A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo Controlled Study to Assess the Efficacy and Safety of Intercostal Nerve Block With Liposome Bupivacaine in Subjects Undergoing Posterolateral Thoracotomy
Phase: PHASE3
Conditions: Posterolateral Thoracotomy, Postoperative Pain
Sponsor: Pacira Pharmaceuticals, Inc

Pacira Pharmaceuticals, Inc. 
 
 
EXPAREL 
Document: 
Clinical Study Protocol 
Official Title: 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study to Assess the Efficacy and Safety of 
Intercostal Nerve Block with Liposome Bupivacaine in Subjects 
Undergoing Posterolateral Thoracotomy 
NCT Number: 
NCT01802411 
Document Date: 
September 23, 2012 
 

Clinical Study Protocol Amendment 1
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group,
Placebo-Controlled Study to Assess the Efficacy and Safety of Intercostal Nerve Block with
Liposome Bupivacaine in Subjects Undergoing Posterolateral Thoracotomy
Confidentiality Statement
The information contained in this document is confidential and the property of Pacira Pharmaceuticals, 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 Pharmaceuticals, Inc.
Protocol No.:
402-C-322
EudraCT No.:
2012-003275-19
IND No.:
69,198
Study Phase:
3
Study Drug:
Liposome bupivacaine
Date:
23 September 2012 (Amendment 1)
08 August 2012 (original)
Study Sites:
Up to 30 sites in the United States and Europe
Sponsor:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
Tel: (858) 625-2424

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Clinical Study Protocol Amendment 1
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23 September 2012
SUMMARY OF CHANGES
The changes made to the original study protocol are as follows:
General
Minor clarifications were made throughout the protocol.
Section 2 (Synopsis)

Methodology:
o
The dosage guidance for the second rescue medication was revised for both the
US and European sites.
o
The time frame of the cardiac assessment (ECG recording) was changed
from: "The cardiac assessment (i.e., ECG recordings) will be recorded at baseline
(approximately 1 hour prior to surgery) and during the first 72 hours after
surgery" to: "The cardiac assessment (i.e., ECG recordings) will be started at
baseline (approximately 1 hour prior to surgery) and continue for a total of
72 hours."
o
The end of the AE/SAE reporting time frame was clarified from: "Day 30"
to: "until the Day 30 follow-up contact."

Eligibility Criteria:
o
Inclusion criterion #5 was changed from: "Able to demonstrate sensory function
by exhibiting sensitivity in each of the dermatomes in which study drug will be
administered" to: "Able to demonstrate sensory function by exhibiting sensitivity
to cold anywhere within the dermatomes supplied by any of the nerves to which
study drug will be administered."
o
Exclusion criterion #3: "acetaminophen/paracetamol" was deleted.

Reference Product:
o
For consistency, "preservative-free sodium chloride" was changed to
"preservative-free normal saline."

Efficacy Endpoints:
o
The sensitivity to cold endpoint was changed from: "Proportion of subjects at
each time point with sensitivity to cold in one of the dermatomes" to: "Proportion
of subjects at each time point with sensitivity to cold anywhere within the
dermatomes supplied by any of the nerves to which study drug was administered."

Safety Assessments:
o
The time frame of the cardiac assessment (ECG recording) was changed as stated
above.

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Clinical Study Protocol Amendment 1
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o
The ECG assessment was changed from: "Electrocardiogram changes will be
examined using the ECG data closest to the median Tmax" to: "Electrocardiogram
changes will be examined using the ECG data closest to the Tmax."
Section 4 (List of Abbreviations)
"HR," "QTcB," and "QTcF" were added to the List of Abbreviations.
Table 1 (Time and Events Schedule of Study Procedures)
The time window for the 72-hour time point assessments was changed from: ±2 hours
to: ±4 hours.
Sections 9, 10, 11, 12, 13, and 14
The changes made in the Synopsis (listed above) were made to Sections 9 though 14.
Section 11.5.1 (Blinding Procedures)
The blinding procedures were clarified.
Section 11.6.1 (Prior and Concomitant Medications and Therapy)
Acetaminophen/paracetamol was deleted.
Section 11.8 (Accountability of Study Drug)
Text was revised.
Section 13.1.3 (Neurological Assessment)
Text pertaining to the assessment of the subject's orientation was added.
Section 13.1.4 – Cardiac Assessment (Electrocardiogram Recordings)
The cardiac assessment procedures were revised.
Section 13.5 – Procedures After Surgery Through 72 Hours
o
The second bullet under "US sites" was deleted due to redundancy.
o
For consistency, the bullet pertaining to the sensory function assessment was
changed from: "..or until the subject’s sensitivity to cold has returned to the
baseline level in two consecutive evaluations..." to "... or until the subject’s
sensitivity to cold has returned in two consecutive evaluations."

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Section 15.6.3.3 – Tertiary Efficacy Measures
Under the subheading Categorical Measures of Efficacy, text was changed from:
"A chi-square test or Cochran-Mantel-Haenszel test will be used to compare liposome
bupivacaine to placebo" to: "A chi-square test or Wilcoxon Rank Sum test will be used to
compare liposome bupivacaine to placebo."
Section 15.6.5.4 – Rating of Physician's Satisfaction with Wound Healing
Text was changed from: "To test for significant differences between liposome
bupivacaine and placebo, an ANOVA with treatment as the main effect will be used"
to: "To test for significant differences between liposome bupivacaine and placebo,
a Wilcoxon Rank Sum test with treatment as the main effect will be used."
Section 16 – References
The date of the Investigator's Brochure was changed to match the date of the recently
updated IB.
Appendix 2 (Neurological Assessment)
The following sentence was added: "If the subject is not oriented, record as an AE."
Appendix 5 (Physician's Satisfaction with Wound Healing)
The scale used for the wound healing assessment was changed from an 11-point NRS to a
5-point Likert scale.
Appendix 7 (Dermatome Map)
The text was revised to match the changes stated above.

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Clinical Study Protocol Amendment 1
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SIGNATURE PAGE
25 September 2012
Erol Onel, MD
Executive Medical Director
Date
25 September 2012
Gary Patou, MD
Chief Medical Officer
Date
26 September 2012
Patricia Mills, RN
Sr. Director, Drug Safety and
Pharmacovigilance
Date

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2.
SYNOPSIS
Name of Sponsor/Company:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
(858) 625-2424
Individual Study Table Referring
to Part of the Dossier
Volume:
Page:
(For National Authority Use
Only)
Name of Finished Product:
Liposome Bupivacaine
Name of Active Ingredient:
Bupivacaine 1.3%, 13.3 mg/mL
Title of Study: A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to
Assess the Efficacy and Safety of Intercostal Nerve Block with Liposome Bupivacaine in Subjects Undergoing
Posterolateral Thoracotomy
Principal Investigators: To be determined.
Study Center(s): Up to 30 sites in the United States and Europe.
Publications (Reference): None.
Objectives:
Primary Objective:
The primary objective is to evaluate the efficacy of intercostal nerve block using liposome bupivacaine compared
with placebo in subjects undergoing posterolateral thoracotomy.
Secondary Objectives:
The secondary objectives are to evaluate additional efficacy parameters, characterize the pharmacokinetic (PK)
profile of liposome bupivacaine when administered as an intercostal nerve block, and further assess the safety
profile of liposome bupivacaine.
Methodology:
This is a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled study conducted to
investigate the efficacy and safety of liposome bupivacaine (total of 266 mg in 20 mL) divided into three equal
doses in three syringes of approximately 88 mg in 6.6 mL volume per nerve and administered to each of three
nerve segments (index nerve, nerve above, and nerve below) compared with saline placebo nerve block.
After completing screening procedures, eligible subjects undergoing posterolateral thoracotomy will be
randomized 1:1 to receive either liposome bupivacaine or placebo. Study drug will be administered in a blinded
manner after the posterolateral thoracotomy is completed (i.e., just prior to the surgical site closure). The use of
opioids (other than fentanyl), acetaminophen/paracetamol, ketorolac or other non-steroidal anti-inflammatory
drugs (NSAIDs), and local anesthetics other than the study drug will not be permitted intraoperatively, except for
emergency use to treat an AE.
At all US sites only, subjects will have a patient-controlled analgesia (PCA) pump established prior to the
completion of the surgery. The PCA pump will not be loaded at this time. All subjects will be required to remain
in the study site for a minimum of 72 hours following surgery for postsurgical assessments.
Postsurgical Rescue Medication
Rescue medication should only be provided upon subject request, as needed.
First Rescue Medication
The first rescue medication will be intravenous (IV) fentanyl 100 mcg, which will be administered once via bolus
only. At this time, the PCA pump should be loaded with opioid (morphine or hydromorphone only) for subjects
at the US sites only.

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Clinical Study Protocol Amendment 1
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Name of Sponsor/Company:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
(858) 625-2424
Individual Study Table Referring
to Part of the Dossier
Volume:
Page:
(For National Authority Use
Only)
Name of Finished Product:
Liposome Bupivacaine
Name of Active Ingredient:
Bupivacaine 1.3%, 13.3 mg/mL
Postsurgical Rescue Medication (Cont.)
Second Rescue Medication
For the US sites only, the second rescue medication will be PCA-administered opioid (morphine or
hydromorphone). The PCA pump will be programmed to deliver either of the following recommended doses:
(1) on-demand morphine boluses of 1.5 mg with a lockout interval of 6 minutes and an initial maximum hourly
dose of 15 mg, or (2) on-demand hydromorphone boluses of 0.2 mg with a lockout interval of 10 minutes and an
initial maximum hourly dose of 1.2 mg. A continuous infusion (background or basal rate) of morphine is not
permitted. The recommended bolus doses may be adjusted according to local hospital practices; however,
adding a basal rate is prohibited.
For the European sites only, the second rescue medication will be intramuscular (IM) administered opioid
(morphine) up to10 mg every 4 hours.
At all sites, once a subject is tolerating oral (PO) medication, PO immediate-release oxycodone may
be administered (but not more than 10 mg every 4 hours).
Subjects who do not achieve adequate pain relief with this regimen will be withdrawn from the study and
followed for safety only.
Postsurgical Assessments
Subjects will be evaluated for pain intensity using the numeric rating scale at rest (NRS-R) at baseline and 1, 2, 4,
8, 12, 24, 36, 48, 60, and 72 hours following surgery, at first request for rescue pain medication, and on Day 12
(see Appendix 1). Subjects also will be evaluated for pain intensity with activity (defined as pain intensity with
cough) using the NRS with activity (NRS-A) at baseline and 24, 48, and 72 hours following surgery and on
Day 12 (see Appendix 1). Note: At time points when the pain intensity assessments coincide, the NRS-R will be
conducted before the NRS-A. Additionally, if chest tube removal or a PK blood draw coincides with pain
intensity assessment(s), the pain intensity assessment(s) must be conducted before the other procedures.
Neurological assessments will be conducted at baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 18, 24, 30, 36,
42, 48, 60, and 72 hours after surgery (see Appendix 2). The cardiac assessment (i.e., ECG recordings) will be
started at baseline (approximately 1 hour prior to surgery) and continue for a total of 72 hours. The sensory
function assessment (i.e., cold test) will be conducted at baseline, when the subject wakes up after surgery, and at
2, 4, 12, 24, 36, 48, 60, and 72 hours after surgery, or until the subject’s sensitivity to cold has returned in two
consecutive evaluations (see Appendix 7).
The overall benefit of analgesia score (OBAS) questionnaire will be completed at 24, 48, and 72 hours following
surgery (see Appendix 3). The subject's overall satisfaction with postsurgical pain control will be assessed at
72 hours following surgery, on Day 12, and on Day 30 using a 5-point Likert scale (see Appendix 4). A wound
healing assessment will be performed on Day 12 (see Appendix 5). Predefined, treatment-emergent opioid-
related AEs will be assessed at 72 hours after surgery (see Appendix 6). Adverse events will be recorded through
the Day 30 follow-up contact. If a cardiac or neurological event occurs during the study that the Investigator
believes may be associated with high levels of systemic bupivacaine, an unscheduled PK blood sample should be
collected at the time that the event is noted.
Pharmacokinetic Assessments: Blood samples for PK analysis will be obtained from subjects at specific sites at
baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after the end of surgery. Placebo
samples will be collected to maintain the treatment double-blind but will not be analyzed. (Note: At time points
when the PK and NRS pain intensity assessments coincide, the NRS pain intensity assessments will be conducted
before the blood draw.)

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Name of Sponsor/Company:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
(858) 625-2424
Individual Study Table Referring
to Part of the Dossier
Volume:
Page:
(For National Authority Use
Only)
Name of Finished Product:
Liposome Bupivacaine
Name of Active Ingredient:
Bupivacaine 1.3%, 13.3 mg/mL
Number of Subjects (Planned):
A total of 180 subjects are planned for enrollment into this study in a 1:1 randomization, resulting in
approximately 90 subjects in the 266 mg liposome bupivacaine group and 90 subjects in the placebo group.
Eligibility Criteria:
Inclusion Criteria
Subjects eligible for study entry must meet all of the following criteria:
1.
Male or female, ≥18 years of age.
2.
Scheduled to undergo a thoracotomy of at least 3 inches (7.6 cm) of intercostal incisional length or
requiring insertion of an inter-rib spreader/retractor for a primary thoracic non-infectious indication
under general anesthesia.
3.
American Society of Anesthesiologists (ASA) Physical Status 1 - 3.
4.
Able to provide informed consent, adhere to the study visit schedule, and complete all study
assessments.
5.
Able to demonstrate sensory function by exhibiting sensitivity to cold anywhere within the dermatomes
supplied by any of the nerves to which study drug will be administered.
Exclusion Criteria:
A subject will not be eligible for the study if he/she meets any of the following criteria:
1.
Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after
study drug administration. Female subjects must be surgically sterile, at least 2 years menopausal, or
using an acceptable method of birth control. If of childbearing potential, must have a documented
negative pregnancy test within 24 hours before surgery.
2.
Any planned pleurodesis as part of the surgical procedure.
3.
Use of any of the following medications within the times specified before surgery: long-acting opioid
medication, NSAID, or aspirin (except for low-dose aspirin used for cardioprotection) within 3 days and
any opioid medication within 24 hours.
4.
Use of selective serotonin reuptake inhibitors (SSRIs), gabapentin, pregabalin (Lyrica®), or duloxetine
(Cymbalta®) within 3 days of surgery.
5.
Concurrent painful physical condition or concurrent surgery that may require analgesic treatment
(such as an NSAID or opioid) in the postsurgical period for pain that is not strictly related to the surgery,
and which may confound the postsurgical assessments (e.g., cancer pain, chronic neuropathic pain,
concurrent abdominal surgery).
6.
Current use of systemic glucocorticosteroids within 1 month of enrollment.
7.
Body weight < 50 kilograms (110 pounds) or a body mass index ≥35 kg/m2.
8.
Contraindication to any of the pain-control agents planned for surgical or postsurgical use (i.e., fentanyl,
morphine, hydromorphone, oxycodone, or bupivacaine).
9.
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.
10. Previous participation in a liposome bupivacaine study.

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Clinical Study Protocol Amendment 1
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Name of Sponsor/Company:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
(858) 625-2424
Individual Study Table Referring
to Part of the Dossier
Volume:
Page:
(For National Authority Use
Only)
Name of Finished Product:
Liposome Bupivacaine
Name of Active Ingredient:
Bupivacaine 1.3%, 13.3 mg/mL
Exclusion Criteria (Cont.)
11. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s),
or alcohol within the past 2 years.
12. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the Investigator,
could interfere with study assessments or compliance.
13. Current or historical evidence of any clinically significant disease or condition, especially cardiovascular
or neurological conditions that, in the opinion of the Investigator, may increase the risk of surgery or
complicate the subject’s postsurgical course or interfere with the determination of pain intensity related
solely to the surgery.
14. Significant medical conditions (including widely disseminated metastatic disease) or laboratory results
that, in the opinion of the Investigator, indicate an increased vulnerability to study drugs and procedures.
15. Subjects who are planned to receive Entereg® (alvimopan).
16. Subjects who will receive prophylactic antiemetics or planned postsurgical antiemetics given without
regard to the subject's emesis needs.
Test Product, Dose, Mode of Administration, and Lot Number:
Name: Liposome bupivacaine
Active Ingredient: Bupivacaine 1.3%, 13.3 mg/mL.
Dosage: Single total administration of 266 mg (approximately 88 mg to each of three nerve segments) of 6.6 mL
volume each for a total of 20 mL.
Lot Number: To be determined.
Mode of Administration: Nerve block (intercostal).
Reference Product, Dose, Mode of Administration, and Lot Number:
Name: Placebo (normal saline for injection).
Dosage: Single total administration of 266 mg (approximately 88 mg to each of three nerve segments) of 6.6 mL
volume each for a total of 20 mL.
Lot Number: To be determined.
Mode of Administration: Nerve block (intercostal).
Duration of Subject Participation in Study: Each subject’s participation in this study may be up to 64 days
(up to 30 days for screening and 34 days for post-dosing follow-up).
Efficacy Assessments:
The following efficacy measurements will be conducted at the times specified after the end of surgery:

Pain intensity scores using the NRS-R at baseline and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours
following surgery, at first request for rescue pain medication, and on Day 12.

Pain intensity scores using the NRS-A (where the prescribed activity is cough) at baseline and 24, 48,
and 72 hours following surgery, and on Day 12.

Time of first opioid rescue.

Opioid use.

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CONFIDENTIAL
23 September 2012
Name of Sponsor/Company:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
(858) 625-2424
Individual Study Table Referring
to Part of the Dossier
Volume:
Page:
(For National Authority Use
Only)
Name of Finished Product:
Liposome Bupivacaine
Name of Active Ingredient:
Bupivacaine 1.3%, 13.3 mg/mL
Efficacy Assessments (Cont.)

Sensory function assessment (i.e., cold test) at baseline, when the subject wakes up after surgery, and at
2, 4, 12, 24, 36, 48, 60, and 72 hours after surgery, or until the subject’s sensitivity to cold has returned
in two consecutive evaluations.

Overall benefit of analgesia score questionnaire at 24, 48, and 72 hours.

Subject’s satisfaction with postsurgical pain control at 72 hours, Day 12, and Day 30 using a 5-point
Likert scale.

Predefined treatment-emergent opioid-related AEs at 72 hours following surgery.
Efficacy Endpoints:
The efficacy endpoints listed below will be assessed based on the efficacy measurements conducted at the
specified time points after the end of surgery.
Primary Endpoint
The primary efficacy endpoint is the area under the curve (AUC) of the NRS-R pain intensity scores through
72 hours.
Secondary Endpoints
The following secondary endpoints will be analyzed using a hierarchical testing procedure:

Total postsurgical opioid consumption (in mg) through 72 hours.

Time to first opioid rescue.
Tertiary Endpoints

Total postsurgical opioid consumption (in mg) through 24, 36, 48, and 60 hours.

Overall benefit of analgesia score questionnaire at 24, 48, and 72 hours.

Subject satisfaction with postsurgical pain control at 72 hours, Day 12, and Day 30.

The NRS-R and NRS-A pain intensity scores at each assessed time point.

The AUC of the NRS-R pain intensity scores through 24, 36, 48, and 60 hours.

The AUC of the NRS-R pain intensity scores from 24-48 and 48-72 hours.

Proportion of subjects who are pain free (defined as an NRS pain intensity score of 0 or 1) at each
assessed time point.

Proportion of subjects who receive the following rescue medication(s):
o
Subjects who receive no rescue medication.
o
Subjects who only receive IV fentanyl as a rescue medication.
o
Subjects who receive IV fentanyl and a second opioid medication.

Incidence of predefined treatment-emergent opioid-related AEs (diffuse pruritus, overt respiratory
depression, urinary retention as measured by need for postsurgical bladder catheterization, constipation,
sedation, confusion, delirium, vomiting, or need for antiemetic medication) at 72 hours.

Proportion of subjects at each time point with sensitivity to cold anywhere within the dermatomes
supplied by any of the nerves to which study drug was administered.

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Name of Sponsor/Company:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
(858) 625-2424
Individual Study Table Referring
to Part of the Dossier
Volume:
Page:
(For National Authority Use
Only)
Name of Finished Product:
Liposome Bupivacaine
Name of Active Ingredient:
Bupivacaine 1.3%, 13.3 mg/mL
Pharmacokinetic Endpoints:
Pharmacokinetic parameters will be estimated from the plasma bupivacaine measurements using non-
compartmental analysis, based on the sampling schedule described above (at baseline, 15 minutes, 30 minutes,
and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after the end of surgery). The following parameters will be
determined:

Peak plasma concentration (Cmax).

Time to peak plasma concentration (Tmax).

Area under the plasma concentration versus time curve from time 0 to the last collection time after drug
administration (AUC0-last).

Area under the plasma concentration versus time curve from time 0 extrapolated to infinity after drug
administration (AUC0-∞).

The apparent terminal elimination rate constant (λz).

The apparent terminal elimination half-life (t1/2 el).
Safety Assessments:
The following safety assessments will be conducted:

Adverse events from the time of randomization through the Day 30 follow-up contact.

Vital signs (resting heart rate and blood pressure) at screening, baseline, and 1, 12, 24, 48, and 72 hours
after surgery.

Neurological assessment at baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48,
60, and 72 hours after surgery.

Cardiac assessment (i.e., ECG recordings) started at baseline (approximately 1 hour prior to surgery) and
continued for a total of 72 hours. Electrocardiogram changes will be examined using the ECG data
closest to the Tmax.

Physician's satisfaction with wound healing on Day 12.
Safety Endpoints:
The following safety endpoints will be assessed based on the safety measurements conducted at the specified time
points:

Incidence of treatment-emergent adverse events (TEAEs) and SAEs through the Day 30 follow-up
contact.

Change from baseline in vital signs (resting heart rate and blood pressure) at each assessed time point.

Summary of neurological assessments (proportion of subjects who are oriented, and proportion of
subjects who have any of the neurologic events).

Change from baseline in ECG data closest to the Tmax.

Rating of physician's satisfaction with wound healing on Day 12.

Pacira Pharmaceuticals, Inc.
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CONFIDENTIAL
23 September 2012
Name of Sponsor/Company:
Pacira Pharmaceuticals, Inc.
10450 Science Center Drive
San Diego, CA 92121
(858) 625-2424
Individual Study Table Referring
to Part of the Dossier
Volume:
Page:
(For National Authority Use
Only)
Name of Finished Product:
Liposome Bupivacaine
Name of Active Ingredient:
Bupivacaine 1.3%, 13.3 mg/mL
Statistical Methods:
A comprehensive statistical analysis plan will be developed for this study.
Descriptive summaries will be provided by treatment group. Liposome bupivacaine will be compared with
placebo using analysis of covariance (ANCOVA) with treatment as the main effect and the baseline NRS-R pain
intensity score as a covariate for AUC of the NRS-R pain intensity scores through 72 hours, using analysis of
variance after a natural logarithm transformation for total postsurgical opioid consumption, and using a log-rank
test for time to first opioid rescue. For analyzing the two secondary endpoints, a hierarchical testing procedure
will be used. First the total postsurgical opioid consumption will be tested. If the test is significant at the
0.05 level then, and only then, the time to first opioid rescue will be tested. The result will be declared
statistically significant at the 0.05 significance level.
Safety data will be summarized by treatment group.

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23 September 2012
Table 1.
Time and Events Schedule of Study Procedures
Screen
Visit
Day -1 to
Day 1
Day 1 15min 30min
1h
2h
4h
8h
12h 18h 24h
30h
36h 42h
48h
60h 72h
Day
12
Day
3010
Time Window
Within
30 days
±5 min ±5 min
± 15
min
± 30
min
± 30
min
± 30
min
± 30
min ± 1h ± 1h ± 2h ± 2h ±2h
±2h
±2h ±4h
±4
days
±4
days
Obtain signed informed consent form
X
Assess/confirm eligibility
X
X
Medical/surgical history
X
X
Demographics and baseline characteristics
X
Urine pregnancy test (for women of childbearing
potential)1
X
Physical examination including height and weight
X
Vital signs2
X
X
X
X
X
X
X
Perform neurological assessment3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Perform cardiac assessment (ECG recordings)4
X
Perform sensory function assessment (cold test)5
X
X
X
X
X
X
X
X
X
Randomize subject and prepare study drug
X
Administer study drug; record start and stop time
X
Record start and stop time of surgery
X
Record location of chest tube
X
Record intraoperative opioids administered and doses
X
For US sites, install unloaded PCA pump (prior to
the completion of the surgery)
X
Conduct NRS-R pain intensity assessment6
X
X
X
X
X
X
X
X
X
X
X
X
Conduct NRS-A pain intensity assessment
X
X
X
X
X
Record times and amounts of rescue medication
administered
Specific sites only: Collect blood sample for PK
analysis7
X
X
X
X
X
X
X
X
X
X
X
X
X
Record time of chest tube removal
Record time subject is moved into and out of the ICU
Complete OBAS questionnaire
X
X
X
Subject satisfaction with pain control (Likert scale)
X
X
X
Question subject re: predefined treatment-emergent
ORAEs
X
Physician satisfaction with wound healing
X
Record concomitant medications8
Record AEs (starting at randomization) 9

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AE = adverse event; ECG = electrocardiogram; h = hour; ICU = Intensive Care Unit; NRS-A = numeric rating scale with activity; NRS-R = numeric rating scale at rest; OBAS =
overall benefit of analgesia score; ORAEs = opioid-related AEs; PCA = patient-controlled analgesia; PK = pharmacokinetic.
1
Before study drug administration.
2
Measure heart rate and blood pressure after subject has rested for at least 5 minutes in the supine position.
3
If the neurological assessment reveals a neurological event that the Investigator believes may be associated with high levels of systemic bupivacaine, an unscheduled PK blood
sample should be collected at the time that the event is noted.
4
Electrocardiogram testing will be started at baseline (approximately 1 hour prior to surgery) and continue for a total of 72 hours.
5
Sensory function will be assessed at baseline, when the subject wakes up after surgery, and at 2, 4, 12, 24, 36, 48, 60, and 72 hours after the end of surgery, or until the subject’s
sensitivity to cold has returned in two consecutive evaluations.
6
Also record NRS-R at first request for rescue pain medication.
7
Collect blood samples for PK analysis at baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after the end of surgery.
8
Instruct subject to discontinue prohibited medications. Record date/time of all medications starting 3 days prior to surgery through 72 hours after surgery.
Record medications administered for treatment of an AE through the Day 30 follow-up contact.
9
If a cardiac or neurological event occurs during the study that the Investigator believes may be associated with high levels of systemic bupivacaine, an unscheduled PK blood
sample should be collected at the time that the event is noted.
10
Day 30 assessments will be conducted via a telephone call.

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3.
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
SUMMARY OF CHANGES...........................................................................................................2
2.
SYNOPSIS ...................................................................................................................6
3.
TABLE OF CONTENTS ...........................................................................................15
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19
4.1.
List of Abbreviations ..................................................................................................19
4.2.
Definition of Terms ....................................................................................................20
5.
ETHICS ......................................................................................................................21
5.1.
Institutional Review Board/Independent Ethics Committee ......................................21
5.2.
Ethical Conduct of the Study......................................................................................21
5.3.
Subject Information and Consent ...............................................................................21
6.
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE.................22
7.
INTRODUCTION......................................................................................................23
7.1.
Indication ....................................................................................................................23
7.2.
EXPAREL (bupivacaine liposome injectable suspension).........................................23
7.3.
Summary of Human Experience with Liposome Bupivacaine...................................24
8.
OBJECTIVES.............................................................................................................25
8.1.
Primary Objective.......................................................................................................25
8.2.
Secondary Objectives .................................................................................................25
9.
OVERALL STUDY DESIGN AND PLAN...............................................................26
9.1.
Study Design...............................................................................................................26
9.1.1.
Duration of the Study and Subject Participation ........................................................27
9.1.2.
Study Stopping Rules .................................................................................................27
9.2.
Discussion of Study Design........................................................................................28
10.
STUDY POPULATION.............................................................................................29
10.1.
Inclusion Criteria ........................................................................................................29
10.2.
Exclusion Criteria.......................................................................................................29
10.3.
Removal of Subjects from Therapy or Assessment....................................................30
10.3.1.
Withdrawal Secondary to Adverse Events .................................................................30
10.3.2.
Voluntary or Study Investigator Withdrawal .............................................................30

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11.
TREATMENTS..........................................................................................................31
11.1.
Treatment to be Administered ....................................................................................31
11.1.1.
Administration Technique ..........................................................................................31
11.1.2.
Study Drug Administration Considerations................................................................31
11.2.
Identity of Investigational Product(s).........................................................................32
11.2.1.
Description of Liposome Bupivacaine .......................................................................32
11.2.2.
Description of Reference Product...............................................................................32
11.3.
Method of Assigning Subjects to Treatment ..............................................................32
11.3.1.
Randomization Scheme ..............................................................................................32
11.3.2.
Randomization Procedures .........................................................................................32
11.3.3.
Replacement of Subjects.............................................................................................32
11.4.
Selection of Doses in the Study..................................................................................32
11.5.
Blinding ......................................................................................................................33
11.5.1.
Blinding Procedures....................................................................................................33
11.5.2.
Unblinding Procedures ...............................................................................................34
11.6.
Prior and Concomitant Therapy and Medications......................................................34
11.6.1.
Prior and Concomitant Medications and Therapy......................................................34
11.6.2.
Permitted and Restricted Therapy or Medications During Surgery ...........................34
11.6.3.
Permitted Therapy or Medications After Surgery through 72 Hours After
Surgery........................................................................................................................35
11.7.
Treatment Compliance................................................................................................35
11.8.
Accountability of Study Drug.....................................................................................35
12.
STUDY ENDPOINTS AND MEASUREMENTS ....................................................36
12.1.
Efficacy Assessments .................................................................................................36
12.2.
Efficacy Endpoints......................................................................................................36
12.3.
Pharmacokinetic Measurements .................................................................................37
12.4.
Pharmacokinetic Endpoints ........................................................................................37
12.5.
Safety Assessments.....................................................................................................38
12.6.
Safety Endpoints.........................................................................................................38
12.7.
Appropriateness of Measures .....................................................................................38
13.
STUDY PROCEDURES............................................................................................39
13.1.
Instructions for Conducting Procedures and Measures ..............................................39
13.1.1.
Numeric Rating Scale Pain Intensity Assessments ....................................................39

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13.1.2.
Overall Benefit of Analgesia Score Questionnaire.....................................................39
13.1.3.
Neurological Assessment............................................................................................39
13.1.4.
Cardiac Assessment (Electrocardiogram Recordings) ...............................................40
13.1.5.
Sensory Function Assessment (Cold Test).................................................................41
13.1.6.
Vital Signs ..................................................................................................................41
13.1.7.
Subject's Satisfaction with Postsurgical Pain Control ................................................41
13.1.8.
Physician's Satisfaction with Wound Healing............................................................41
13.2.
Screening Procedures..................................................................................................41
13.3.
Baseline Procedures (Day -1 to Day 1) ......................................................................41
13.4.
Intraoperative Procedures ...........................................................................................42
13.5.
Procedures After Surgery Through 72 Hours.............................................................42
13.6.
Postsurgical Study Visit Procedures (Day 12)............................................................44
13.7.
Day 30 Follow-Up Contact.........................................................................................44
14.
ADVERSE EVENT REPORTING ............................................................................45
14.1.
Adverse Events ...........................................................................................................45
14.1.1.
Definitions ..................................................................................................................45
14.1.2.
Recording Adverse Events .........................................................................................46
14.1.3.
Severity of Adverse Events ........................................................................................46
14.1.4.
Relationship of Adverse Events to Study Drug..........................................................46
14.1.5.
Outcome of Adverse Events.......................................................................................47
14.1.6.
Action Taken with Subject due to an Adverse Event.................................................47
14.2.
Serious Adverse Events ..............................................................................................48
14.2.1.
Definition of a Serious Adverse Event .......................................................................48
14.2.2.
Reporting Serious Adverse Events .............................................................................48
15.
STATISTICAL METHODS.......................................................................................50
15.1.
Study Hypothesis........................................................................................................50
15.2.
Study Endpoints..........................................................................................................50
15.3.
Determination of Sample Size....................................................................................50
15.4.
Analysis Populations ..................................................................................................50
15.5.
Handling Subject Dropouts and Discontinuations......................................................51
15.6.
Statistical Analyses.....................................................................................................51
15.6.1.
Baseline Characteristics..............................................................................................51
15.6.2.
Study Compliance.......................................................................................................51

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15.6.3.
Efficacy Analyses .......................................................................................................51
15.6.4.
Pharmacokinetic Analyses..........................................................................................53
15.6.5.
Safety Analyses ..........................................................................................................53
15.7.
Significance Testing ...................................................................................................54
15.8.
Interim Analyses.........................................................................................................54
16.
REFERENCES ...........................................................................................................55
17.
INVESTIGATOR AGREEMENT .............................................................................56
18.
APPENDICES ............................................................................................................57
Appendix 1:
Subject’s Reported Pain Intensity (Numeric Rating Scale) ...................................58
Appendix 2:
Neurological Assessment .......................................................................................59
Appendix 3:
Overall Benefit of Analgesia Score Questionnaire ................................................60
Appendix 4:
Subject Satisfaction with Postsurgical Pain Control (Likert Scale).......................61
Appendix 5:
Physician's Satisfaction with Wound Healing........................................................62
Appendix 6:
Treatment-Emergent Opioid-Related Adverse Events Questionnaire ...................63
Appendix 7:
Dermatome Map.....................................................................................................64
LIST OF TABLES
Table 1.
Time and Events Schedule of Study Procedures ........................................................13

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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
4.1.
List of Abbreviations
AE
Adverse event
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
ASA
American Society of Anesthesiologists
AUC
Area under the curve
AUC0-tlast
The area under the plasma concentration-time curve from the time
of administration to the time of the last quantifiable concentration
calculated using the lin/log trapezoidal rule
AUC0-∞
The area under the plasma concentration-time curve from the time
of administration extrapolated to infinity
CFR
Code of Federal Regulations
CI
Confidence interval
Cmax
The maximum observed plasma concentration obtained directly
from the experimental data without interpolation
CRF
Case Report Form
ECG
Electrocardiogram
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HR
Heart rate
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IM
Intramuscular
IRB
Institutional Review Board
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
NRS
Numeric rating scale
NRS-A
Numeric rating scale with activity
NRS-R
Numeric rating scale at rest
NSAIDs
Non-steroidal anti-inflammatory drugs
OBAS
Overall benefit of analgesia score

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PCA
Patient-controlled analgesia
PK
Pharmacokinetic
PO
Oral
QTcB
The heart rate-corrected QT interval using Bazett's formula
QTcF
The heart rate-corrected QT interval using Fridericia's formula
PTAE
Pre-treatment adverse event
SAE
Serious adverse event
SAP
Statistical analysis plan
λz
The apparent terminal elimination rate constant
t1/2el
The apparent terminal elimination half-life
TEAE
Treatment-emergent adverse event
Tmax
The time to attain Cmax
US
United States
wWOCF
windowed Worst-Observation-Carried-Forward
4.2.
Definition of Terms
Pharmacokinetic (PK) terms are defined in Section 12.4.

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5.
ETHICS
5.1.
Institutional Review Board/Independent Ethics Committee
Prior to enrolling subjects into this study, the study site will obtain the approval of an
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that complies with the
International Conference on 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/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/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/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]).

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6.
INVESTIGATORS AND STUDY ADMINISTRATION
STRUCTURE
Information regarding the investigators, sites, laboratories, and other service providers is
available upon request to the IRB/ECs and regulatory agencies.

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7.
INTRODUCTION
7.1.
Indication
Liposome bupivacaine 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. It is indicated for use as an analgesic injected into the surgical site for postsurgical
pain relief. This study will explore the safety, efficacy, and PK profile of liposome bupivacaine
when administered via a new route – intercostal nerve block.
Intercostal nerve blocks provide excellent analgesia for chest and upper abdominal surgery
including thoracotomy. As with many other regional techniques, the advantages of ICNBs
include superior analgesia, improved pulmonary mechanics, and opioid-sparing effects such as
reduced central nervous system depression and avoidance of urinary retention. However,
supplemental systemic analgesia is always necessary (Ho AMH 2012).
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.
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 reported as less than 8 hours. EXPAREL® (Pacira
Pharmaceuticals, Inc., San Diego, California) 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. A small amount of extra-liposomal bupivacaine (i.e., not bound within the DepoFoam
particles) enables EXPAREL to have a similar onset of action to standard bupivacaine.
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 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 products
DepoCyt® (1999) and DepoDur® (2004). The form of DepoFoam used in each of the
three products – DepoCyt, DepoDur, and EXPAREL – has a slightly different mixture of

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lipid components. However, unlike the other two products, EXPAREL employs a novel
lipid excipient (dierucoylphosphatidylcholine [DEPC]) in its formulation.
7.3.
Summary of Human Experience with Liposome Bupivacaine
Pacira has completed 21 clinical studies and 1 observational follow-up study to investigate
liposome bupivacaine. Across these studies, over 1300 human subjects received liposome
bupivacaine at doses ranging from 9 mg to 665 mg administered by various routes: local
infiltration into the surgical wound, subcutaneous, perineural, and epidural. The product
generally has been well tolerated and, in active comparator studies, reported adverse events
(AEs) occurred at a similar rate as the corresponding bupivacaine HCl controls.
Two nerve block studies have been completed. SKY0402-002 was a Phase 1 dose escalation
study conducted to evaluate the safety, pharmacodynamics, and pharmacokinetics of liposome
bupivacaine. A total of 37 healthy subjects were administered liposome bupivacaine
perineurally for unilateral ankle block in healthy male volunteers (24 subjects received liposome
bupivacaine and 12 subjects received bupivacaine HCl). The incidence and types of adverse
events experienced were similar across treatment groups. All AEs were mild or moderate in
severity; those related to liposome bupivacaine were mild in severity. There were no serious
adverse events (SAEs), deaths, or discontinuations due to adverse events.
SKY0402-C-203 was a Phase 2 nerve block study in which three doses of liposome bupivacaine
(155, 199, and 310 mg) were compared to bupivacaine HCl (125 mg) in a bunionectomy. A total
of 38 patients received liposome bupivacaine. Liposome bupivacaine was well tolerated and
several doses demonstrated statistically significant separation from bupivacaine HCl using
multiple efficacy measures at multiple time points throughout the 72 hours; a PK curve also was
defined.
In doses up to 665 mg, no adverse safety signal attributed to either the central nervous system
or cardiovascular system was reported with liposome bupivacaine. Adverse events that are
occasionally reported with high doses of standard bupivacaine solution have not been
observed. In two rigorous QTc studies, liposome bupivacaine did not cause significant QTc
prolongation even at the highest dose evaluated.
The robust nature of the efficacy results in both pivotal studies (SKY0402-C-316 and SKY0402-
C-317) was demonstrated across subgroups of patients with various prognostic features and
across demographic subgroups.
Following the NDA submission of EXPAREL (bupivacaine liposome injectable suspension),
numerous clinical studies were initiated in which liposome bupivacaine was administered via
various routes of administration (including infiltration into the transversus abdominis plane
[TAP] and intraoperative wound infiltration or instillation); final results are not available at this
time.
Please refer to the Investigator’s Brochure for additional information regarding the completed
studies. Please see the EXPAREL Full US Prescribing Information for safety information
regarding EXPAREL (liposome bupivacaine) in the setting of wound infiltration.

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8.
OBJECTIVES
8.1.
Primary Objective
The primary objective is to evaluate the efficacy of intercostal nerve block using liposome
bupivacaine compared with placebo in subjects undergoing posterolateral thoracotomy.
8.2.
Secondary Objectives
The secondary objectives are to evaluate additional efficacy parameters, assess the PK profile of
liposome bupivacaine when administered as an intercostal nerve block, and further characterize
the safety profile of liposome bupivacaine.

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9.
OVERALL STUDY DESIGN AND PLAN
9.1.
Study Design
This is a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled
study conducted to investigate the efficacy and safety of liposome bupivacaine (total of 266 mg
in 20 mL) divided into three equal doses in three syringes of approximately 88 mg in 6.6 mL
volume per nerve and administered to each of three nerve segments (index nerve, nerve above,
and nerve below) compared with saline placebo nerve block.
After completing screening procedures, eligible subjects undergoing posterolateral thoracotomy
will be randomized 1:1 to receive either liposome bupivacaine or placebo. Study drug will be
administered after the posterolateral thoracotomy is completed (i.e., just prior to the surgical site
closure). Study drug administration will be performed in a blinded manner (see Section 11.5.1).
The use of opioids (other than fentanyl), acetaminophen/paracetamol, ketorolac, or other
non-steroidal anti-inflammatory drugs (NSAIDs), and local anesthetics other than the study drug
will not be permitted intraoperatively except for emergency use to treat an AE. At all US sites
only, subjects will have a patient-controlled analgesia (PCA) pump established prior to the
completion of the surgery. The PCA pump will not be loaded at this time. All subjects will be
required to remain in the study site for a minimum of 72 hours following surgery for postsurgical
assessments.
Postsurgical Rescue Medication
Rescue medication should only be provided upon subject request, as needed.
First Rescue Medication
The first rescue medication will be intravenous (IV) fentanyl 100 mcg, which will be
administered once via bolus only. At this time, the PCA pump should be loaded with opioid
(morphine or hydromorphone only) for subjects at the US sites only.
Second Rescue Medication
For the US sites only, the second rescue medication will be PCA-administered opioid (morphine
or hydromorphone). The PCA pump will be programmed to deliver either of the following
recommended doses: (1) on-demand morphine boluses of 1.5 mg with a lockout interval of
6 minutes and an initial maximum hourly dose of 15 mg, or (2) on-demand hydromorphone
boluses of 0.2 mg with a lockout interval of 10 minutes and an initial maximum hourly dose
of 1.2 mg. A continuous infusion (background or basal rate) of morphine is not permitted.
The recommended bolus doses may be adjusted according to local hospital practice; however,
adding a basal rate is prohibited.
For the European sites only, the second rescue medication will be intramuscular (IM)
administered opioid (morphine) up to 10 mg every 4 hours.
At all sites, once a subject is tolerating oral (PO) medication, PO immediate-release oxycodone
may be administered, as needed (but not more than 10 mg every 4 hours).
Subjects who do not achieve adequate pain relief with this regimen will be withdrawn from the
study and followed for safety only.

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Postsurgical Assessments
Subjects will be evaluated for pain using the numeric rating scale at rest (NRS-R) at baseline
and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours following surgery, at first request for rescue pain
medication, and on Day 12 (see Appendix 1). Subjects also will be evaluated for pain with
activity (defined as pain intensity with cough) using the NRS with activity [NRS-A] at baseline
and 24, 48, and 72 hours following surger y and on Da y 12 (see Appendix 1). (Note: At time
points when the NRS pain intensity assessments coincide, the NRS-R will be conducted before
the NRS-A.) Additionally, if chest tube removal or a PK blood draw coincides with pain
intensity assessment(s), the pain intensity assessment(s) must be conducted before the other
procedures.
Neurological assessments will be conducted at baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8,
12, 18, 24, 30, 36, 42, 48, 60, and 72 hours after surgery (see Appendix 2). The cardiac
assessment (i.e., ECG recordings) will be started at baseline (approximately 1 hour prior to
surgery) and continue for a total of 72 hours. The sensory function assessment (i.e., cold test)
will be conducted at baseline, when the subject wakes up after surgery, and at 2, 4, 12, 24, 36,
48, 60, and 72 hours after surgery, or until the subject’s sensitivity to cold has returned in two
consecutive evaluations (see Appendix 7).
The overall benefit of analgesia score (OBAS) questionnaire will be completed at 24, 48, and
72 hours following surgery (see Appendix 3). The subject's overall satisfaction with postsurgical
pain control will be assessed 72 hours following surgery, on Day 12, and on Day 30 using
a 5-point Likert scale (see Appendix 4). A wound healing assessment will be performed by the
physician on Day 12 (see Appendix 5). Predefined, treatment-emergent opioid-related AEs will
be assessed at 72 hours following surgery (see Appendix 6). Adverse events will be recorded
through the Day 30 follow-up contact. If a cardiac or neurological event occurs during the study
that the Investigator believes may be associated with high levels of systemic bupivacaine, an
unscheduled PK blood sample should be collected at the time that the event is noted.
Pharmacokinetic Assessments
Blood samples for PK analysis will be obtained from subjects at specific sites at baseline,
15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after the end of surgery.
Placebo samples will be collected to maintain the treatment double-blind but will not be
analyzed. (Note: At time points when the PK and NRS pain intensity assessments coincide,
the NRS pain intensity assessments will be conducted before the blood draw.)
Unscheduled blood samples also may be collected during the study if a cardiac or neurological
event occurs that the Investigator believes may be associated with high levels of systemic
bupivacaine.
9.1.1.
Duration of the Study and Subject Participation
No more than 30 days should pass between signing of the ICF and performance of the surgery.
Therefore, each subject may participate in the study for a maximum of 64 days.
9.1.2.
Study Stopping Rules
No formal stopping rules are planned for this study. If, however, Pacira, the Investigator, or
officials from regulatory authorities discover conditions during the study that indicate that the

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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).
9.2.
Discussion of Study Design
Liposome bupivacaine is approved for infiltration into a surgical wound. This Phase 3,
multicenter, randomized, double-blind, parallel-group study is a comparison of the efficacy and
safety of liposome bupivacaine to placebo when administered as an intercostal nerve block in
subjects undergoing posterolateral thoracotomy. The study is double blind, which is intended to
avoid potential bias resulting from subject or Investigator knowledge of the assigned treatment.
This study will explore the safety and efficacy of liposome bupivacaine when administered via a
new route – intercostal nerve block. Posterolateral thoracotomy model was selected as patients
experience moderate to severe postsurgical pain that typically lasts for 2-3 days.
All subjects may receive opioids, as needed, to control breakthrough postsurgical pain as defined
in Section 11.6.3.
Neurological and cardiac assessments will be conducted to rule out bupivacaine toxicity related
to high plasma exposure. Additionally, sensory assessments will be conducted in order to test
for restoration of nerve function.

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10.
STUDY POPULATION
10.1.
Inclusion Criteria
Subjects eligible for study entry must meet all of the following criteria:
1. Male or female, ≥18 years of age.
2. Scheduled to undergo a thoracotomy of at least 3 inches (7.6 cm) of intercostal incisional
length or requiring insertion of an inter-rib spreader/retractor for a primary thoracic non-
infectious indication under general anesthesia.
3. American Society of Anesthesiologists (ASA) Physical Status 1 - 3.
4. Able to provide informed consent, adhere to the study visit schedule, and complete all
study assessments.
5. Able to demonstrate sensory function by exhibiting sensitivity to cold anywhere within
the dermatomes supplied by any of the nerves to which study drug will be administered.
10.2.
Exclusion Criteria
A subject will not be eligible for the study if he/she meets any of the following criteria:
1. Currently pregnant, nursing, or planning to become pregnant during the study or within
1 month after study drug administration. Female subjects must be surgically sterile, at
least 2 years menopausal, or using an acceptable method of birth control. If of
childbearing potential, must have a documented negative pregnancy test within 24 hours
before surgery.
2. Any planned pleurodesis as part of the surgical procedure.
3. Use of any of the following medications within the times specified prior to surgery:
Long-acting opioid medication, NSAID, or aspirin (except for low-dose aspirin used for
cardioprotection) within 3 days and any opioid medication within 24 hours.
4. Use of selective serotonin reuptake inhibitors (SSRIs), gabapentin, pregabalin (Lyrica®),
or duloxetine (Cymbalta®) within 3 days of surgery.
5. Concurrent painful physical condition or concurrent surgery that may require analgesic
treatment (such as an NSAID or opioid) in the postsurgical period for pain that is not
strictly related to the surgery, and which may confound the postsurgical assessments
(e.g., cancer pain, chronic neuropathic pain, concurrent abdominal surgery).
6. Current use of systemic glucocorticosteroids within 1 month of enrollment.
7. Body weight < 50 kilograms (110 pounds) or a body mass index ≥35 kg/m2.
8. Contraindication to any of the pain-control agents planned for surgical or postsurgical use
(i.e., fentanyl, morphine, hydromorphone, oxycodone, or bupivacaine).
9. 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.
10. Previous participation in a liposome bupivacaine study.
11. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription
medicine(s), or alcohol within the past 2 years.
12. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of
the Investigator, could interfere with study assessments or compliance.
13. Current or historical evidence of any clinically significant disease or condition, especially
cardiovascular or neurological conditions that, in the opinion of the Investigator, may
increase the risk of surgery or complicate the subject’s postsurgical course or interfere
with the determination of pain intensity related solely to the surgery.
14. Significant medical conditions (including widely disseminated metastatic disease) or
laboratory results that, in the opinion of the Investigator, indicate an increased
vulnerability to study drugs and procedures.
15. Subjects who are planned to receive Entereg® (alvimopan).
16. Subjects who will receive prophylactic antiemetics or planned postsurgical antiemetics
given without regard to the subject's emesis needs.
10.3.
Removal of Subjects from Therapy or Assessment
Every reasonable effort should be made to maintain subject compliance and participation in the
study. Reasons for discontinuation of any subject from the study will be recorded.
Subjects who withdraw from the study after receiving study drug should be followed for safety
through Day 30. If a subject who withdraws from the study has an ongoing AE, every effort
must be made to follow 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 him/her incapable of continuing with the remaining
study assessments, then he/she will be discontinued from further participation in the study. A
final evaluation should be performed so that the subject’s study participation can be terminated
in a safe and orderly manner.
10.3.2.
Voluntary or Study Investigator Withdrawal
Subjects are free to discontinue from the study at any time, without prejudice to future treatment.
Nevertheless, subjects will be encouraged to complete at least the study safety assessments. In
addition, a subject may be discontinued from the study if he/she refuses to comply with study
procedures. 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 liposome bupivacaine, he/she should be followed for safety through Day 30. A final
evaluation should be performed so that the subject can be terminated in a safe and orderly
manner.

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11.
TREATMENTS
11.1.
Treatment to be Administered
Liposome bupivacaine (total of 266 mg in 20 mL) or placebo (preservative-free normal saline)
will be divided into three equal doses in three syringes of approximately 88 mg in 6.6 mL
volume per nerve and administered to each of three nerve segments (index nerve, nerve above,
and nerve below) according to the randomization schedule. Study drug administration will be
performed in a blinded manner utilizing syringes masked by finger cots.
Rescue Medication
Rescue medication should only be provided upon subject request.
First Rescue Medication
The first rescue medication will consist of IV fentanyl 100 mcg, which will be administered once
via bolus only. At this time, the PCA pump should be loaded with opioid (morphine or
hydromorphone only) for subjects at the US sites only.
Second Rescue Medication
For the US sites only, the second rescue medication will be PCA-administered opioid (morphine
or hydromorphone). The PCA pump will be programmed to deliver either of the following
recommended doses: (1) on-demand morphine boluses of 1.5 mg with a lockout interval of
6 minutes and an initial maximum hourly dose of 15 mg, or (2) on-demand hydromorphone
boluses of 0.2 mg with a lockout interval of 10 minutes and an initial maximum hourly dose
of 1.2 mg. A continuous infusion (background or basal rate) of morphine is not permitted.
The recommended bolus doses may be adjusted according to local hospital practices; however,
adding a basal rate is prohibited.
For the European sites only, the second rescue medication will be IM-administered opioid
(morphine) up to10 mg every 4 hours.
For all sites, once the subject is tolerating PO medication, PO immediate-release oxycodone may
be administered, as needed (but not more than 10 mg every 4 hours).
Subjects who do not achieve adequate pain relief with this regimen will be withdrawn from the
study and followed for safety only.
11.1.1.
Administration Technique
Immediately prior to closure, study drug (liposome bupivacaine or placebo) will be administered
under direct visualization by the surgeon into the index nerve as well as the nerve immediately
above and immediately below using the surgeon's normal and usual technique. The volume to be
administered is approximately 6.6 mL to each nerve, for a total of 20 mL.
11.1.2.
Study Drug Administration Considerations
Since there is a potential risk of severe adverse effects associated with the administration of
bupivacaine, the study site must be equipped to manage subjects with any evidence of cardiac
toxicity.

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Administration of additional local anesthetics including bupivacaine or lidocaine is prohibited.
Liposome bupivacaine may not be administered to a subject if it has been held in a syringe for
more than 4 hours after preparation. In order to prevent the study drug from settling, gently
inverting and re-inverting the syringes several times prior to administration is recommended.
11.2.
Identity of Investigational Product(s)
11.2.1.
Description of Liposome Bupivacaine
Liposome bupivacaine is formulated as a sterile, non-pyrogenic, white to off-white, preservative-
free, homogeneous suspension of bupivacaine encapsulated into multivesicular lipid-based
particles (the DepoFoam drug delivery system). Bupivacaine is present at a nominal
concentration of 13.3 mg/mL. Liposome bupivacaine will be provided in 20 mL, 1.3%
(13.3 mg/mL) single-use, clear glass vials.
11.2.2.
Description of Reference Product
Placebo will consist of preservative-free normal saline for injection and will be supplied by the
study sites. Subjects in the placebo group will receive 20 mL of placebo.
11.3.
Method of Assigning Subjects to Treatment
11.3.1.
Randomization Scheme
Subjects will be centrally randomized to receive 266 mg liposome bupivacaine or placebo
(normal saline for injection) in a 1:1 ratio. The randomization code will be generated by a
centralized randomization system, which will also be used to communicate subject
randomizations to study sites. All randomized subjects will have both a unique subject identifier
and a unique random code identifier. No subject or random code identifiers are to be reused
once assigned. The randomization will be stratified by region (US and Europe).
11.3.2.
Randomization Procedures
Once a subject is identified as being qualified for the study per the eligibility criteria (see Section
10.1 and Section 10.2) and is at the study site for surgery, the research pharmacist or designee
will contact the centralized randomization service to obtain a randomization assignment (4-digit
random code identifier). The subject will be considered randomized into the study once the
assignment is received.
11.3.3.
Replacement of Subjects
Subjects who are randomized but are withdrawn from the study before receiving study drug may
be replaced. Once 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.
11.4.
Selection of Doses in the Study
During the clinical development of liposome bupivacaine, single doses ranging from 9 mg to
665 mg were safely administered via various routes. Pharmacokinetic studies have shown that

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because liposome bupivacaine releases bupivacaine gradually as the lipid structure breaks down,
administration of liposome bupivacaine 266 mg results in a maximum plasma concentration
equivalent to that seen with standard bupivacaine 100 mg. Based on this experience, a similar
total dose was deemed appropriate for this study.
11.5.
Blinding
11.5.1.
Blinding Procedures
Liposome bupivacaine and placebo are visually distinguishable; therefore, to maintain the
double-blind study design, only unblinded study personnel who are NOT involved with
protocol-specific, postsurgical assessments may prepare the study drug. Staff members
conducting study-specific, postsurgical assessments and the subjects will remain blinded to the
assigned treatment throughout the study. 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.
Unblinded randomization assignments will be provided via a randomization system. At each
site, only the individual(s) who are identified in the randomization system to receive unblinded
randomization assignments will be responsible for preparing study drug.
Site surveys suggest that study sites will vary in their standard (and feasible) procedures for
preparing sterile study drug in a blinded fashion. Therefore, each site will be responsible for
providing their written blinding procedures for study drug preparation and transportation to the
operating room. This documentation will be made available to Pacira for review before the site
enrolls a subject into the study. Assignment of blinded and unblinded responsibilities regarding
the preparation of study drug should take into account that liposome bupivacaine may not be
held in a syringe for more than 4 hours after preparation for administration.
Once the study drug is prepared in syringes as a sterile preparation, it will be placed under a
sterile drape on a sterile tray for use when needed in the operating room. The individuals
preparing study drug will not be allowed to perform any of the postsurgical assessments or reveal
the assigned study treatment to any other members of the study team at any time. Syringes
containing study drug and covered by finger cots 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 in the operating room charts using the minimal
amount of information necessary to avoid unblinding staff who will be participating in blinded
procedures. No crossover will be permitted between the blinded and unblinded study site
personnel during the study period. The assignment of site monitors will also be segregated.
Blinded monitors will review case report forms (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 operating room records to not record information in an unblinded
fashion. Pharmacy or any other clinic records providing unblinded information (e.g.,
randomization, study drug preparation, study drug accountability, study drug administration) will
be reviewed by unblinded monitors who will notify Pacira of treatment noncompliance.

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11.5.2.
Unblinding Procedures
Subject treatment assignments should not be unblinded during the study by blinded study
personnel. The Investigator will have the ability to unblind a subject if he or she feels that
subject safety warrants such unblinding. However, the Investigator should discuss the safety
issues with the Medical Monitor before attempting such unblinding, if possible. Any unblinding
will be documented through immediate notification of the Pacira study team and the Investigator.
Any accidental unblinding events (i.e., through mishaps in the operating room or
miscommunication among study staff) must be reported to Pacira immediately.
Only designated staff at Pacira will have the option to unblind treatment assignment through the
randomization system, which will be designed to document such a transaction and notify the lead
member of each functional group 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.
11.6.
Prior and Concomitant Therapy and Medications
11.6.1.
Prior and Concomitant Medications and Therapy
Prior medications
Long-acting opioid medications, NSAIDs, or aspirin (except for low-dose aspirin used for
cardioprotection ) are not permitted within 3 days of study drug administration. No opioid
medications are permitted within 24 hours of study drug administration.
Concomitant medications
All medications taken within 3 days of study drug administration and up to 72 hours after the end
of surgery will be recorded on the CRF. Any medications administered in association with AEs
occurring during the study will be recorded through the Day 30 follow-up contact.
11.6.2.
Permitted and Restricted Therapy or Medications During Surgery
Permitted

Short and ultra-short acting opioids (e.g., fentanyl) will be allowed during surgery.
Restricted

No agents are to be admixed with liposome bupivacaine (e.g., epinephrine,
dexamethasone, or clonidine).

The use of opioids other than fentanyl (e.g., morphine, hydromorphone HCl),
acetaminophen/paracetamol, ketorolac or other NSAIDs, and local anesthetics other than
the study drug will not be permitted intraoperatively except for emergency use to treat
an AE.

Lidocaine and other local anesthetics will not be permitted to be locally administered
during the surgery because they are known to interact with liposome bupivacaine
resulting in the displacement of bupivacaine and elevated plasma levels.

Entereg (alvimopan) use is prohibited.

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11.6.3.
Permitted Therapy or Medications After Surgery through 72 Hours After
Surgery
Permitted

Rescue medication use is permitted as described in Section 11.1.
Restricted

No other analgesics are permitted during the first 72 hours following study drug
administration.

Local anesthetics.

Entereg (alvimopan) use is prohibited.

Prophylactic antiemetics or planned postsurgical antiemetics given without regard to the
subject's emesis needs.
For study purposes, it is important to standardize pain management modalities during the first
72 hours following study drug administration. Therefore, the study staff must adhere closely to
the treatment options and requirements noted in the protocol. After 72 hours, the analgesic
regimen may be adjusted for each subject individually, as deemed appropriate by the physician
responsible for the subject’s postsurgical care.
All concomitant medication will be recorded through 72 hours after the end of surgery.
11.7.
Treatment Compliance
Not applicable, since study drug (liposome bupivacaine or placebo) will be administered
intraoperatively.
11.8.
Accountability of Study Drug
Any shipment of liposome bupivacaine for the study will contain a study drug transmittal and
receipt form to assist the unblinded pharmacist or designee in maintaining current and accurate
inventory records. At a minimum, the unblinded pharmacist 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 unblinded
pharmacist or designee must retain vials containing used, unused, or expired liposome
bupivacaine for return or destruction, as instructed by Pacira, following confirmation of study
drug accountability data by an unblinded monitor. A record of drug return or destruction will be
maintained in the pharmacy binder and a copy provided to Pacira. Inventory records must be
readily available for inspection by the unblinded monitor and/or 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 on the Delegation of Authority and Accountability Log will have the ability
to access, prepare, and administer the study drug.

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12.
STUDY ENDPOINTS AND MEASUREMENTS
12.1.
Efficacy Assessments
The following efficacy measurements will be conducted at the times specified after the end of
surgery:

Pain intensity scores using the NRS-R at baseline and 1, 2, 4, 8, 12, 24, 36, 48, 60, and
72 hours following surgery, at first request for rescue pain medication, and on Day 12
(Appendix 1).

Pain intensity scores using the NRS-A (where the prescribed activity is cough) at baseline
and 24, 48, and 72 hours following surgery, and on Day 12 (Appendix 1).

Time of first opioid rescue.

Opioid use.

Sensory function assessment (i.e., cold test) at baseline, when the subject wakes up after
surgery, and at 2, 4, 12, 24, 36, 48, 60, and 72 hours after surgery, or until the subject’s
sensitivity to cold has returned in two consecutive evaluations (Appendix 7).

Overall benefit of analgesia score questionnaire at 24, 48, and 72 hours (see Appendix 3).

Subject’s satisfaction with postsurgical pain control at 72 hours, on Day 12, and on
Day 30 using a 5-point Likert scale (Appendix 4).

Predefined treatment-emergent opioid-related AEs at 72 hours following surgery
(see Appendix 6).
12.2.
Efficacy Endpoints
The efficacy endpoints listed below will be assessed based on the efficacy measurements
conducted at the specified time points after the end of surgery.
Primary Endpoint
The primary efficacy endpoint is the AUC of the NRS-R pain intensity scores through 72 hours.
Secondary Endpoints
The following secondary endpoints will be analyzed using a hierarchical testing procedure:

Total postsurgical opioid consumption (in mg) through 72 hours.

Time to first opioid rescue.
Tertiary Endpoints

Total postsurgical opioid consumption (in mg) through 24, 36, 48, and 60 hours.

Overall benefit of analgesia score questionnaire at 24, 48, and 72 hours.

Subject satisfaction with postsurgical pain control at 72 hours, Day 12, and Day 30.

The NRS-R and NRS-A pain intensity scores at each assessed time point.

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
The AUC of the NRS-R pain intensity scores through 24, 36, 48, and 60 hours.

The AUC of the NRS-R pain intensity scores from 24-48 and 48-72 hours.

Proportion of subjects who are pain free (defined as an NRS pain intensity score of
0 or 1) at each assessed time point.

Proportion of subjects who receive the following rescue medication(s):
o
Subjects who receive no rescue medication.
o
Subjects who only receive IV fentanyl as a rescue medication.
o
Subjects who receive IV fentanyl and a second opioid medication.

Incidence of predefined treatment-emergent opioid-related AEs (diffuse pruritus, overt
respiratory depression, urinary retention as measured by need for postsurgical bladder
catheterization, constipation, sedation, confusion, delirium, vomiting, or need for
antiemetic medication) at 72 hours.

Proportion of subjects at each time point with sensitivity to cold anywhere within the
dermatomes supplied by any of the nerves to which study drug was administered.
12.3.
Pharmacokinetic Measurements
Blood samples for PK analysis will be obtained from subjects at specific sites at baseline,
15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after the end of surgery.
Placebo samples will be collected to maintain the treatment double-blind but will not be
analyzed. (Note: At time points when the PK and NRS pain intensity assessments coincide,
the NRS pain intensity assessments will be conducted before the blood draw.)
12.4.
Pharmacokinetic Endpoints
Pharmacokinetic parameters are to be estimated from the plasma bupivacaine concentration-time
profiles by non-compartmental analysis and are to include the following:
AUC0-tlast
The area under the plasma concentration-time curve from the time of
administration to the time of the last quantifiable concentration calculated using
the lin/log trapezoidal rule.
AUC0-∞
The area under the plasma concentration-time curve from the time of
administration extrapolated to infinity. The residual area from the time of the last
quantifiable concentration (Ctlast) to infinity is to be calculated using the
approximation: AUCt-∞= Ctlast/ λz.
Cmax
The maximum observed plasma concentration obtained directly from the
experimental data without interpolation.
Tmax
The time to attain Cmax.
λz
The apparent terminal elimination rate constant determined by log-linear
regression of the terminal log-linear segment of the plasma concentration-time
curve.
t1/2el 
The apparent terminal elimination half-life calculated as 0.693/λz.

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12.5.
Safety Assessments
The following safety assessments will be conducted:

Adverse events from the time of randomization through the Day 30 follow-up contact.

Vital signs (resting heart rate and blood pressure) at screening, baseline, and 1, 12, 24,
48, and 72 hours after surgery.

Neurological assessment at baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 18, 24,
30, 36, 42, 48, 60, and 72 hours after surgery (see Appendix 2).

Cardiac assessment (i.e., ECG recordings) started at baseline (approximately 1 hour prior
to surgery) and continued for a total of 72 hours. Electrocardiogram changes will be
examined using the ECG data closest to the Tmax.

Physician's satisfaction with wound healing on Day 12 (see Appendix 5).
12.6.
Safety Endpoints
The following safety endpoints will be assessed based on the safety measurements conducted at
the specified time points:

Incidence of treatment-emergent adverse events (TEAEs) and SAEs through the Day 30
follow-up contact.

Change from baseline in vital signs (resting heart rate and blood pressure) at each
assessed time point.

Summary of neurological assessments (proportion of subjects who are oriented, and
proportion of subjects who have any of the neurological events).

Change from baseline in ECG data closest to the Tmax.

Rating of physician's satisfaction with wound healing on Day 12.
12.7.
Appropriateness of Measures
Endpoints selected for this study were based on validated methodologies and other well
established clinical measurements used in peer-reviewed studies in both the peer-reviewed
literature and at regulatory authorities.
The neurological and cardiac safety assessments are based on the known signs and symptoms
associated with systemic bupivacaine toxicity. The sensory function assessment is a standard
test to determine restoration of nerve function.

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13.
STUDY PROCEDURES
A time and events schedule for all study procedures is provided in Table 1.
13.1.
Instructions for Conducting Procedures and Measures
All assessments conducted after baseline will be timed from end of surgery. Day 1 is defined as
the day on which study drug is administered. The beginning of surgery is defined as the time of
the first incision. The end of surgery is defined as the time of the last suture/staple. Postsurgical
is defined as after the end of surgery.
Subjects will be hospitalized for at least 72 hours after surgery; therefore, postsurgical analgesia
and collection of study data will take place under the supervision of site study staff.
13.1.1.
Numeric Rating Scale Pain Intensity Assessments
Pain intensity will be assessed using the NRS-R and the NRS-A (see Appendix 1). To assess
pain intensity at rest (NRS-R), the subject will assume a resting position that does not exacerbate
his or her postsurgical pain. The subject will rest in this position for at least 5 minutes before
responding to the following question, “On a scale of 0 to 10, where 0 = no pain and 10 = worst
possible pain, how much pain are you having right now?” The subject’s response will be
recorded.
The subject’s pain intensity will be assessed with activity (NRS-A), where the prescribed activity
will consist of a cough. The subject will respond to the following question, “On a scale of 0 to
10, where 0 = no pain and 10 = worst possible pain, how much pain are you having right now?”
The subject’s response will be recorded.
Note: At time points when the NRS pain intensity assessments coincide, the NRS-R will be
conducted before the NRS-A. Additionally, if chest tube removal or a PK blood draw coincides
with an NRS pain intensity assessment(s), the NRS pain intensity assessment(s) must be
conducted before the other procedures. If a blood draw and pain intensity assessment coincide,
the pain intensity assessment will be conducted first.
13.1.2.
Overall Benefit of Analgesia Score Questionnaire
The OBAS questionnaire (Lehmann 2010) will be completed at 24, 48 and 72 hours after surgery
(see Appendix 3).
13.1.3.
Neurological Assessment
A neurological assessment will be conducted at baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8,
12, 18, 24, 30, 36, 42, 48, 60, and 72 hours after surgery. The examination will include the
subject's orientation. Additionally, the subject will be asked whether s/he is experiencing any
numbness of the mouth, tongue, or lips; a metallic taste; problems with hearing; problems with
vision; or muscle twitching (see Appendix 2). For assessing the subject’s orientation, the
assessor should take into account what their normal expectation would be for a person at this
time postsurgically. For example, if the subject is able to be woken up and is still slightly
disoriented but in accordance with what would be expected for that time after surgery, then the

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answer would be “Yes”. If the subject is responding abnormally, then this would be marked
“No” and it would be recorded as an AE. If the subject answers “Yes” to any of the additional
questions on this assessment, the event will be recorded as an AE. If the neurological assessment
reveals a neurological event that the Investigator believes may be associated with high levels of
systemic bupivacaine, an unscheduled PK blood sample should be collected at the time that the
event is noted.
13.1.4.
Cardiac Assessment (Electrocardiogram Recordings)
Digital 12-lead holter ECGs will be recorded using the Mortara Instrument Digital H12+™ECG
continuous recorder (Mortara Instrument, Inc., Milwaukee, Wisconsin), which will continuously
record all 12 leads simultaneously from baseline (approximately 1 hour prior to surgery) and
continue for 72 hours. The ECG signal will be recorded on compact flash memory cards
provided to the sites. The subject’s unique identification number and demographic information
will be recorded for each flash card. Without knowledge of subject treatment assignment, the
central laboratory will generate a 10-second, 12-lead digital ECG at each time point specified in
the protocol. If targeted ECG time points are artifactual and of poor quality, the central
laboratory will capture analyzable 10-second ECGs as close as possible to the targeted time
points.
Digital ECGs will be transmitted by the central laboratory and processed via its validated data
management system, EXPERT. Interval duration measurements will first be obtained by trained
analysts using the proprietary validated electronic caliper system applied on a computer screen
utilizing the method of Global Median Beat. The Global Median Beat is created by an
algorithm, where one representative beat for each of the 12 leads is selected and superimposed,
creating a single superimposed (Global Median) beat. Trained analysts will then review for
correct interval duration measurement (IDM) caliper placement and adjudicate the pre-placed
algorithm calipers as necessary. A cardiologist will then verify the interval durations and
perform the morphology analysis, noting any T-U wave complex that suggests an abnormal form
compatible with an effect on cardiac repolarization.
On-screen measurements of heart rate (HR), PR, QRS, and QT interval durations will be
performed and derived variables RR, QTcF, and QTcB will be calculated using the following
formulae:
QTcB = QT/RR
QTcF = QT/3RR
RR = 60/HR
Each fiducial point (onset of P wave, onset of Q wave, offset of S wave, and offset of T wave)
will be marked. The original ECG waveform and such annotations will be saved separately in
XML format for independent review.
Electrocardiogram changes in RR, PR, QRS, QT, QTcF, and QTcB will be examined at the time
closest to the Tmax.

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13.1.5.
Sensory Function Assessment (Cold Test)
For the sensory function assessment, the subject’s sensitivity to cold anywhere within the
dermatomes supplied by any of the nerves to which study drug is administered will be assessed
at baseline, when the subject wakes up after surgery, and at 2, 4, 12, 24, 36, 48, 60, and 72 hours
after surgery, or until the subject’s sensitivity to cold has returned in two consecutive evaluations
(see Appendix 7).
The subject's skin will be wiped with ice or an alcohol pad. The subject will then be asked,
"Does this feel cold - yes or no?"
13.1.6.
Vital Signs
Vital signs (heart rate and blood pressure) will be measured at screening, baseline, and 1, 12, 24,
48, and 72 hours after surgery. Vital signs will be taken after the subject has rested in a supine
position for at least 5 minutes and before the NRS pain intensity assessment(s) when the
assessments coincide. The subject will remain in a supine position during the assessment.
13.1.7.
Subject's Satisfaction with Postsurgical Pain Control
The subject’s satisfaction with postsurgical pain control will be assessed at 72 hours, Day 12,
and Day 30 using the Likert Scale (see Appendix 4).
13.1.8.
Physician's Satisfaction with Wound Healing
The physician's satisfaction with wound healing will be assessed on Day 12 (see Appendix 5).
13.2.
Screening Procedures

Explain study purpose and procedures.

Obtain signed ICF.

Assess eligibility.

Record relevant medical/surgical history, demographics, and baseline characteristics.

Measure vital signs (heart rate and blood pressure) after subject has rested for at least
5 minutes in the supine position.

Record concomitant medications taken within 3 days prior to surgery.
13.3.
Baseline Procedures (Day -1 to Day 1)

Confirm eligibility.

Update relevant medical/surgical history.

Perform urine pregnancy test for women of childbearing potential.

Perform physical examination.

Measure vital signs (heart rate and blood pressure) after subject has rested for at least
5 minutes in the supine visit.

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
Record subject’s baseline assessment of pain intensity using the NRS-R followed by
the NRS-A (Appendix 1).

Perform neurological assessment (see Appendix 2).

Start the 12-lead digital ECG recording approximately 1 hour prior to surgery.

Perform sensory function assessment (i.e., cold test) (see Appendix 7).

Collect baseline blood sample for PK analysis (specific sites only).

Record concomitant medications taken within 3 days prior to surgery.

Randomize subject and prepare study drug (Day 1).

Record AEs and any treatment(s) for the events starting after randomization.
13.4.
Intraoperative Procedures

Divide study drug into three syringes containing equal doses of approximately 88 mg
in 6.6 mL volume per nerve.

Administer study drug to each of three nerve segments (index nerve, nerve above,
and nerve below) after the surgical procedure is completed according to the
randomization schedule.

For the US sites, install unloaded PCA pump prior to the completion of the surgery.

Record start and stop times of surgery.

Record start and stop time of study drug administration.

Record location of chest tube.

Record intraoperative opioids administered.

Record concomitant medications.

Record AEs and any treatment(s) for the events.

If a cardiac or neurological event occurs that the Investigator believes may be
associated with high levels of systemic bupivacaine, an unscheduled PK blood sample
should be collected at the time that the event is noted.
13.5.
Procedures After Surgery Through 72 Hours

Administer first rescue medication for breakthrough pain (IV fentanyl 100 mcg) via
bolus only, if needed.

Record date and time of IV fentanyl administration.

Record date(s) and time(s) of second rescue medication administration

US sites only
o
Load PCA pump with morphine or hydromorphone immediately after IV
fentanyl is administered. Program PCA pump dosing per Section 11.1

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o
Once a subject is tolerating PO medication, administer PO immediate-release
oxycodone, as needed, but not more than 10 mg every 4 hours.
o
Record date, time, and amount of all rescue medication administered through
72 hours after surgery.

European sites only
o
Administer second rescue medication (IM-administered morphine), as needed,
per Section 11.1.
o
Once a subject is tolerating PO medication, PO immediate-release oxycodone
may be administered, as needed, but not more than 10 mg every 4 hours.
o
Record date, time, and amount of all rescue medication administered through
72 hours after surgery.

Record all other concomitant medications.

Measure vital signs (heart rate and blood pressure) after subject has rested for at
least 5 minutes in the supine position at the following time points: 1, 12, 24, 48, and
72 hours after surgery.

Record subject’s assessment of pain intensity using the NRS-R at the following time
points: 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after surgery and at first request for
rescue pain medication, if appropriate (see Appendix 1).

Record subject’s assessment of pain intensity using the NRS-A at the following time
points: 24, 48, and 72 hours after surgery (see Appendix 1).

Perform neurological assessment at 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 18, 24,
30, 36, 42, 48, 60, and 72 hours after surgery per Section 13.1.3 (see Appendix 2).

Continue the cardiac assessment (i.e., 12-lead digital ECG recordings) for a total of
72 hours.

Perform sensory function assessment (i.e., cold test) when the subject wakes up after
surgery, and at 2, 4, 12, 24, 36, 48, 60, and 72 hours after surgery, or until the
subject’s sensitivity to cold has returned in two consecutive evaluations (see
Appendix 7).

Collect scheduled blood samples for PK analysis (specific sites only) at 15 minutes,
30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after the end of surgery
per Section 12.3.

Complete the OBAS questionnaire at 24, 48, and 72 hours after surgery (see
Appendix 3).

Obtain overall rating of subject satisfaction with postsurgical pain control using the
Likert scale at 72 hours after surgery (see Appendix 4).

Record date and time of chest tube removal.

Record date and time subject is moved into and out of the Intensive Care Unit (ICU).

Record AEs and any treatment(s) for the events.

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
If a cardiac or neurological event occurs that the Investigator believes may be
associated with high levels of systemic bupivacaine, an unscheduled PK blood sample
should be collected at the time that the event is noted.

Question subject regarding the predefined treatment-emergent opioid-related AEs at
72 hours after surgery (see Appendix 6).
13.6.
Postsurgical Study Visit Procedures (Day 12)

Record subject’s assessment of pain intensity using the NRS-R and NRS-A
(see Appendix 1).

Obtain overall rating of subject satisfaction with postsurgical pain control using the
Likert scale (see Appendix 4).

Assess physician satisfaction with wound healing (see Appendix 5).

Record AEs and any treatment(s) for the events.
13.7.
Day 30 Follow-Up Contact

Obtain overall rating of subject satisfaction with postsurgical pain control using the
Likert scale (see Appendix 4).

Record AEs and any treatment(s) for the events.

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14.
ADVERSE EVENT REPORTING
Consistent with the current regulatory guidance provided by the US CFR and the ICH GCP,
AEs and SAEs are defined in Section 14.1.1 and Section 14.2.1, respectively.
The concepts of AEs and SAEs represent regulatory instruments used to evaluate and monitor
the safety of clinical study subjects. Therefore, these terms only apply in light of their regulatory
definition. The term serious, in a regulatory sense, does not necessarily mean severe. The SAE
concept is used primarily to identify, during the conduct of the study, those SAEs that may
require expedited reporting to regulatory authorities.
14.1.
Adverse Events
14.1.1.
Definitions
Definition of Adverse Event (AE): 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 is randomized, including frequency or pattern changes for a fluctuating
condition (e.g., migraine) is considered an AE.
An AE that occurs after randomization and before the start of the study drug administration is
identified as a pretreatment AE (PTAE). An AE that occurs after administration of the study
treatment is considered a TEAE. All AEs must be recorded and reported accordingly, whether
they appear causally related to the study drug or not.
Adverse events will be followed until the outcome is known or until the end of the study.
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. For the purposes of IND safety reporting, ‘reasonable possibility’
means there is evidence to suggest a causal relationship between the drug and 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.

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14.1.2.
Recording Adverse Events
It is the responsibility of the Investigator to document all AEs with an onset after the subject is
randomized (i.e., PTAEs and AEs). For the purpose of this study, all AEs that occur through the
Day 30 follow-up contact must be recorded regardless of whether or not they are considered
related to study drug. Whenever feasible, AE terms should be documented as medical diagnoses
(highest possible level of integration); otherwise, the AEs should 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 should 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 should be recorded and the symptoms collapsed (removed – i.e., lined
through and initialed). Whenever possible, abnormal laboratory results should be reported as
their clinical corollary (e.g., low potassium should be recorded as hypokalemia).
All AEs will be followed through progression and regression of their severity. For example,
if an AE is reported as mild in severity but changes to moderate, the AE of mild will have an
outcome of changed AE characteristic and the AE will be re-entered. The AE with a moderate
severity must have the same start date as the mild event stop date. If the AE then becomes mild,
the AE with a moderate severity will have an outcome of changed AE characteristic and the AE
will be re-entered with a severity of mild; the start date of the mild AE must be the same as the
stop date of the moderate AE.
Any condition noted before the subject is randomized 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 randomization, 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 study drug, action taken for
the AE, and the outcome of the AE, including the date and time of resolution, if applicable.
14.1.3.
Severity of Adverse Events
In general, the severity of an AE should be categorized using the following guidelines:
Mild:
An AE that is easily tolerated by the subject, causing minimal
discomfort and not interfering with everyday activities.
Moderate:
An AE that is discomforting and interferes with normal everyday
activities.
Severe:
An AE that prevents normal everyday activities.
14.1.4.
Relationship of Adverse Events to Study Drug
The Investigator will assess the relationship of the AE to study drug after careful medical
consideration on a case-by-case basis. General guidelines are provided below:

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Not Related:
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).
Related:
There is reason to conclude that the drug caused the event (i.e., there
is a reasonable possibility based on evidence to suggest that the drug
caused the event).
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.)

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14.2.
Serious Adverse Events
14.2.1.
Definition of a Serious Adverse Event
Definition of a Serious Adverse Event (SAE): An AE is considered “serious” if, in the view of
either the Investigator or Sponsor, it results in any of the following outcomes:

Death1.

A life-threatening adverse event2.

Inpatient hospitalization or prolongation of existing hospitalization3.

A persistent or significant incapacity4.

Congenital anomaly/birth defect.

Medically significant5.
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 should make every effort to obtain and document the cause of death for all subjects
who die during the study. If, despite all efforts, the cause of death remains unknown, the AE
should be documented as an “unspecified fatal event.”
2Life-threatening: An AE is considered life-threatening if, in the view of either the Investigator
or Sponsor, 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 should 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 should be reported as an SAE.
4Persistent or significant incapacity: A substantial disruption of a person’s ability to conduct
normal life functions.
5Medically 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 randomization through the Day 30 follow-up
contact, whether or not related to study drug, must be reported by the Investigator or designee to
Pacira Drug Safety or designee by telephone or fax within 24 hours of discovery. Telephone
contact information for Pacira Drug Safety/designee can be found in the regulatory binder.

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Investigators should not wait to receive additional information to fully document the event
before notifying Pacira Drug Safety or designee of the SAE. The telephone or fax report should
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
should be obtained and all subject-identifying information redacted prior to forwarding to Pacira
Drug Safety or designee. 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 SAE after the Day 30 follow-up contact, the SAE should
also be reported to Pacira Drug Safety or designee provided the SAE is considered related to
study drug. 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 developed for this study. A separate
SAP will be developed for the ECG results.
15.1.
Study Hypothesis
The primary null hypothesis is:
H0: The means of the AUC of NRS-R pain intensity scores through 72 hours are not
different between the liposome bupivacaine and placebo groups.
The alternative hypothesis is:
HA: The mean AUC of the NRS-R pain intensity scores through 72 hours for the
liposome bupivacaine group is less than for the placebo group.
15.2.
Study Endpoints
The endpoints to be assessed in this study are listed in Section 12.2 (Efficacy Endpoints),
Section 12.4 (PK Endpoints), and Section 12.6 (Safety Endpoints).
15.3.
Determination of Sample Size
A study population of approximately 180 subjects is planned with approximately 90 subjects in
each treatment group (liposome bupivacaine and placebo). The sample size was estimated based
on the results of a Phase 3 wound infiltration hemorrhoidectomy study of liposome bupivacaine
versus placebo where the mean (standard deviation) AUC of the NRS-R pain intensity scores
through 72 hours was 141 (101) and 202 (104) for the liposome bupivacaine and placebo groups,
respectively. A two-group t-test with 0.05 two-sided significance level will have 97% power to
detect a difference in means of 61, assuming that the common standard deviation is 104, when
the sample size in each group is 90.
15.4.
Analysis Populations
The following analysis sets are planned:
Safety: The safety analysis set will include all subjects who receive study drug and will be based
on actual treatment received.
Efficacy: The efficacy analysis set will include all subjects in the safety analysis set who receive
study drug in all three nerves and will be based on randomized treatment, regardless of actual
treatment received.
Pharmacokinetic: The PK analysis set will include all subjects in the safety analysis set who
receive liposome bupivacaine and who provide sufficient samples to allow for calculation of the
PK parameters required for analysis.

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15.5.
Handling Subject Dropouts and Discontinuations
For the calculation of AUC of NRS pain intensity scores through any of the time periods, the
following methods will be used for imputing missing data:
Missing scores before the first non-missing score will be replaced by the median score at the
missing time point from other subjects in the same treatment group. Missing scores after the last
non-missing score will be replaced by the last non-missing score (last observation carried
forward). Linear interpolation will be used to replace missing scores between two non-missing
scores. Subjects who have no pain scores after surgery will have the missing scores replaced by
the median score at the missing time point from other subjects in the same treatment group.
Additional methods for dealing with missing data 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 Compliance
The percentage of subjects in each analysis set and the percentage who fail to complete the study
(as well as the reasons for discontinuation) will be displayed by treatment group.
15.6.3.
Efficacy Analyses
All efficacy analyses will be based on randomized treatment, regardless of actual treatment
received.
15.6.3.1
Primary Efficacy Measure
The primary efficacy measure in this study is the AUC of the NRS-R pain intensity scores
through 72 hours.
For the AUC of the NRS-R pain intensity scores through 72 hours, liposome bupivacaine will be
compared to placebo using analysis of covariance (ANCOVA) with treatment as the main effect
and the baseline NRS-R pain intensity score as the covariate. Based on the model, the difference
between the treatment groups will be estimated along with the 2-sided 95% confidence intervals
(CI).
Handling of Subjects Requiring Rescue Medication
For the AUC of the NRS-R pain intensity scores, prior to analysis the windowed Worst-
Observation-Carried-Forward (wWOCF) imputation method will be applied. For subjects who
take rescue pain medication, their NRS-R pain intensity scores recorded within the window of
controlled type of rescue medication (6 hours for IV fentanyl or oxycodone, 4 hours for
morphine, and 2 hours for IV hydromorphone) will be replaced by the ‘worst’ observation.
The worst observation will be the highest score in the time interval from the end of surgery up to
the time prior to taking their first rescue pain medication. Note that NRS-R pain intensity scores
in the window that are higher than the worst value prior to rescue pain medication will not be

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overwritten. If no NRS-R pain intensity score is available prior to the first rescue pain
medication, the worst observation from all available measurements will be used instead.
15.6.3.2
Secondary Efficacy Measures
The secondary efficacy measures in this study are:

Total postsurgical opioid consumption through 72 hours.

Time to first opioid rescue.
These efficacy measures will be analyzed using a hierarchical fixed-sequence stepwise testing
procedure. To protect the Type 1 error rate, the testing will be performed in a sequentially
rejective fashion. First, the total postsurgical opioid consumption through 72 hours will be
tested. If the test of opioid consumption is significant at the two-sided 0.05 level then, and only
then, the time to first opioid rescue will be tested. Each test will be declared positive at the
two-sided 0.05 significance level.
For total postsurgical opioid consumption, opioid medications will be converted to a morphine
equivalent amount. All opioids administered through 72 hours will be included in the analysis.
Prior to analysis, the natural logarithm transformation will be applied to the total amount. To test
for a significant difference between liposome bupivacaine and placebo, an analysis of variance
(ANOVA) with treatment as the main effect will be used. Based on the model, liposome
bupivacaine will be compared to placebo and a two-sided 95% CI about the difference will be
presented.
The time from end of surgery to the first use of an opioid rescue through 72 hours after surgery
will be summarized with medians and Kaplan-Meier estimates. A log-rank test will be used to
compare liposome bupivacaine to placebo.
15.6.3.3
Tertiary Efficacy Measures
Continuous Measures of Efficacy
For the AUC of pain intensity scores, missing data will be imputed as described in Section 15.5
and fully described in the SAP.
For total postsurgical opioid consumption, opioid medications will be converted to a morphine
equivalent amount. All opioids administered through 72 hours will be included in the analysis.
Prior to analysis, the natural logarithm transformation will be applied to the total amount.
Summary statistics for each measure will be shown at each time point by treatment group.
To test for significant differences between liposome bupivacaine and placebo with respect to
continuous measures of efficacy, an ANOVA with treatment as the main effect or ANCOVA
with treatment as the main effect and the baseline value as the covariate will be used. Based on
the model, liposome bupivacaine will be compared with placebo and two-sided 95% CIs about
the differences will be presented.

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Categorical Measures of Efficacy
The proportion of subjects in each category will be calculated and summarized at each time point
by treatment group. A chi-square test or Wilcoxon Rank Sum test will be used to compare
liposome bupivacaine to placebo.
15.6.4.
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.
15.6.5.
Safety Analyses
All safety analyses will be based on actual treatment received.
15.6.5.1
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). All summaries of AEs will
only include TEAEs. Events that start prior to the start of study drug administration will be
identified in listings only. 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 study drug-related TEAEs and by
severity. 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.
15.6.5.2
Vital Signs
Descriptive statistics for each vital sign for baseline and change from baseline at each time point
will be summarized for each treatment group.
15.6.5.3
Neurological Assessments
The proportion of subjects who are oriented at each time point will be summarized for each
treatment group. The proportion of subjects who have at least one of the neurological events will
be summarized for each treatment group.
15.6.5.4
Rating of Physician’s Satisfaction with Wound Healing
The physician’s satisfaction with wound healing will be summarized for each treatment group.
To test for significant differences between liposome bupivacaine and placebo, a Wilcoxon Rank
Sum test with treatment as the main effect will be used. Based on the model, liposome
bupivacaine will be compared with placebo and the two-sided 95% CI about the difference will
be presented.

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15.7.
Significance Testing
All tests will be two-sided and based on a significance level of 0.05.
15.8.
Interim Analyses
An interim analysis is not planned.

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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.
EXPAREL Full Prescribing Information, October 2011.
Ho AMH, Karmakar MK. Intercostal Nerve Block.
http://www.nysora.com/peripheral_nerve_blocks/nerve_stimulator_techniques/3098-intercostal-
nerve-block.html. Website accessed on 21 May 2012.
EXPAREL Investigator’s Brochure, Edition 15, 09 July 2012.
Lehmann N, Joshi GP, Dirkmann D, et al. Development and longitudinal validation of the
overall benefit of analgesia score: a simple multi-dimensional quality assessment instrument.
Br J Anasth. 2010;105(4):511-518. Epub 2010 Aug 6.

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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. (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

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Appendix 1:
Subject’s Reported Pain Intensity (Numeric Rating Scale)
Subjects will be evaluated for pain intensity using the NRS-R at baseline and 1, 2, 4, 8, 12, 24,
36, 48, 60, and 72 hours following surgery, at the first request for rescue medication, and on
Day 12.
Subjects will be evaluated for pain intensity using the NRS-A (where the prescribed activity is
cough) at baseline, and 24, 48, and 72 hours following surgery and on Day 12.
At time points when the pain intensity assessments coincide, the NRS-R will be conducted
before the NRS-A. Additionally, if chest tube removal or a PK blood draw coincides with the
pain intensity assessment(s), the pain intensity assessment(s) must be conducted before the other
procedures.
Pain Intensity Assessment (Numeric Rating Scale)
On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, circle the number that best
describes how much pain are you having right now? (Circle one number only.)
0
1
2
3
4
5
6
7
8
9
10
No pain
Worst
possible pain

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Appendix 2:
Neurological Assessment
A neurological assessment will be conducted at baseline, 15 minutes, 30 minutes, and 1, 2, 4, 8,
12, 18, 24, 30, 36, 42, 48, 60, and 72 hours after surgery.
The examination will include the subject's orientation.

Is the subject oriented?
Yes
No
If the subject is not oriented, record as an AE.
Additionally, the subject will be asked the following questions:

Do you have numbness of the lips, the tongue, or around the mouth?
Yes
No

Do you have a metallic taste in your mouth?
Yes
No

Are you having problems with your hearing?
Yes
No

Are you having problems with your vision?
Yes
No

Are your muscles twitching?
Yes
No
If the subject answers "Yes" to any of these additional questions, the event should be recorded as
an AE.
If the neurological assessment reveals a neurological event that the Investigator believes may be
associated with high levels of systemic bupivacaine, an unscheduled PK blood sample should be
collected at the time that the event is noted.

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Appendix 3:
Overall Benefit of Analgesia Score Questionnaire
Note: The OBAS questionnaire will be completed 24, 48, and 72 hours following surgery.
1. Please rate your current pain at rest on a scale between
0=minimal pain and 4=maximum imaginable pain
2. Please grade any distress and bother from vomiting in the past 24 h
(0=not at all to 4=very much)
3. Please grade any distress and bother from itching in the past 24 h
(0=not at all to 4=very much)
4. Please grade any distress and bother from sweating in the past 24 h
(0=not at all to 4=very much)
5. Please grade any distress and bother from freezing in the past 24 h
(0=not at all to 4=very much)
6. Please grade any distress and bother from dizziness in the past 24 h
(0=not at all to 4=very much)
7. How satisfied are you with your pain treatment during the past 24 h
(0=not at all to 4=very much)

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Appendix 4:
Subject Satisfaction with Postsurgical Pain Control (Likert
Scale)
Note: The subject's satisfaction with postsurgical pain control will be conducted 72 hours after
surgery, on Day 12, and on Day 30.
Please circle the number below that best describes your overall satisfaction with the pain
medication you received after surgery. (Circle one number only.)
1. Extremely dissatisfied
2. Dissatisfied
3. Neither satisfied nor dissatisfied
4. Satisfied
5. Extremely satisfied

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Appendix 5:
Physician's Satisfaction with Wound Healing
Note: The physician's satisfaction with wound healing will be conducted on Day 12.
Please circle the number below that best describes your satisfaction with the subject’s wound
healing after surgery. (Circle one number only.)
1. Extremely dissatisfied
2. Dissatisfied
3. Neither satisfied nor dissatisfied
4. Satisfied
5. Extremely satisfied

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Appendix 6:
Treatment-Emergent Opioid-Related Adverse Events
Questionnaire
The treatment-emergent opioid-related AE questionnaire will be completed at 72 hours after
surgery. The subject will be asked the questions below.
Since your operation, have you had:

Itching all over your body?
Yes
No

Excessive tiredness?
Yes
No

Difficulty breathing?
Yes
No

Did you need a postsurgical bladder catheter?
Yes
No

Vomiting?
Yes
No

Need for medicine to prevent vomiting?
Yes
No

Constipation?
Yes
No

Confusion?
Yes
No

Delirium?
Yes
No
If the subject answers "Yes" to any of these questions, the event should be recorded as an AE.

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Appendix 7:
Dermatome Map
For the sensory function assessment, the subject’s sensitivity to cold within the dermatomes
supplied by any of the nerves to which study drug was administered will be assessed at baseline,
when the subject wakes up after surgery, and at 2, 4, 12, 24, 36, 48, 60, and 72 hours after
surgery, or until the subject’s sensitivity to cold has returned in two consecutive evaluations.
The subject's skin will be wiped with ice or an alcohol pad. The subject will then be asked,
"Does this feel cold - yes or no?"