descriptive statistic summaries. 
 
9.7. 
Pharmacodynamic Analysis 
9.7.1. Sensory Function 
Separately for sciatic and saphenous nerve, 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 9.5.2.2. See Section 9.5.2.4 for 
how to handle censoring time. 
The number (and %) of subjects with normal sensation and no sensation will be tabulated by 
treatment group and timepoint.  Because patients are not required to continue the onset or offset 
assessment after they have reached the onset or offset respectively, missing scheduled 
assessment will be imputed using the last observation carried forward (LOCF) method.   
Additionally, mean PK concentration and % subjects with motor block “on” will be overlaid 
and plotted over time to show the dynamic relationship between the two for each of the 3 
treatment groups. 
9.7.2. 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 9.5.2.2. Cumulative subject incidence plot (1 – [minus] Kaplan-Meier curves) 
will also be presented.   
The number (and %) of subjects with complete motor function and partial/no motor function 
will be tabulated by treatment group and timepoint.  Missing assessment will be imputed by 
LOCF. 
Additionally, PD plot similar to the one described in Section 9.7.1 will be created for the sciatic 
distal and saphenous distal sensory nerves.  
 
9.8. 
Safety Assessments  
Adverse events (AEs) and Serious AEs (SAEs) will be recorded from the time of informed 
consent through POD14.  
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Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
version 23.1).  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 POD 14±3 days. 
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 %) of unique subjects in the following 
categories: 
x Any TEAE 
o Maximum severity: Mild 
o Maximum severity: Moderate 
o Maximum severity: Severe 
x At least one related TEAE 
x At least one serious TEAE 
x Subjects discontinued due to a TEAE 
x Died on study 
Subjects will be counted once in each of the above categories. 
The subject incidence of all TEAEs will be tabulated by the number (and %) 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 purpose, 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.  A summary 
of subjects reporting at least one TEAE during the study will also be presented. 
x TEAEs by PT (Preferred Term) sorted by the decreasing order of subject incidence in 
the group combining EXPAREL and EXPAREL admixed with 0.25% bupivacaine HCl 
x TEAEs by SOC (System Organ Class) and PT sorted alphabetically  
x TEAEs by SOC and PT, and worst severity  
x TEAEs by SOC and PT and study drug-relationship 
x TEAE of special interest (TEAESI) by SOC and PT 
x Serious TEAE of special interest (TEAESI) by SOC and PT 
x Non-Serious TEAE of special interest (TEAESI) by SOC and PT 
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A subject data listing will be provided for all adverse events. 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 subjects who die on study, experience SAEs, have 
TEAEs leading to study discontinuation, or AEs of special interest. A listing of the mapping of 
the SOC and PT to verbatim terms will be presented. 
AE of special interest will be extracted based on the MedDRA terms below. 
x Persistent tingling   
x Persistent numbness   
x Persistent weakness   
x Hypersensitivity   
x Seizures   
x Tremors   
x Dizziness   
x Hematoma formation   
x Cardiovascular depression   
x Dyspnea   
x Cardiovascular arrest   
x Altered sensorium   
x Visual disturbances   
x Local anesthetic systemic toxicity 
 
9.9. 
Interim Analysis 
An unblinded efficacy interim analysis conducted by an independent committee will occur 
when approximately 60 subjects (20 in each arm) have been randomized, treated, and provided 
their primary efficacy outcome. An interim analysis will be conducted to evaluate and compare 
the clinical efficacy between EXAPREL only and 0.25% bupivacaine HCl only. Primary 
purpose of this interim analysis is to evaluate the sample size assumptions and evaluate futility. 
Full details on the planned or additional interim analysis will be covered in a separate 
prospective interim analysis plan. 
 
 
 
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Statistical Analysis Plan 
EXPAREL 
402-C-333 
 
 
CONFIDENTIAL 
Page 39 of 39 
27 April 2021 
10. 
SAMPLE SIZE CALCULATIONS 
The sample size was calculated based on the primary efficacy endpoint of the AUC of the NRS 
pain intensity scores from 0 through 96 hours post-surgery comparing EXPAREL to 0.25% 
bupivacaine HCl.  
The sample size for Cohort 1 was based on the number of subjects necessary to characterize the 
PK following administration.  
Cohort 1 and Cohort 2 subjects will be combined within treatment groups for the efficacy and 
safety analyses; therefore, the overall sample size was based on the primary efficacy endpoint 
of the AUC of the NRS pain intensity scores from 0 through 96 hours post-surgery. Assuming 
a 2-sided 0.05 alpha, common standard deviation (SD) of 170 a sample size of 40 subjects for 
EXPAREL and 40 subjects for 0.25% bupivacaine HCl should have at least 90% power to 
detect a true difference of 150-units in the AUCs. Therefore, since Cohort 1 will have 60 
subjects (20 EXAPREL, 20 EXPAREL admixed with 0.25% bupivacaine HCl and 20 0.25% 
bupivacaine HCl), Cohort 2 will need to enroll 60 subjects (20 EXAPREL, 20 EXPAREL 
admixed with 0.25% bupivacaine HCl and 20 0.25% bupivacaine HCl) to meet the total 
requirements.  
 
11. 
REFERENCES 
Rubin, DB. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
& Sons. 
Schafer, JL. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman & Hall. 
 
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