Conditions: Posterolateral Thoracotomy Postoperative Pain
Keywords: liposome bupivacaine posterolateral thoracotomy intercostal nerve block postoperative pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 191
Healthy volunteers: no

Brief summary:
The purpose of the study is to examine the safety and efficacy of liposome bupivacaine for intercostal nerve block in subjects undergoing posterolateral thoracotomy.

Detailed description:

Arms:
arm 1: Intercostal nerve block using single total administration of 20 mL EXPAREL (bupivacaine liposome injectable suspension) 266 mg (approximately 88 mg \[6.6 mL\] to each of three nerve segments) arm 2: Intercostal nerve block using single total administration of 20 mL normal saline (6.6 mL to each of three nerve segments)

Interventions: intervention 1: EXPAREL 266 mg intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
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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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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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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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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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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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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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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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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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?"

SAP_001.pdf: 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
Document: 
Statistical Analysis Plan 
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: 
February 26, 2013 


 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
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 
 
 
 
Protocol No.: 402-C-322 
IND No.: 69,198 
Study Phase: 3 
Study Drug: Liposome Bupivacaine 
Date: 
26 February 2013 
Prepared by: Janice Lookabaugh, MPH 
Statistician, Consultant 
 
Sponsor: Pacira Pharmaceuticals, Inc. 
10450 Science Center Drive 
San Diego, CA 92121 
Telephone: (858) 625-2424 
Fax: (858) 625-0804 
 
 
 
 
 
 
 
 
 
 
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. 


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Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 3 of 98 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SIGNATURE PAGE ........................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1. 
LIST OF ABBREVIATIONS .......................................................................................... 5 
2. 
INTRODUCTION ............................................................................................................ 7 
3. 
STUDY OBJECTIVES..................................................................................................... 8 
4. 
STUDY OVERVIEW ....................................................................................................... 9 
5. 
DEFINITIONS ................................................................................................................ 11 
6. 
ANALYSIS SETS.......................................................................................................12 
7. 
STATISTICAL METHODS OF ANALYSIS ............................................................... 13 
7.1. 
General Principles .......................................................................................................13 
7.1.1. 
Calculation of AUC of NRS .......................................................................................13 
7.1.2. 
Imputation of NRS Pain Intensity Scores ....................................................................14 
7.1.3. 
Handling Missing Values. ...........................................................................................15 
7.1.4. 
Multiplicity Adjustments ............................................................................................16 
7.1.5. 
By-Center Analyses ........................................................................................................ 17 
7.2. 
Subject Disposition .....................................................................................................17 
7.3. 
Description of Demographics and Baseline Characteristics........................................17 
7.4. 
Prior and Concomitant Medication .............................................................................17 
7.5. 
Measurements of Treatment Compliance ...................................................................18 
7.6. 
Efficacy Analysis ............................................................................................................ 18 
7.6.1. 
Efficacy Variables .......................................................................................................18 
7.6.2. 
Methods of Analysis ....................................................................................................... 19 
7.7. 
Pharmacokinetic Analyses .............................................................................................. 23 
7.7.1. 
Pharmacokinetic Parameter Calculation Methods.......................................................23 
7.7.2. 
Pharmacokinetic Concentrations and Variables ..........................................................24 
7.8. 
Safety Analyses. .............................................................................................................. 24 
7.8.1. 
Adverse Events ...........................................................................................................24 
7.8.2. 
Laboratory Parameters ................................................................................................25 


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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
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Page 4 of 98 
 
 
7.8.3. 
Vital Signs ...................................................................................................................25 
7.8.4. 
Other Safety Parameters ..............................................................................................25 
7.9. 
Interim Analysis .............................................................................................................. 25 
8. 
SAMPLE SIZE CALCULATIONS ............................................................................... 26 
9. 
REFERENCES ...........................................................................................................27 
10. 
LAYOUT OF TABLES, LISTINGS, AND FIGURES ................................................ 28 


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Liposome Bupivacaine 
Statistical Analysis Plan 
 
 
1. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ASA 
American Society of Anesthesiologists 
ATC 
Anatomic therapeutic chemical 
AUC 
Area under the curve 
AUC(0-inf) 
Area under the plasma concentration versus time curve from 
time 0 extrapolated to infinity 
AUC(0-last) 
Area under the plasma concentration versus time curve from 
time 0 to the last collection time after drug administration 
BLOQ 
Below the limit of quantification 
CI 
Confidence interval 
Cmax 
The maximum observed plasma concentration obtained 
directly from the experimental data without interpolation 
%CV 
Coefficient of variation 
CRF 
Case report form 
CSR 
Clinical study report 
C(t) 
Last observed quantifiable concentration 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 


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Statistical Analysis Plan 
 
 
 
IM 
Intramuscular 
IV 
Intravenous 
λz 
Apparent terminal elimination rate constant 
LOCF 
Last observation carried forward 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric rating scale 
NRS-A 
Numeric rating scale with activity 
NRS-R 
Numeric rating scale at rest 
OBAS 
Overall benefit of analgesia score 
ORAE 
Opioid-related adverse event 
PCA 
Patient-controlled analgesia 
PK 
Pharmacokinetic 
PO 
Oral 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
tlast 
Time to last quantifiable concentration 
Tmax 
Time to maximum concentration 
t½ 
Half-life calculated from the apparent terminal elimination 
rate 
WHO-DD 
World Health Organization Drug Dictionary 
wWOCF 
Windowed worst observation carried forward 


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Statistical Analysis Plan 
 
 
 
 
 
2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analysis and reporting of the 
clinical study 402-C-322 titled “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”. 
 
The structure and content of this SAP provide sufficient detail to meet the requirements 
identified by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials [1].  All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association [2] and the Royal Statistical 
Society [3], for statistical practice. 
The purposes of this SAP are to: 
• 
Outline the types of analyses and presentations of data that will form the basis for 
drawing conclusions to the study objectives and hypotheses outlined in the protocol. 
 
• 
Explain in detail how the data will be handled and analyzed, adhering to commonly 
accepted standards and practices for Good Statistical Practice. 
 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post- 
hoc, or unplanned, exploratory analyses performed will be clearly identified as such in the final 
CSR. 
 
The following documents were reviewed in preparation of this SAP: 
 
• 
Protocol 402-C-322 Amendment 1 issued on 23 September 2012. 
 
• 
Case report forms (CRFs) for Protocol 402-C-322. 
 
• 
ICH Guidance on Statistical Principles for Clinical Trials (E9). 
 
The reader of this SAP is encouraged to also read the clinical study protocol and other identified 
documents for details on the planned conduct of this study. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analyses. 
 
A separate SAP will be written for the analysis of electrocardiogram (ECG) data. 


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Statistical Analysis Plan 
 
 
 
 
 
3. 
STUDY OBJECTIVES 
The primary objective of this study is to evaluate the efficacy of intercostal nerve block using 
liposome bupivacaine compared with placebo in subjects undergoing posterolateral thoracotomy. 
 
The secondary objectives are to evaluate additional efficacy parameters, assess the 
pharmacokinetic (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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Statistical Analysis Plan 
 
 
 
 
 
4. 
STUDY OVERVIEW 
This is a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study in subjects undergoing posterolateral thoracotomy. 
 
After completing screening procedures, eligible subjects 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). 
 
All subjects will be required to remain in the study site for a minimum of 72 hours after the end 
of 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. 
Second Rescue Medication 
For the US sites only, the second rescue medication will be a patient-controlled analgesia (PCA) 
pump 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.  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. 
 
Postsurgical Assessments 
Subjects will be evaluated for pain using the numeric rating scale (NRS) 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. Subjects will also be evaluated for pain with activity 
using the NRS with activity (NRS-A) at baseline, and 24, 48, and 72 hours following surgery and 
on Day 12. 
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. The cardiac assessment (i.e., ECG 


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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. 
The overall benefit of analgesia score (OBAS) questionnaire will be completed at 24, 48, and 72 
hours following surgery. 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.  A 
wound healing assessment will be performed by the physician on Day 12. Predefined, treatment- 
emergent opioid-related adverse events (AEs) will be assessed at 72 hours following surgery. 
Adverse events will be recorded through the Day 30 follow-up contact. 
 
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 surgery. 
 
Unscheduled blood samples also may be collected if a cardiac or neurological event occurs that 
the Investigator believes may be associated with high levels of systemic bupivacaine. 


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5. 
DEFINITIONS 
The terms "study site" and "center" are used interchangeably. 
 
Time 0 is defined as the start time of study drug administration for the PK analyses, and as the 
end time of surgery for the efficacy analyses. 
 
Study day: Day 1 is defined as the day study drug is administered. Positive study days will be 
measured forward in time from Day 1, with Day 2 being the calendar day immediately following 
the day study drug is administered. Day -1 is the calendar day immediately preceding the day 
study drug is administered and negative study days will be measured backward from Day -1. 
 
Study visits and time points will be determined from the scheduled times as reported on the 
electronic CRFs (eCRFs) for the summarization and analysis of data that are shown by time 
point, unless otherwise specified. 


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6. 
ANALYSIS SETS 
The safety analysis set will include all subjects who receive study drug and will be based on 
actual treatment received. 
 
The efficacy analysis set will include all subjects in the safety analysis set and will be based on 
randomized treatment, regardless of actual treatment received. 
 
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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7. 
STATISTICAL METHODS OF ANALYSIS 
 
7.1. 
General Principles 
Descriptive statistics (the number of subjects [n], mean, standard deviation [SD], median, 
minimum, and maximum) will be used to summarize continuous variables. Means and medians 
will be presented to one more decimal place than the recorded data. Standard deviations will be 
presented to two more decimal places than the recorded data.  Minimum and maximum values 
will be presented using the same number of decimal places as the recorded data. Percentages 
will be presented to one decimal place. 
 
In addition, for PK parameters, geometric means and between-subject coefficient of variations 
(%CV) will be presented. 
 
Frequency distributions (number [n] and percentage of subjects [%]) will be used to summarize 
categorical or qualitative variables.  In general, the denominator for the percentage calculation 
will be based upon the total number of subjects in the study population for the treatment groups, 
unless otherwise specified. 
 
All statistical tests will be performed against a two-sided alternative hypothesis with a 
significance level of 5% (α = 0.05), and all confidence intervals (CIs) calculated will be 
two-sided 95% CIs.  All tests will be declared to be statistically significant if the calculated 
p-value is ≤ 0.05 unless specified otherwise.  Tests for binomial proportions will be conducted 
(1) using a normal approximation whenever each classification cell for each group to be 
compared contains expected cell counts of 5 or more subjects, or (2) using an exact method 
whenever any one classification cell for any one group to be compared contains expected cell 
counts of fewer than 5 subjects. 
All analyses will be performed using SAS® software Version 9.2 or later. 
Pharmacokinetic parameters will be derived using noncompartmental methods with WinNonlin 
Professional Version 5.2 or later. 
 
For the listings subjects will be listed under their randomized treatment, regardless of actual 
treatment received.  Subjects who are randomized but do not receive study drug will be included 
in the listings with the treatment group identified as “Liposome bupivacaine 266 mg, Not 
Treated” or “Placebo, Not Treated”, depending on their randomized treatment. 
 
7.1.1. 
Calculation of AUC of NRS 
Area under the curve (AUC) will be calculated using the trapezoidal method with the actual NRS 
pain intensity scores reported by the subject. Missing values will be imputed as described in 
Section 7.1.2.  The time points “Baseline” and “First Rescue” will not be included in the 
calculation of AUC.  However, “First Rescue” might be used for imputation purposes as 


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described in Section 7.1.2.  Time 0 NRS score will be set to a score of 0. Actual times, not 
scheduled times, when available will be used in the calculations. Linear interpolation will be 
used to calculate the pain intensity score at the end of an interval. For 72 hours, as an example, if 
the actual time is prior to 72 hours post-dose then the actual time and the reported score will be 
used.  In addition, the reported score will be carried forward to 72 hours. If the actual time is 
after 72 hours then linear interpolation between the 60-hour and 72-hour scores will be used to 
calculate the score at 72 hours and the time will be set to 72. 
 
7.1.2. 
Imputation of NRS Pain Intensity Scores 
For calculation of AUC of NRS pain intensity scores, the windowed worst observation carried 
forward (wWOCF) and last observation carried forward (LOCF) imputation procedure will be 
used as follows: 
 
a) Windowed worst observation carried forward for rescue medications 
For subjects who take a rescue medication, (either a per-protocol opioid or a non-per protocol 
opioid) or a non-opioid analgesic postsurgically, their NRS scores recorded within the 
window of controlled type of rescue medication (see the table below for the windows for the 
per-protocol rescue medications) will be replaced by the ‘worst’ observation. The worst 
observation will be the highest score in the time interval from Time 0 to up to the time prior 
to taking the first rescue medication.  The NRS score at the first rescue will be included in 
this calculation.  Note that NRS scores in the window that are higher than the worst value 
prior to rescue medication will not be overwritten. If no NRS score is available prior to the 
first rescue the worst observation from all available NRS scores from the subject will be used 
instead. 
 
Medication 
Route 
Window Used to Impute NRS 
Fentanyl 
IV 
6 hours 
Oxycodone 
PO 
6 hours 
Morphine 
IV 
4 hours 
Hydromorphone 
IV 
2 hours 
IV = intravenous; NRS = numeric rating scale; PO = oral. 
If non-per protocol rescue medications are given then the window will be determined post-hoc prior to breaking 
the blind. For non-opioid analgesics the half-life of the analgesic, if known, will be used for the window. 
 
b) Missing scores before the first non-missing score will be replaced by the median score at 
the missing time point from the other subjects in the same treatment group. 
c) Missing scores after the last non-missing score will be replaced by the LOCF. 
d) Missing scores between two non-missing scores will not be replaced (i.e., linear 
interpolation will be used). 


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e) Subjects who have no pain intensity scores recorded after surgery will have the missing 
scores replaced by the median score at each time point from all subjects in the same 
treatment group. 
7.1.3. 
Handling Missing Values 
Surgery Date or Time 
It is expected that all necessary information on surgery (start and stop date and time) and 
postsurgical rescue medication (start dates and times, doses, frequency) will be complete.  Any 
such information that is missing and cannot be obtained through query resolution may be 
imputed, on a case-by-case basis, in a conservative manner that minimizes bias. For example, if 
pain medication taken on Day 1 has no time of administration recorded, the imputed time will be 
the end of surgery. 
 
Rescue Pain Medication 
For calculation of the total rescue pain medication usage (morphine equivalent) through a time 
point, if a subject is discontinued early (e.g., dies, withdraws consent, is withdrawn from the 
study, or is lost to follow-up) before the end of the time interval (e.g., 24 hours after study drug 
administration), his or her total rescue pain medication usage through the time interval will be a 
projected amount.  For example, if a subject discontinues early at 6 hours after surgery, the 
projected amounts through 24 hours will be actual amount + average amount (actual amount/6 
hours) multiplied by the number of hours remaining in the time interval (24-6). 
 
Adverse Event or Concomitant Medications Dates or Times 
For AEs or concomitant medications with missing or partially missing start/stop date/time, the 
following imputation rules will be applied: 
 
For partial start date/time: 
 
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
 
• If the month is unknown, then: 
 
i) 
If the year matches the year of the dose of study drug date, then the month and day 
of the dose of study drug date will be imputed. 
ii) 
Otherwise, ‘January’ will be assigned. 
 
• If the day is unknown, then: 
 
i) 
If the month and year match the month and year of the dose of study drug date, 
then the day of the dose of study drug date will be imputed. 
ii) 
Otherwise, ‘01’ will be assigned. 
 
• If the time is unknown, then: 


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i) 
If the date (day, month, and year) matches the date of the administration of study 
drug, then the time of the dose of study drug time will be imputed. 
ii) 
Otherwise, “00’ will be assigned. 
For partial stop date/time: 
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
 
• If the month is unknown, then ‘December’ will be assigned. 
 
• If the day is unknown, then the last day of the month will be assigned. 
 
• If the time is unknown, then the last time of the day will be assigned (23:59). 
 
If the above rules for stop dates result in an illogical date with regards to the dates the subject is in 
the study, then the stop date will be replaced with the subject’s date of completion/withdrawal. 
Further, should the above rules not result in the most conservative date, then the imputed value 
may be replaced by a date that will lead to a more conservative analysis. Should this situation 
arise, specific details will be provided in the derived dataset specification documentation or 
documented in the derived analysis data set program using comments. 
 
Adverse Event Severity or Relationship to Study Drug 
If severity of an AE is not reported, then for tables of AEs by severity, the event will be classified 
as ‘Severe’.  If relationship to study drug is not reported for an AE, then for tables of study-drug 
related AEs, the event will be classified as related. 
 
Time to Event 
For calculating time to an event when only the hour, and not the minutes, is reported for the time 
of the event, then the minutes will be set to zero. 
 
7.1.4. 
Multiplicity Adjustments 
Since no multiple comparisons of the primary efficacy variable will be made, no alpha- 
adjustments will be made. 
 
Also, since there is only one primary efficacy variable and all other efficacy variables are 
considered secondary, no alpha-adjustments for the primary response variable will be made. 
 
There are two secondary efficacy variables that will be analyzed using a hierarchical fixed- 
sequence stepwise testing procedure (see Section 7.6.1). 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. 


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7.1.5. 
By-Center Analyses 
Up to 30 sites/centers in the US and Europe will enroll subjects in this study. The primary 
efficacy results will be summarized by site and region (US and Europe) but site will not be 
included in any models. Region will be included in the models. 
 
7.2. 
Subject Disposition 
The number and percentage of subjects who are in each analysis set, who completed the study, 
and who discontinued early from the study, along with reasons for early withdrawal, will be 
summarized by treatment group and for all subjects. In addition, the same summary will be 
produced by site and region. 
 
7.3. 
Description of Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and for all 
subjects for the safety analysis set.  The variables to be included in the summary are age, gender, 
ethnicity, race, American Society of Anesthesiologists (ASA) physical status class, height (cm), 
and weight (kg). 
 
Conversions between units for height and weight will use the following formulas: 
Weight (kg) = weight (lb) / 2.2046226 
Height (cm) = height (in) / 2.54. 
 
If any subjects are randomized to the liposome bupivacaine group and receive placebo or any 
subjects are randomized to the placebo group and receive liposome bupivacaine then a similar 
table will be created using the efficacy analysis set. 
 
7.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD) and will be classified according to the default anatomical therapeutic 
chemical (ATC) classification system code and preferred term. 
 
Prior medications are defined as medications with a stop date/time prior to study drug 
administration.  Concomitant medications are defined as medications taken after the start of 
study drug administration (i.e., started prior to the start of study drug administration and 
continued after or started after the start of study drug administration). 
 
Prior and concomitant medications will be summarized using n (%) of subjects by treatment 
group and for all subjects and by ATC class and preferred term for the safety analysis set. 
Subjects may have more than one medication per ATC category and preferred term. At each 
level of subject summarization, a subject will be counted once if he/she reports one or more 
medications at that level. 


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The tables of concomitant medications will not include protocol-specified rescue pain 
medications. 
 
7.5. 
Measurements of Treatment Compliance 
Study drug administration will be summarized by treatment group for the safety analysis set. The 
variables to be included are duration of injection and volume of study drug administered. 
Surgery will be summarized by treatment group for the efficacy analysis set.  The variables to be 
included in the summary are length of surgery (end time minus start time, in minutes), level of 
index nerve injected, length of time in the Intensive Care Unit (ICU) (hours), and number and 
percentage of subjects with at least one chest tube and length of time from end of surgery to 
removal of last chest tube, for subjects who have a chest tube inserted. 
 
7.6. 
Efficacy Analysis 
All summaries of the efficacy variables will use the efficacy analysis set, which will be based on 
randomized treatment. 
 
7.6.1. 
Efficacy Variables 
The primary efficacy variable is the AUC of the NRS-R pain intensity scores through 72 hours. 
The secondary efficacy variables are: 
• Total postsurgical opioid consumption (in mg) through 72 hours. 
• Time to first opioid rescue. 
 
The tertiary efficacy variables are (the order of these variables has been changed from the order 
in the protocol to reflect how they will be discussed in the CSR): 
 
• 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. 
• Total postsurgical opioid consumption (in mg) through 24, 36, 48, and 60 hours. 
• 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. 
• Overall benefit of analgesia score questionnaire at 24, 48, and 72 hours. 


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• Subject satisfaction with postsurgical pain control at 72 hours, Day 12, and Day 30. 
• Time to sensitivity to cold (listed in the protocol as “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”). 
• Incidence of predefined treatment-emergent opioid-related AEs (ORAEs) (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. 
 
7.6.2. 
Methods of Analysis 
7.6.2.1 Primary Efficacy Variable 
 
The primary efficacy variable is the AUC of the NRS-R pain intensity scores through 72 hours 
calculated using the wWOCF + LOCF imputation method described in Section 7.1.2. 
 
Liposome bupivacaine will be compared to placebo using analysis of covariance (ANCOVA) 
with treatment and region (US and Europe) as main effects and the baseline NRS-R pain 
intensity score as a covariate.  Based on the model, the least squares (LS) means, LS mean 
difference between the two treatment groups, 95% CI for the LS mean difference(s) between 
liposome bupivacaine and placebo, and p-value will be reported. 
 
Descriptive statistics of the primary efficacy variable will also be shown by region and site. 
 
7.6.2.2 Secondary Efficacy Variables 
 
The secondary efficacy variables for this study are: 
 
• Total postsurgical opioid consumption through 72 hours. 
 
• Time to first opioid rescue. 
 
For total postsurgical opioid consumption, opioid medications will be converted to a morphine 
equivalent amount (see the table below). The converted amounts will be totaled for each subject 
and used in the analysis.  Projected amounts, for subjects who discontinue early, will be 
calculated as described in Section 7.1.3. 


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Medication 
Unit 
Route 
Conversion (Multiplication) 
Factor 
Fentanyl 
mcg 
IV 
0.1 
Oxycodone 
mg 
PO 
0.5 
Morphine 
mg 
IV or IM 
1 
Hydromorphone 
mg 
IV 
6.7 
IV = intravenous; PO = oral. 
If any other opioids are administered, then the conversion factor will be determined post-hoc prior to breaking 
the blind. 
 
Prior to analysis, the natural logarithm transformation will be applied to the total amount. When 
total amount of opioids used is 0, the result will be changed to the lesser of 1 or 0.5 of the 
smallest total amount observed in the study prior to being transformed with the natural logarithm. 
To test for significant differences between liposome bupivacaine and placebo, an analysis of 
variance (ANOVA) with treatment and region (US and Europe) as main effects will be used. 
Based on the model, the geometric LS means, geometric LS mean ratio of liposome bupivacaine 
to placebo, 95% CI for the geometric LS mean ratio of liposome bupivacaine to placebo, and p- 
value will be reported. 
 
For the analysis of time to first opioid rescue, time to first opioid rescue will be computed in 
hours as the date/time of the first opioid rescue minus the date/time of the end of surgery. If a 
subject is not administered an opioid, the time to first administration will be censored at 72 hours 
after surgery or at the time of last follow-up, whichever is earliest. Time of last follow-up will be 
defined as the later of (1) the last pain assessment, (2) the start time of the last rescue or 
concomitant medication, or (3) the start time of the last AE. 
 
Time to first opioid rescue will be analyzed by the Kaplan-Meier method. The n (%) of subjects 
administered an opioid as well as the n (%) of censored observations will be presented for each 
treatment group.  In addition, Kaplan-Meier estimates in terms of the median and its 95% CI, and 
the 25th and 75th percentiles will be presented for each treatment. A Log-rank test with region 
(US and Europe) as a stratifying variable will be used to compare liposome bupivacaine to 
placebo. 
 
The secondary 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. 


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7.6.2.3 Tertiary Efficacy Variables 
 
The following describes the statistical analyses to be performed. 
 
NRS-R, NRS-A, and AUC of the NRS-R Pain Intensity Scores 
 
For the tertiary efficacy variables NRS-R, NRS-A, and the AUC of the NRS-R pain intensity 
scores, the same analyses as those for the primary efficacy variable will be performed, except that 
the baseline NRS-A score will be used as the covariate for all variables using the NRS-A. 
 
Proportion of Subjects Who are Pain Free 
 
‘Pain free’ is defined as an NRS-R pain intensity score of 0 or 1. The number and percentage of 
subjects who are pain free will be summarized by treatment group for each time point. A chi- 
square test will be used to compare liposome bupivacaine to placebo. 
 
Total Postsurgical Opioid Consumption Through 24, 36, 48, and 60 Hours 
 
For the tertiary efficacy variable of total opioid consumption through each of the time periods, 
the same analysis as that for the secondary efficacy variable of total opioid consumption through 
72 hours will be performed. 
 
Subjects Who Receive Rescue Medication 
 
The category of ‘Subjects who received no rescue medication’ is defined as subjects who did not 
receive any medication reported on the three Rescue Medication eCRFs. 
 
The category of ‘Subjects who only received IV fentanyl as a rescue medication’ is defined as 
subjects who received IV fentanyl based on the First Rescue Medication eCRF and did not 
receive any medication based on all of the Second Rescue Medication eCRFs. 
 
The category of ‘Subjects who received IV fentanyl and a second opioid medication’ is defined 
as subjects who received IV fentanyl based on the First Rescue Medication eCRF and who either 
received a medication based on any of the Second Rescue Medication eCRFs or reported an 
opioid on the Concomitant Medications eCRF (with a start date within 72 hours of the end of 
surgery). 
 
The number and percentage of subjects who are in each of the above categories will be 
summarized by treatment group. A chi-square test will be used to compare liposome bupivacaine 
to placebo for each of the categories. 
 
Overall Benefit of Analgesia Score Questionnaire 
 
The OBAS is calculated as follows: 


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1. Add all of the scores of questions one to six. 
2. To this number, add four. 
3. Subtract the score of question seven from this number. 
 
Summary statistics will be provided by treatment group at each time point. A Wilcoxon Rank 
Sum test will be used to compare liposome bupivacaine to placebo. 
 
Subject Satisfaction with Postsurgical Pain Control 
 
Subjects will rate their satisfaction with postsurgical pain control as ‘Extremely dissatisfied’, 
‘Dissatisfied’, ‘Neither satisfied nor dissatisfied’, ‘Satisfied’, or ‘Extremely satisfied’ at 72 hours 
and on Day 30.  The categories will be summarized by treatment group at each time point. 
A Wilcoxon Rank Sum test will be used to compare liposome bupivacaine to placebo. 
 
Time to Sensitivity to Cold 
 
Once a subject reports sensitivity to cold on two consecutive evaluations the subject will no 
longer be tested.  The time to sensitivity to cold will be defined as the time of the first of two 
consecutive evaluations when the subject reports sensitivity to cold.  Time to sensitivity to cold 
will be calculated from the end of surgery. If a subject never reports sensitivity to cold or never 
reports sensitivity to cold on two consecutive evaluations then the time will be censored at 72 
hours after the end of surgery or at the time of the last follow-up, whichever is earliest. Time of 
last follow-up will be defined as the later of (1) the last pain assessment, (2) the start time of the 
last rescue or concomitant medication, or (3) the start time of the last AE. 
 
Time to sensitivity to cold will be analyzed by the Kaplan-Meier method. The n (%) of subjects 
with sensitivity to cold as well as the n (%) of censored observations will be presented for each 
treatment group.  In addition, Kaplan-Meier estimates in terms of the median and its 95% CI, and 
the 25th and 75th percentiles will be presented for each treatment group.  A log-rank test will be 
used to compare liposome bupivacaine to placebo. 
 
Incidence of Predefined Treatment-Emergent Opioid-Related Adverse Events 
 
The determination of whether a subject had a treatment-emergent ORAE will be based solely on 
responses on the Predefined Treatment-Emergent ORAEs eCRF. The number and percentage of 
subjects who have at least one ORAE will be summarized by treatment group. A chi-square test 
will be used to compare liposome bupivacaine to placebo. 
 
The number and percentage of subjects who have each of the individual ORAEs will also be 
summarized by treatment group, although no statistical tests will be performed. 


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7.7. 
Pharmacokinetic Analyses 
7.7.1. 
Pharmacokinetic Parameter Calculation Methods 
Pharmacokinetic parameters will be calculated by noncompartmental analysis method from 
concentration-time data using WinNonlin Professional following these guidelines: 
 
• Actual sampling times relative to study drug administration will be used for all 
calculations of the PK parameters.  If there is any doubt as to the actual time a sample 
was taken, then the scheduled time will be used. Descriptive statistics will be used to 
summarize the PK parameters. 
• There will be no imputation of missing data. 
 
For the calculation of AUCs from PK concentrations, concentration below the limit of 
quantification (BLOQ) will be handled as follows: 
 
• Pre-dose values will be set to zero. 
• All remaining BLOQ values will be set to missing. 
 
Pharmacokinetic parameters will be estimated according to the following guidelines: 
 
• The maximum observed plasma concentration (Cmax) will be obtained directly from the 
concentration-time data. 
• Time to maximum concentration (Tmax) is the time at which Cmax is observed. 
• The apparent terminal elimination rate constant (λZ) will be estimated at terminal phase by 
linear regression after log-transformation of the concentrations: 
• Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression. 
• A minimum number of three data points in the terminal phase will be used in calculating 
λz with the line of regression starting at any post-Cmax data point (Cmax should not be part 
of the regression slope) and including the last observed quantifiable concentration (C(t)) 
and the time to last quantifiable concentration (tlast). 
• The adjusted correlation coefficient (R2 adjusted) in general should be greater than 0.90. 
Any value less than 0.90 may be used at the pharmacokineticist's best knowledge and 
judgment. 
• An appropriate number of decimal places should be used for λz to enable the reported 
value of half-life (t½) to be calculated. 
• Half-life (t1/2) will be calculated as ln2/λZ. 


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t
 
• The AUC will be calculated as follows: 
• The linear trapezoidal method will be employed for all incremental trapezoids arising 
from increasing concentrations and the logarithmic trapezoidal method will be used for 
those arising from decreasing concentrations. 
• 
AUC(0-t) = 0  C(t )dt . 
 
t 
 
• AUC(0-inf) = 0  C(t )dt ＋ t C ( t )dt = AUC(0-t)＋Ct/λz. 
• C(t) is last observed quantifiable concentration. 
 
7.7.2. 
Pharmacokinetic Concentrations and Variables 
The analysis of the PK data will be based on the PK analysis set. Only data from the subjects in 
the liposome bupivacaine treatment group will be presented in the summary tables and listings. 
 
Bupivacaine plasma concentrations will be listed by subject, nominal time, and actual time. 
Concentrations that are BLOQ will be indicated by BLOQ in this listing. 
 
Plasma concentrations will be summarized at each time point. The following descriptive 
statistics will be presented for plasma concentrations obtained at each nominal time point: n, 
geometric mean, arithmetic mean, SD, %CV, minimum, median, and maximum. 
 
Pharmacokinetic parameters will be summarized. Descriptive statistics for calculated PK 
parameters will include: n, arithmetic mean, SD, %CV, geometric mean, median, minimum and 
maximum values.  Geometric mean will not be presented for Tmax. Values of %AUC 
extrapolated > 20% will be flagged in the listings. 
 
Individual plasma concentration versus actual times will be plotted in linear and semi- 
logarithmic scale. 
 
7.8. 
Safety Analyses. 
All summaries of the safety data will use the safety analysis set. 
 
7.8.1. 
Adverse Events 
All AEs will be coded and summarized by system organ class (SOC) and preferred term based on 
the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary. 
 
An AE will be considered treatment-emergent if the onset is any time on or after study drug 
administration through Day 30. 
 
Only treatment-emergent AEs (TEAEs) that were not solicited from the Neurological 
Assessment or from the Opioid-Related Adverse Event Questionnaire will be summarized in the 
tables. All other AEs, those that occur after randomization but prior to study drug 


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administration, AEs that occur after Day 30, or AEs that were solicited from the Neurological 
Assessment or from the Opioid-Related Adverse Event Questionnaire will appear in listings only. 
 
Treatment-emergent AEs will be summarized [n (%)] and grouped by SOC and preferred term 
for each treatment group and for all subjects. If a subject experiences more than one episode of a 
particular TEAE, the subject will be counted only once for that event at each level of 
summarization (overall, by SOC, and by preferred term). 
 
Similarly, TEAEs will be summarized in terms of maximum severity (‘Mild’, ‘Moderate’, and 
‘Severe’), study drug-related TEAEs, and serious AEs. 
 
7.8.2. 
Laboratory Parameters 
Not applicable. 
 
7.8.3. 
Vital Signs 
Descriptive summaries of actual value and changes from Baseline will be calculated for systolic 
blood pressure, diastolic blood pressure, and heart rate. 
 
7.8.4. 
Other Safety Parameters 
Neurological Assessments 
The proportion of subjects who are oriented will be summarized by treatment group at each time 
point.  Subjects who were ‘not assessable’ will not be included in the calculation of the 
proportion.  The proportion of subjects who have at least one of the neurological events and the 
proportion of subjects who have each of the neurologic events will be summarized by treatment 
group. 
 
Physician’s Satisfaction with Wound Healing 
 
The physician’s satisfaction with wound healing will be assessed as ‘Extremely dissatisfied’, 
‘Dissatisfied’, ‘Neither satisfied nor dissatisfied’, ‘Satisfied’, or ‘Extremely satisfied’ on Day 30. 
The categories will be summarized by treatment group at each time point. A Wilcoxon Rank 
Sum test will be used to compare liposome bupivacaine to placebo. 
 
7.9. 
Interim Analysis 
No interim analyses are planned. 


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8. 
SAMPLE SIZE CALCULATIONS 
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 (SD) 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 SD is 104, when the sample size in each 
group is 90. 


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9. 
REFERENCES 
1. US Federal Register. International Conference on Harmonisation; Guidance on Statistical 
Principles for Clinical Trials. Department of Health and Human Services: Food and Drug 
Administration [Docket No. 97D-0174].  Federal Register Volume 63, Number 179, 
pages 49583-49598.  16 September 1998. 
 
2. American Statistical Association.  Ethical Guidelines for Statistical Practice. Prepared by 
the Committee on Professional Ethics, 07 August 1999. 
http://www.amstat.org/profession/ethicalstatistics.html 
 
3. Royal Statistical Society.  The Royal Statistical Society: Code of Conduct, August 1993. 
http://www.rss.org.uk/about/conduct.html. 


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10. 
LAYOUT OF TABLES, LISTINGS, AND FIGURES 
The following are planned summary tables for Protocol 402-C-322. Tables will be numbered 
according to the nomenclature used to support the CSR. The final table numbering may be 
different from the SAP.  No amendment will be made for changes in table numbering. All 
headers, titles, footnotes, and footers specified in the table templates will be displayed in the 
produced output unless otherwise specified. Notes to programmers will not be included in the 
tables. There will be a footnote in all tables that includes the program name, SAS version 
number, and the date that the output was produced. 
 
 
 
Planned Tables 
 
Table 
Number 
Table Title 
14.1.1.1 
Subject Disposition 
(All Subjects) 
14.1.1.2 
Subject Disposition by Region and Site 
(All Subjects) 
14.1.2 
Demographic and Baseline Characteristics 
(Safety Analysis Set) 
14.1.3.1 
Prior Medications 
(Safety Analysis Set) 
14.1.3.2 
Concomitant Medications 
(Safety Analysis Set) 
14.2.1.1 
Study Drug Administration 
(SafetyAnalysis Set) 
14.2.1.2 
Surgery 
(Efficacy Analysis Set) 
14.2.2.1.1 
AUC of NRS-R Pain Intensity Scores Through 72 Hours 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
14.2.2.1.2 
AUC of NRS-R Pain Intensity Scores Through 72 Hours by Region and 
Site 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
14.2.2.2 
Total Postoperative Consumption (mg) of Opioid Rescue Pain Medication 
Through 72 Hours 
(Efficacy Analysis Set) 


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Planned Tables Continued 
 
Table 
Number 
Table Title 
14.2.2.3.2 
Time to First Opioid Rescue 
(Efficacy Analysis Set) 
14.2.2.4 
NRS-R Pain Intensity Scores 
(Efficacy Analysis Set) 
14.2.2.5 
NRS-A Pain Intensity Scores 
(Efficacy Analysis Set) 
14.2.2.6 
AUC of NRS-R Pain Intensity Scores Through 24, 36, 48, and 60 Hours 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
14.2.2.7 
AUC of NRS-R Pain Intensity Scores 24-48 and 48-72 Hours 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
14.2.2.8 
Percentage of Subjects who are Pain Free at Each Time Point 
(Efficacy Analysis Set) 
14.2.2.9 
Total Postoperative Consumption (mg) of Opioid Rescue Pain Medication 
Through 24, 36, 48, and 60 Hours 
(Efficacy Analysis Set) 
14.2.2.10 
Subjects who Received Rescue Medication Through 72 Hours 
(Efficacy Analysis Set) 
14.2.2.11 
Overall Benefit of Analgesia Score Questionnaire (Total Scores) 
(Efficacy Analysis Set) 
14.2.2.12 
Subject Satisfaction with Postsurgical Pain Control 
(Efficacy Analysis Set) 
14.2.2.13 
Time to Sensitivity to Cold 
(Efficacy Analysis Set) 
14.2.2.14 
Incidence of Predefined Treatment-Emergent Opioid-Related Adverse 
Events 
(Efficacy Analysis Set) 
14.2.3.1 
Bupivacaine Plasma Concentrations (ng/mL) 
Study Part 1 
(PK Analysis Set) 
14.2.3.2 
Bupivacaine Plasma Pharmacokinetic Parameters 
Study Part 1 
(PK Analysis Set) 
14.3.1.1 
Overview of Treatment-Emergent Adverse Events 
(Safety Analysis Set) 
14.3.1.2 
Incidence of Treatment-Emergent Adverse Events 
(Safety Analysis Set) 
14.3.1.3 
Incidence of Study Drug Related Treatment-Emergent Adverse Events 
(Safety Analysis Set) 


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Planned Tables Continued 
 
Table 
Number 
Table Title 
14.3.1.4 
Incidence of Treatment-Emergent Adverse Events by Severity 
(Safety Analysis Set) 
14.3.1.5 
Incidence of Serious Treatment-Emergent Adverse Events 
(Safety Analysis Set) 
14.3.2.1 
Vital Signs 
(Safety Analysis Set) 
14.3.2.2 
Vital Signs Change from Baseline 
(Safety Analysis Set) 
14.3.3 
Neurological Assessment 
(Safety Analysis Set) 
14.3.4 
Physician Satisfaction with Wound Healing 
(Safety Analysis Set) 


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Planned Listings 
 
Listing 
Number 
Listing Title 
16.1.1 
Eligibility 
16.1.2 
Unblinding 
16.1.3 
Subject Populations and Discontinuations 
16.1.4 
Hospital Discharge 
16.2 
Demographics and Baseline Characteristics 
16.3.1 
Medical History 
16.3.2 
Physical Examination 
16.3.3 
Electrocardiogram Recording (Holter Monitoring) 
16.3.4 
Prior and Concomitant Medications (Except for Protocol-Defined Rescue 
Pain Medications) 
16.4.1 
Study Drug Exposure 
16.4.2 
Surgery 
16.4.3 
Intensive Care Unit and Chest Tube Removal 
16.5.1.1 
Pain Intensity Scores at Rest and with Activity 
16.5.1.2 
AUC of NRS-R Pain Intensity Scores 
wWOCF + LOCF Imputation for the Pain Scores 
16.5.2 
Postoperative Consumption of Opioid Rescue Pain Medication 
16.5.3 
Overall Benefit of Analgesia Score Questionnaire 
16.5.4 
Subject Satisfaction with Postsurgical Pain Control 
16.5.5 
Sensitivity to Cold 
16.5.6 
Predefined Treatment-Emergent Opioid-Related Adverse Events at 
72 Hours 
16.6.1 
Scheduled Bupivacaine Plasma Concentrations 
16.6.2 
Bupivacaine Plasma Pharmacokinetic Parameters 
16.6.3 
Unscheduled Bupivacaine Plasma Concentrations 
16.7.1.1 
Adverse Events (Part 1 of 2) 
16.7.1.2 
Adverse Events (Part 2 of 2) 
16.7.1.3 
Serious Adverse Events (Part 1 of 2) 
16.7.1.4 
Serious Adverse Events (Part 2 of 2) 
16.7.1.5 
Deaths 
16.8 
Height, Weight, and Vital Signs 
16.9 
Neurological Assessment 
16.10 
Physician’s Satisfaction with Wound Healing 


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Table 14.1.1.1 (Page x of Y) 
Subject Disposition 
(All Subjects) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
(N=XX) 
  
n (%)  
(N=XX) 
n (%)  
(N=XX) 
n (%)  
 
 
Safety Analysis Set [1] 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Efficacy Analysis Set [2] 
PK Analysis Set [3] 
00 (00.0) 
00 (00.0) 
NA 
00 (00.0) 
Subjects Who Completed the Study 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Subjects Who Terminated Early 
Reason for Early Termination 
Subject Death 
00 (00.0) 
00 (00.0) 
00 (00.0) 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Adverse Event 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Lack of Efficacy 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Lost to Follow-up 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Withdrawal by Subject 
00 (00.0) 
00 (00.0) 
00 (00.0) 
  
Other  
00 (00.0)  
00 (00.0)  
00 (00.0)  
 
LB = liposome bupivacaine; PK = pharmacokinetic. 
[1] The safety analysis set includes all subjects who received study drug and is based on actual treatment received. 
[2] The efficacy analysis set includes all subjects in the safety analysis set and is based on randomized treatment. 
[3] The PK analysis set includes all subjects in the safety analysis set who received liposome bupivacaine and provided sufficient samples to allow for 
calculation of the PK parameters required for analysis. 
 
Reference: Listing 16.1.3. 


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Table 14.1.1.2 (Page x of Y) 
Subject Disposition by Region and Site 
(All Subjects) 
 
LB 
All 
266 mg 
Placebo 
Subjects 
(N=XX) 
(N=XX) 
(N=XX) 
Region 
Site 
  
n (%)  
n (%)  
n (%)  
 
US 
All Sites 
Safety Analysis Set [1] 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Efficacy Analysis Set [2] 
PK Analysis Set [3] 
00 (00.0) 
00 (00.0) 
NA 
00 (00.0) 
Subjects Who Completed the Study 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Subjects Who Terminated Early 
Reason for Early Termination 
Subject Death 
00 (00.0) 
00 (00.0) 
00 (00.0) 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Adverse Event 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Lack of Efficacy 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Lost to Follow-up 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Withdrawal by Subject 
00 (00.0) 
00 (00.0) 
00 (00.0) 
  
Etc  
Other 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
LB = liposome bupivacaine; PK = pharmacokinetic. 
[1] The safety analysis set includes all subjects who received study drug and is based on actual treatment received. 
[2] The efficacy analysis set includes all subjects in the safety analysis set and is based on randomized treatment. 
[3] The PK analysis set includes all subjects in the safety analysis set who received liposome bupivacaine and provided sufficient samples to allow for 
calculation of the PK parameters required for analysis. 
 
Reference: Listing 16.1.3. 


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Table 14.1.2 (Page x of Y) 
Demographic and Baseline Characteristics 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
  
(N=XX) 
(N=XX) 
(N=XX)  
 
Age (years) 
 
N 
00 
00 
00 
Mean 
00.0 
00.0 
00.0 
SD 
00.00 
00.00 
00.00 
Median 
00 
00 
00 
Minimum, Maximum 
00, 00 
00, 00 
00, 00 
Age Category 
 
<65 
00 (00.0) 
00 (00.0) 
00 (00.0) 
>=65 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
Gender 
Male 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Female 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Ethnic Group 
 
Hispanic or Latino 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Not Hispanic or Latino 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Race [1] 
 
American Indian/Alaskan Native 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Asian 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Black or African American 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Native Hawaiian/Other Pacific Islander 
00 (00.0) 
00 (00.0) 
00 (00.0) 
White 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Other 
LB = liposome bupivacaine. 
[1] Subjects may be counted in more than one category. 
Reference: Listing 16.2. 


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Table 14.1.2 (Page x of Y) 
Demographic and Baseline Characteristics 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
  
(N=XX) 
(N=XX) 
(N=XX)  
 
ASA Class 
 
1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
3 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
Height (cm) 
 
n 
00 
00 
00 
Mean 
00.0 
00.0 
00.0 
SD 
00.00 
00.00 
00.00 
Median 
00 
00 
00 
Minimum, Maximum 
00, 00 
00, 00 
00, 00 
 
Weight (kg) 
 
n 
00 
00 
00 
Mean 
00.0 
00.0 
00.0 
SD 
00.00 
00.00 
00.00 
Median 
00 
00 
00 
Minimum, Maximum 
00, 00 
00, 00 
00, 00 
ASA = American Society of Anesthesiologists; LB = liposome bupivacaine. 
[1] Subjects may be counted in more than one category. 
 
Reference: Listing 16.2. 


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Table 14.1.3.1 (Page x of Y) 
Prior Medications 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
ATC Class 
  
WHO-DD Preferred Term  
(N=XX) 
n (%)  
(N=XX) 
n (%)  
(N=XX) 
n (%)  
 
Any Prior Medication 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
ATC Class 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
…. 
 
ATC Class 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 3 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 4 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Etc. 
 
ATC = Anatomical Therapeutic Chemical classification system; LB = liposome bupivacaine; WHO-DD = World Health Organization Drug 
Dictionary 
Note: Prior medications are defined as medication with a stop date/time prior to study drug administration. 
At each level of summation (overall, ATC class, and preferred term), subjects are only counted once. 
 
Reference: Listing 16.3.4. 


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Table 14.1.3.2 (Page x of Y) 
Concomitant Medications 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
ATC Class 
  
WHO-DD Preferred Term  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
 
Any Prior Medication 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
ATC Class 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
…. 
 
ATC Class 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 3 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 4 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Etc. 
 
ATC = Anatomical Therapeutic Chemical classification system; LB = liposome bupivacaine; WHO-DD = World Health Organization Drug 
Dictionary. 
Note: Concomitant medications are defined as medications (other than rescue pain medication) taken on or after the start of study drug 
administration. This table does not include rescue pain medications. 
At each level of summation (overall, ATC class, and preferred term), subjects are only counted once. 
Reference: Listing 16.3.4. 


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Table 14.2.1.1 (Page x of Y) 
Study Drug Administration 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
  
(N=XX) 
(N=XX)  
 
Duration of Injection (min) 
n 
Mean 
SD 
Median 
Minimum, Maximum 
 
00 
00.0 
00.00 
00 
00, 00 
 
00 
00.0 
00.00 
00 
00, 00 
 
Volume of Study Drug Administered (mL) 
n 
Mean 
SD 
Median 
Minimum, Maximum 
LB = liposome bupivacaine. 
 
Reference: Listing 16.4.1. 
 
00 
00.0 
00.00 
00 
00, 00 
 
00 
00.0 
00.00 
00 
00, 00 


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Table 14.2.1.2 (Page x of Y) 
Surgery 
(Efficacy Analysis Set) 
 
LB 
266 mg 
Placebo 
  
(N=XX) 
(N=XX)  
 
Duration of Surgery (min) 
n 
Mean 
SD 
Median 
Minimum, Maximum 
 
00 
00.0 
00.00 
00 
00, 00 
 
00 
00.0 
00.00 
00 
00, 00 
 
Level of Index Nerve Injected 
T3 
T4 
Etc. 
 
00 (00.0) 
00 (00.0) 
 
00 (00.0) 
00 (00.0) 
 
Location of Index Nerve Injected 
Left 
Right 
 
00 (00.0) 
00 (00.0) 
 
00 (00.0) 
00 (00.0) 
 
 
At Least One Chest Tube Inserted 
Yes 
No 
 
 
00 (00.0) 
00 (00.0) 
 
 
00 (00.0) 
00 (00.0) 
 
Time With Chest Tube(s) Inserted (min) [1] 
n 
Mean 
SD 
Median 
Minimum, Maximum 
 
00 
00.00 
00.000 
00.00 
00.0, 00.0 
 
00 
00.00 
00.000 
00.00 
00.0, 00.0 
 
Time in ICU (hours) 


Pacira Pharmaceuticals, Inc. 
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n 
Mean 
SD 
Median 
Minimum, Maximum 
ICU = Intensive Care Unit; LB = liposome bupivacaine. 
00 
00.0 
00.00 
00 
00, 00 
00 
00.0 
00.00 
00 
00, 00 
[1] Since end of surgery. Only includes subjects who had at least one chest tube inserted. 
Reference: Listing 16.4.2 and 16.4.3. 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
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Table 14.2.2.1.1 (Page x of Y) 
AUC of NRS-R Pain Intensity Scores Through 72 Hours 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
 
LB 
266 mg 
Placebo 
  Statistics 
(N=XX) 
(N=XX)  
 
n 
Mean 
SD 
Median 
Minimum, Maximum 
00 
000.0 
00.00 
0000 
000, 000 
00 
000.0 
00.00 
0000 
000, 000 
 
LSM (Standard Error) [1] 
LSM Difference (Standard Error) [2] 
95% CI for Difference [2] 
P-value [2] 
00.0 (00.00) 
00.0 (00.00) 
00.0, 00.0 
0.0000 
00.0 (00.00) 
 
AUC = area under the curve calculated using the trapezoidal method; CI = confidence interval; LB = liposome bupivacaine; LSM = least 
squares mean; NRS-R = numeric rating scale at rest. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 
wWOCF + LOCF = imputation using the worst observation carried forward prior to the use of rescue medication within a medication window 
and last observation carried forward for missing values. 
[1] From an analysis of covariance with treatment and region (US and Europe) as main effects and the baseline NRS-R pain intensity score 
as a covariate. 
[2] Difference from placebo. 
 
Reference: Listings 16.5.1.1 and 16.5.1.2. 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
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Table 14.2.2.1.2 (Page x of Y) 
AUC of NRS-R Pain Intensity Scores Through 72 Hours by Region and Site 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
 
Region 
Site 
Statistics 
LB 
266 mg 
(N=XX) 
Placebo 
(N=XX) 
US 
All Sites 
n 
00 
00 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
Etc. 
Etc. 
 
AUC = area under the curve calculated using the trapezoidal method; CI = confidence interval; LB = liposome bupivacaine; LSM = least 
squares mean; NRS-R = numeric rating scale at rest. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 
wWOCF + LOCF = imputation using the worst observation carried forward prior to the use of rescue medication within a medication window 
and last observation carried forward for missing values. 
 
Reference: Listings 16.5.1.1 and 16.5.1.2. 


Pacira Pharmaceuticals, Inc. 
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Table 14.2.2.2 (Page x of Y) 
Total Postoperative Consumption (mg) of Opioid Rescue Pain Medication Through 72 Hours 
(Efficacy Analysis Set) 
 
 
Statistics 
LB 
266 mg 
Placebo 
  
(N=XX) 
(N=XX)  
 
n 
Mean 
Geometric Mean 
SD 
Median 
Minimum, Maximum 
00 
00.00 
00.00 
00.000 
00.00 
00.0, 00.0 
00 
00.00 
00.00 
00.000 
00.00 
00.0, 00.0 
 
Geometric LSM [1] 
Geometric LSM Ratio [2] 
95% CI for Ratio [2] 
   P-value [2]  
00.00 
00.00 
00.00, 00.00 
0.0000  
00.00 
 
CI = confidence interval; LB = liposome bupivacaine; LSM = least squares mean. 
If the total amount of opioid used was 0 mg, the value was set to the lesser of 1 mg or one half of the smallest total amount observed 
in the study prior to being transformed by the natural logarithm. 
[1] From an analysis of variance with treatment and region (US and Europe) as main effects on natural log transformed 
opioid amount. Results are presented in the original, non-transformed scale. 
[2] Geometric LSM Ratio is the anti-log LSM difference (LB/placebo). 
Reference: Listing 16.5.2. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.2.2.3 (Page x of Y) 
Time to First Opioid Rescue 
(Efficacy Analysis Set) 
 
LB 
266 mg 
Placebo 
(N=XX) 
(N=XX) 
 
 
Subjects Administered an Opioid Rescue [n (%)] 
00 (00.00) 
00 (00.00) 
Censored Observations [n (%)] 
00 (00.00) 
00 (00.00) 
 
Quartiles (hours) [1] 
First Quartile (25% Administered an Opioid) 
000 
000 
Median (50% Administered an Opioid) 
000 
000 
Third Quartile (75% Administered an Opioid) 
000 
000 
Minimum,  Maximum 
00, 00* 
00, 00* 
95% CI of Median 
(000, 000) 
(000, 000) 
 
P-value [2] 
0.0000 
 
 
* indicates a censored observation. 
CI = confidence interval; LB = liposome bupivacaine. 
[1] Kaplan-Meier estimates. 
[2] Log-rank test with region (US and Europe) as a stratifying variable. 
Reference: Listing 16.5.2. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.2.2.4 (Page x of Y) 
NRS-R Pain Intensity Scores 
(Efficacy Analysis Set) 
LB 
266 mg 
Placebo 
Time Point 
Statistics 
(N=XX) 
(N=XX) 
Baseline 
n 
00 
00 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
First Request 
n 
00 
00 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
LSM (Standard Error) [1] 
00.0 (00.00) 
00.0 (00.00) 
LSM Difference (Standard Error) [2] 
00.0 (00.00) 
95% CI for Difference [2] 
00.0, 00.0 
P-value [2] 
0.0000 
2 Hours 
n 
00 
00 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Etc. 
Minimum, Maximum 
000, 000 
000, 000 
CI = confidence interval; LB = liposome bupivacaine; LSM = least squares mean; NRS-R = numeric rating scale at rest. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 
[1] From an analysis of covariance with treatment and region (US and Europe) as main effects and the baseline NRS-R pain intensity 
score as a covariate. 
[2] Difference from placebo. 
Reference: Listing 16.5.1.1. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Time Point 
Table 14.2.2.5 (Page x of Y) 
NRS-A Pain Intensity Scores 
(Efficacy Analysis Set) 
Statistics 
LB 
266 mg 
(N=XX) 
Placebo 
(N=XX) 
Baseline 
n 
00 
00 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
First Request 
n 
00 
00 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
LSM (Standard Error) [1] 
00.0 (00.00) 
00.0 (00.00) 
LSM Difference (Standard Error) [2] 
00.0 (00.00) 
95% CI for Difference [2] 
00.0, 00.0 
P-value [2] 
0.0000 
2 Hours 
n 
00 
00 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Etc. 
Minimum, Maximum 
000, 000 
000, 000 
CI = confidence interval; LB = liposome bupivacaine; LSM = least squares mean; NRS-A = numeric rating scale with activity. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 
[1] From an analysis of covariance with treatment and region (US and Europe) as main effects and the baseline NRS-A pain intensity score 
as a covariate. 
[2] Difference from placebo. 
Reference: Listing 16.5.1.1. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.2.2.6 (Page x of Y) 
AUC of NRS-R Pain Intensity Scores Through 24, 36, 48, and 60 Hours 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
LB 
266 mg 
Placebo 
Time Point 
Statistics 
(N=XX) 
(N=XX) 
 
 
24 Hours 
n 
Mean 
SD 
Median 
Minimum, Maximum 
00 
000.0 
00.00 
0000 
000, 000 
00 
000.0 
00.00 
0000 
000, 000 
 
LSM (Standard Error) [1] 
LSM Difference (Standard Error) [2] 
95% CI for Difference [2] 
P-value [2] 
00.0 (00.00) 
00.0 (00.00) 
00.0, 00.0 
0.0000 
00.0 (00.00) 
 
48 Hours 
n 
Mean 
SD 
Median 
Minimum, Maximum 
00 
000.0 
00.00 
0000 
000, 000 
00 
000.0 
00.00 
0000 
000, 000 
 
 
Etc. 
 
AUC = area under the curve calculated using the trapezoidal method; CI = confidence interval; LB = liposome bupivacaine; 
LSM = least squares mean; NRS-R = numeric rating scale at rest. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 
wWOCF + LOCF = imputation using the worst observation carried forward prior to the use of rescue medication within a medication window 
and last observation carried forward for missing values. 
[1] From an analysis of covariance with treatment and region (US and Europe) as main effects and the baseline NRS-R pain intensity 
score as a covariate. 
[2] Difference from placebo. 
Reference: Listings16.5.1.1 and 16.5.1.2. 


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Table 14.2.2.7 (Page x of Y) 
AUC of NRS-R Pain Intensity Scores 24-48 and 48-72 Hours 
wWOCF + LOCF Imputation for the Pain Scores 
(Efficacy Analysis Set) 
LB 
266 mg 
Placebo 
Time Point 
Statistics 
(N=XX) 
(N=XX) 
24-48 Hours 
n 
Mean 
SD 
Median 
Minimum, Maximum 
00 
000.0 
00.00 
0000 
000, 000 
00 
000.0 
00.00 
0000 
000, 000 
 
LSM (Standard Error) [1] 
LSM Difference (Standard Error) [2] 
95% CI for Difference [2] 
P-value [2] 
00.0 (00.00) 
00.0 (00.00) 
00.0, 00.0 
0.0000 
00.0 (00.00) 
 
48-72 Hours 
n 
Mean 
SD 
Median 
Minimum, Maximum 
00 
000.0 
00.00 
0000 
000, 000 
00 
000.0 
00.00 
0000 
000, 000 
 
LSM (Standard Error) [1] 
LSM Difference (Standard Error) [2] 
95% CI for Difference [2] 
P-value [2] 
00.0 (00.00) 
00.0 (00.00) 
00.0, 00.0 
0.0000 
00.0 (00.00) 
 
AUC = area under the curve calculated using the trapezoidal method; CI = confidence interval; LB = liposome bupivacaine; LSM = least 
squares mean; NRS-R = numeric rating scale at rest. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 
wWOCF + LOCF = imputation using the worst observation carried forward prior to the use of rescue medication within a medication window 
and last observation carried forward for missing values. 
[1] From an analysis of covariance with treatment and region (US and Europe) as main effects and the baseline NRS-R pain intensity score 
as a covariate. 
[2] Difference from placebo. 


Pacira Pharmaceuticals, Inc. 
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Reference: Listings 16.5.1.1 and 16.5.1.2. 


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Table 14.2.2.8 (Page x of Y) 
Percentage of Subjects who are Pain Free at Each Time Point 
(Efficacy Analysis Set) 
 
LB 
266 mg 
Placebo 
 
  Time Point  
(N=XX) 
n/N (%)  
(N=XX) 
n/N (%) 
P-value [1]  
 
1 Hour 
00/00 (00.0) 
00/00 (00.0) 
0.0000 
 
2 Hours 
00/00 (00.0) 
00/00 (00.0) 
0.0000 
 
4 Hours 
00/00 (00.0) 
00/00 (00.0) 
0.0000 
 
8 Hours 
00/00 (00.0) 
00/00 (00.0) 
0.0000 
 
12 Hours 
00/00 (00.0) 
00/00 (00.0) 
0.0000 
 
24 Hours 
00/00 (00.0) 
00/00 (00.0) 
0.0000 
 
36 Hours 
00/00 (00.0) 
00/00 (00.0) 
0.0000 
 
   Etc  
 
Pain free is defined as a pain intensity score at rest of 0 or 1. 
LB = liposome bupivacaine. n/N = Number of subjects with a pain score of 0 or 1/Number of subjects with a pain score 
at the time point. 
[1] P-value is from a chi-square test. 
Reference: Listing 16.5.1.1. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.2.2.9 (Page x of Y) 
Total Postoperative Consumption (mg) of Opioid Rescue Pain Medication Through 24, 36, 48, and 60 Hours 
(Efficacy Analysis Set) 
 
LB 
266 mg 
Placebo 
Time Point 
Statistics 
(N=XX) 
(N=XX) 
 
 
24 Hours 
n 
Mean 
Geometric Mean 
SD 
Median 
Minimum, Maximum 
00 
00.00 
00.00 
00.000 
00.00 
00.0, 00.0 
00 
00.00 
00.00 
00.000 
00.00 
00.0, 00.0 
 
 
 
 
 
   Etc.  
Geometric LSM [1] 
Geometric LSM Ratio [2] 
95% CI for Ratio [2] 
P-value [2] 
00.00 
00.00 
00.00, 00.00 
0.0000 
00.00 
 
CI = confidence interval; LB = liposome bupivacaine; LSM = least squares mean. 
If the total amount of opioid used was 0 mg, the value was set to the lesser of 1 mg or one half of the smallest total amount observed 
in the study prior to being transformed by the natural logarithm. 
[1] From an analysis of variance with treatment and region (US and Europe) as main effects on natural log 
transformed opioid amount. Results are presented in the original, non-transformed scale. 
[2] Geometric LSM ratio is the anti-log LSM difference (LB/placebo). 
Reference: Listing 16.5.2. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.2.2.10 (Page x of Y) 
Subjects Who Received Rescue Medication Through 72 Hours 
(Efficacy Analysis Set) 
 
LB 
266 mg 
Placebo 
(N=XX) 
  
n (%)  
(N=XX) 
n (%) 
P-value [1]  
 
 
Received No Rescue Medication 
00 (00.0) 
00 (00.0) 
0.0000 
Received Only the First Rescue 
00 (00.0) 
00 (00.0) 
0.0000 
Received the First Rescue and a Second Opioid 
Rescue 
00 (00.0) 
00 (00.0) 
0.0000 
 
LB = liposome bupivacaine. 
[1] P-value is from a chi-square test 
Reference: Listings 16.5.2. 


Pacira Pharmaceuticals, Inc. 
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Table 14.2.2.11 (Page x of Y) 
Overall Benefit of Analgesia Score Questionnaire (Total Scores) 
(Efficacy Analysis Set) 
 
Time Point 
Statistics 
LB 
266 mg 
(N=XX) 
Placebo 
(N=XX) 
P-value [1] 
24 Hours 
n 
00 
00 
0.0000 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
48 Hours 
n 
00 
00 
0.0000 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
72 Hours 
n 
00 
00 
0.0000 
Mean 
000.0 
000.0 
SD 
00.00 
00.00 
Median 
0000 
0000 
Minimum, Maximum 
000, 000 
000, 000 
LB = liposome bupivacaine. 
Note: The lower the score, the greater the benefit of analgesia. 
[1] P-value is from a Wilcoxon Rank Sum test. 
 
Reference: Listing 16.5.3. 


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Table 14.2.2.12 (Page x of Y) 
Subject Satisfaction with Postsurgical Pain Control 
(Efficacy Analysis Set) 
 
Time Point 
Assessment 
LB 
266 mg 
(N=XX) 
n (%) 
Placebo 
(N=XX) 
n (%) 
P-value [1] 
72 Hours 
Extremely Dissatisfied (1) 
00 (00.0) 
00 (00.0) 
0.0000 
Dissatisfied (2) 
00 (00.0) 
00 (00.0) 
Neither Satisfied nor Dissatisfied (3) 
00 (00.0) 
00 (00.0) 
Satisfied (4) 
00 (00.0) 
00 (00.0) 
Extremely Satisfied (5) 
00 (00.0) 
00 (00.0) 
Day 12 
Extremely Dissatisfied (1) 
00 (00.0) 
00 (00.0) 
0.0000 
Dissatisfied (2) 
00 (00.0) 
00 (00.0) 
Neither Satisfied nor Dissatisfied (3) 
00 (00.0) 
00 (00.0) 
Satisfied (4) 
00 (00.0) 
00 (00.0) 
Extremely Satisfied (5) 
00 (00.0) 
00 (00.0) 
Day 30 
Extremely Dissatisfied (1) 
00 (00.0) 
00 (00.0) 
0.0000 
Dissatisfied (2) 
00 (00.0) 
00 (00.0) 
Neither Satisfied nor Dissatisfied (3) 
00 (00.0) 
00 (00.0) 
Satisfied (4) 
00 (00.0) 
00 (00.0) 
Extremely Satisfied (5) 
00 (00.0) 
00 (00.0) 
 
LB = liposome bupivacaine. 
Note: Percentages are based on number of subjects with a score at the time point. 
[1] P-value is from a Wilcoxon Rank Sum test. 
 
Reference: Listing 16.5.4. 


Pacira Pharmaceuticals, Inc. 
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Table 14.2.2.13 (Page x of Y) 
Time to Sensitivity to Cold 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
(N=XX) 
(N=XX) 
 
 
Subjects with Sensitivity to Cold [n (%)] 
00 (00.00) 
00 (00.00) 
Censored Observations [n (%)] 
00 (00.00) 
00 (00.00) 
 
Quartiles (hours) [1] 
First Quartile (25% with Sensitivity to Cold) 
000 
000 
Median (50% with Sensitivity to Cold) 
000 
000 
Third Quartile (75% with Sensitivity to Cold) 
000 
000 
Minimum,  Maximum 
00,  00* 
00,  00* 
95% CI of Median 
(000, 000) 
(000, 000) 
 
P-value [2] 
0.0000 
0.0000 
 
 
* indicates a censored observation. 
CI = confidence interval; LB = liposome bupivacaine, 
[1] Kaplan-Meier Estimates. 
[2] Log-rank test with region (US and Europe) as a stratifying variable. 
Reference: Listing 16.5.5. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.2.2.14 (Page x of Y) 
Incidence of Predefined Treatment-Emergent Opioid-Related Adverse Events 
(Efficacy Analysis Set) 
 
LB 
266 mg 
Placebo 
(N=XX) 
  
n  (%)  
(N=XX) 
n  (%) 
P-value [2]  
 
Subjects with at Least One Event 
00 (00.0) 
00 (00.0) 
0.0000 
 
Diffuse Pruritus 
00 (00.0) 
00 (00.0) 
Overt Respiratory Depression 
00 (00.0) 
00 (00.0) 
Urinary Retention [1] 
00 (00.0) 
00 (00.0) 
Constipation 
00 (00.0) 
00 (00.0) 
Sedation 
00 (00.0) 
00 (00.0) 
Confusion 
00 (00.0) 
00 (00.0) 
Delirium 
00 (00.0) 
00 (00.0) 
Vomiting 
00 (00.0) 
00 (00.0) 
Need for Antiemetic Medication 
00 (00.0) 
00 (00.0) 
 
LB = liposome bupivacaine. 
[1] Urinary retention was measured by need for postsurgical bladder catheterization. 
[2] P-value is from a chi-square test. 
 
Reference: Listing 16.5.6. 


Pacira Pharmaceuticals, Inc. 
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Table 14.2.3.1 (Page x of Y) 
Bupivacaine Plasma Concentrations (ng/mL) 
(PK Analysis Set) 
 
LB 
266 mg 
  Time Point 
Statistics 
(N=XX)  
 
Baseline 
n 
00 
Mean 
000.00 
SD 
0.000 
%CV 
000.00 
Median 
0.00 
Minimum, Maximum 
00.0, 00.0 
 
15 Minutes 
n 
00 
Mean 
000.00 
SD 
0.000 
%CV 
000.00 
Median 
0.00 
Minimum, Maximum 
00.0, 00.0 
 
30 Minutes 
n 
00 
Mean 
000.00 
SD 
0.000 
%CV 
000.00 
Median 
0.00 
Minimum, Maximum 
00.0, 00.0 
   Etc.  
 
LB = liposome bupivacaine. 
Reference: Listing 16.6.1. 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
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Table 14.2.3.2 (Page x of Y) 
Bupivacaine Plasma Pharmacokinetic Parameters 
(PK Analysis Set) 
 
 
 
 
 
LB 
266 mg 
  Parameter 
Statistics 
(N=XX)  
 
Cmax (ng/mL) 
n 
00 
Mean 
000.00 0 
SD 
0.0000 
%CV 
000.00 
Geometric Mean 
00.0 
Median 
0.000 
Minimum, Maximum 
00.00, 00.00 
 
Tmax (hours) 
n 
00 
Mean 
000.00 0 
SD 
0.0000 
Median 
0.000 
Minimum, Maximum 
00.00, 00.00 
 
AUC0-last (h*ng/mL) 
n 
00 
Mean 
000.00 0 
SD 
0.0000 
%CV 
000.00 
Geometric Mean 
00.0 
Median 
0.000 
Minimum, Maximum 
00.00, 00.00 
   Etc.  
 
LB = liposome bupivacaine. 
Reference: Listing 16.6.2. 
 
Programmer Note: The other parameters should be AUC0-inf (h*ng/mL), and half-life (t1/2) (hours). %CV and geometric mean will not be 
shown for Tmax and half-life 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
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Table 14.3.1.1 (Page x of Y) 
Overview of Treatment-Emergent Adverse Events 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
All 
Subjects 
(N=XX) 
  
n  (%)  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
 
Subjects with at Least One TEAE 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Maximum Severity: Mild 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Maximum Severity: Moderate 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Maximum Severity: Severe 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
At Least One TEAE Related to Study Drug 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
At Least One Serious TEAE 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
Subjects Discontinued Due to a TEAE 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
Deaths on Study 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
 
 
LB = liposome bupivacaine; TEAE = treatment-emergent adverse event. 
Reference: Listings 16.7.1.1 and 16.7.1.2. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
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Table 14.3.1.2 (Page x of Y) 
Incidence of Treatment-Emergent Adverse Events 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
System Organ Class 
  
Preferred Term  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
 
Subjects with at Least One TEAE 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
System Organ Class 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
…. 
 
System Organ Class 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 3 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 4 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
  
Etc.  
 
LB = liposome bupivacaine; TEAE = treatment-emergent adverse event. 
At each level of summation (overall, system organ class, preferred term), subjects are only counted once. 
Reference: Listings 16.7.1.1 and 16.7.1.2. 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
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Table 14.3.1.3 (Page x of Y) 
Incidence of Study Drug Related Treatment-Emergent Adverse Events 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
All 
Subjects 
System Organ Class 
  
Preferred Term  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
 
Subjects with at Least One TEAE 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
System Organ Class 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
…. 
 
System Organ Class 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 3 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 4 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
  
Etc.  
 
LB = liposome bupivacaine; TEAE = treatment-emergent adverse event. 
At each level of summation (overall, system organ class, preferred term), subjects are only counted once. 
Reference: Listings 16.7.1.1 and 16.7.1.2. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.3.1.4 (Page x of Y) 
Incidence of Treatment-Emergent Adverse Events by Severity 
(Safety Analysis Set) 
 
LB 
266 mg 
(N = XX) 
Placebo 
(N = XX) 
All 
Subjects 
(N = XX 
System Organ Class 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
Preferred Term 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Subjects with at Least 
One TEAE 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
System Organ Class 1 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
Preferred Term 1 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
Preferred Term 2 
… 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
System Organ Class 2 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
Preferred Term 3 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
Preferred Term 4 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
00 (00.00) 
   …  
 
LB = liposome bupivacaine; TEAE = treatment-emergent adverse event. 
At each level of summation (overall, system organ class, preferred term), subjects are only counted once using the highest severity. 
Reference: Listings 16.7.1.1 and 16.7.1.2. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
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Table 14.3.1.5 (Page x of Y) 
Incidence of Serious Treatment-Emergent Adverse Events 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
System Organ Class 
  
Preferred Term  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
(N=XX) 
n  (%)  
 
Subjects with at Least One TEAE 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
System Organ Class 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 1 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
…. 
 
System Organ Class 2 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 3 
00 (00.0) 
00 (00.0) 
00 (00.0) 
Preferred Term 4 
00 (00.0) 
00 (00.0) 
00 (00.0) 
 
  
Etc.  
 
LB = liposome bupivacaine; TEAE = treatment-emergent adverse event. 
At each level of summation (overall, system organ class, preferred term), subjects are only counted once. 
Reference: Listings16.7.1.3 and 16.7.1.4. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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Table 14.3.2.1 (Page x of Y) 
Vital Signs 
(Safety Analysis Set) 
LB 
266 mg 
Placebo 
Parameter 
Time Point 
Statistics 
(N=XX) 
(N=XX) 
Heart Rate 
Screening 
n 
00 
00 
Mean 
00.0 
00.0 
SD 
00.00 
00.00 
Median 
00.0 
00.0 
Minimum, Maximum 
00, 00 
00, 00 
Baseline 
n 
00 
00 
Mean 
00.0 
00.0 
SD 
00.00 
00.00 
Median 
00.0 
00.0 
Minimum, Maximum 
00, 00 
00, 00 
1 Hour 
n 
00 
00 
Mean 
00.0 
00.0 
SD 
00.00 
00.00 
Median 
00.0 
00.0 
Etc. 
Etc. 
Minimum, Maximum 
00, 00 
00, 00 
 
LB = liposome bupivacaine. 
Reference: Listing 16.8. 


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Table 14.3.2.2 (Page x of Y) 
Vital Signs Change from Baseline 
(Safety Analysis Set) 
LB 
266 mg 
Placebo 
Parameter 
Time Point 
Statistics 
(N=XX) 
(N=XX) 
Heart Rate 
1 Hour 
n 
00 
00 
Mean 
00.0 
00.0 
SD 
00.00 
00.00 
Median 
00.0 
00.0 
Minimum, Maximum 
00, 00 
00, 00 
12 Hours 
n 
00 
00 
Mean 
00.0 
00.0 
SD 
00.00 
00.00 
Median 
00.0 
00.0 
Minimum, Maximum 
00, 00 
00, 00 
24 Hours 
n 
00 
00 
Mean 
00.0 
00.0 
SD 
00.00 
00.00 
Median 
00.0 
00.0 
Etc. 
Etc. 
Minimum, Maximum 
00, 00 
00, 00 
 
LB = liposome bupivacaine. 
Reference: Listing 16.8. 


Pacira Pharmaceuticals, Inc. 
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Table 14.3.3 (Page x of Y) 
Neurological Assessment 
(Safety Analysis Set) 
 
LB 
266 mg 
Placebo 
 
 
 
 
 
 
All 
Subjects 
 
  Time Point 
Assessment  
(N=XX) 
n/N (%)  
(N=XX) 
n/N (%)  
(N=XX) 
n/N (%)  
 
Baseline 
Oriented [1] 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
At Least one of the Events 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Numbness [2] 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Metallic Taste in Mouth 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Problems with Hearing 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Problems with Vision 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Muscles Twitching 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
 
15 Minutes 
Oriented [1] 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
At Least one of the Events 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Numbness [2] 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Metallic Taste in Mouth 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Problems with Hearing 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Problems with Vision 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
Muscles Twitching 
00/00 (00.0) 
00/00 (00.0) 
00/00 (00.0) 
   Etc.  
LB = liposome bupivacaine. n/N = Number of subjects with a pain score of 0 or 1 / Number of subjects with a pain score at the time point. 
[1] The denominator does not include subjects who were not assessable at the time point. 
[2] Numbness of the lips, the tongue, or around the mouth. 
Reference: Listing 16.9. 


Pacira Pharmaceuticals, Inc. 
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Table 14.3.4 (Page x of Y) 
Physician’s Satisfaction with Wound Healing 
(Safety Analysis Set) 
 
Time Point 
Assessment 
LB 
266 mg 
(N=XX) 
n (%) 
Placebo 
(N=XX) 
n (%) 
P-value [1] 
72 Hours 
Extremely Dissatisfied (1) 
00 (00.0) 
00 (00.0) 
0.0000 
Dissatisfied (2) 
00 (00.0) 
00 (00.0) 
Neither Satisfied or Dissatisfied (3) 
00 (00.0) 
00 (00.0) 
Satisfied (4) 
00 (00.0) 
00 (00.0) 
Extremely Satisfied (5) 
00 (00.0) 
00 (00.0) 
Day 30 
Extremely Dissatisfied (1) 
00 (00.0) 
00 (00.0) 
0.0000 
Dissatisfied (2) 
00 (00.0) 
00 (00.0) 
Neither Satisfied or Dissatisfied (3) 
00 (00.0) 
00 (00.0) 
Satisfied (4) 
00 (00.0) 
00 (00.0) 
Extremely Satisfied (5) 
00 (00.0) 
00 (00.0) 
 
LB = liposome bupivacaine. 
Note: Percentages are based on number of subjects with a score at the time point. 
[1] P-value is from a Wilcoxon Rank Sum test. 
 
Reference: Listing 16.10. 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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LISTINGS 


Pacira Pharmaceuticals, Inc. 
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DOCUMENT NO. 040-00174.001 
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  Treatment Group: YYY  
 
 
Listing 16.1.1 (Page x of Y) 
Eligibility 
 
 
Date Informed 
Consent Form 
 
 
Randomization 
 
 
Randomization 
 
 
Met Eligibility 
 
 
Criteria Not 
Waiver 
Subject ID 
Signed 
Date/Time 
Number 
Visit 
Requirements? 
Met 
Granted? 
Date 
 
 
 
 
 
 
 
 
Programmer note: Visit should be Registration, Screening, and Baseline.  For Screening, the waiver questions should be blank. 


Pacira Pharmaceuticals, Inc. 
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Listing 16.1.2 (Page x of Y) 
Unblinding 
 
Treatment Group: YYY 
 
Subject ID 
Blind Broken? 
Date of Unblinding 
Reason 
 
 
 
 
 
 
 
Person Who 
Performed Unblinding 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
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Listing 16.1.3 (Page x of Y) 
Subject Populations and Discontinuations 
 
  Treatment Group: YYY  
 
Subject Included In: 
Safety 
Efficacy 
PK 
Complete the 
Date of Completion 
or Early 
Reason for Early 
If Lost to 
Follow-up, Date 
Subject ID 
Analysis Set [1] 
Analysis Set [2] 
Analysis Set [3] 
Study? 
Discontinuation 
Discontinuation 
of Last Contact 
 
 
 
 
 
 
PK = pharmacokinetic. 
[1] The safety analysis set includes all subjects who received study drug. 
[2] The efficacy analysis set includes all subjects in the safety analysis set. 
[3] The PK analysis set includes all subjects in the safety analysis set who received liposome bupivacaine and provided sufficient samples to allow for 
calculation of the PK parameters required for analysis. 


Pacira Pharmaceuticals, Inc. 
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Listing 16.1.4 (Page x of Y) 
Hospital Discharge 
 
Treatment Group: YYY  
 
Hospital Discharge 
 
Subject ID 
Date 
Time 
 
 
 
 
 
 
 


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Treatment Group: YYY 
 
 
Listing 16.2 (Page x of Y) 
Demographics and Baseline Characteristics 
 
 
 
 
 
 
ASA 
Subject ID 
Initials 
Date of Birth 
Age 
Gender 
Ethnicity 
Race(s) 
Class 
 
 
 
 
 
 
 
ASA = American Society of Anesthesiologists. 


Pacira Pharmaceuticals, Inc. 
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Listing 16.3.1 (Page x of Y) 
Medical History 
Past Medical Findings or Surgical Procedures 
 
Treatment Group: YYY  
 
 
Subject ID 
Visit Date 
Body System 
Finding/ 
Procedure 
Start Date 
Currently 
Ongoing? 
 
 
 
 
 
 
 
 
 
Programmer note:  Sort categories as on the CRFs, not alphabetically.  If Other is checked for Body System then report as Other: specify. 


Pacira Pharmaceuticals, Inc. 
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Listing 16.3.2 (Page x of Y) 
Physical Examination 
 
Treatment Group: YYY  
 
  
Subject ID 
Performed? 
Date  
 
 
 
 
 
 


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Listing 16.3.3 (Page x of Y) 
Electrocardiogram Recording (Holter Monitoring) 
 
  Treatment Group: YYY  
 
Subject ID 
Started? 
Start Date 
Start Time 
Stop Date 
Stop Time 
 
 
 
 
 
 
 


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Treatment Group: YYY 
Listing 16.3.4 
Prior and Concomitant Medications (Except for Protocol-Defined Rescue Pain Medications) 
Anatomical Main Group/ 
Preferred Term / 
Prior / 
Reason for 
AE Number 
Start Date / 
End Date / 
Subject ID 
Verbatim Term 
Concomitant 
Use 
or NA 
Time 
Time 
Dose / Unit 
Route 
Frequency 
 
 
 
 
 
AE = adverse event; NA = Not applicable. 
Prior medications are defined as medication with a stop date/time prior to study drug administration. 
Concomitant medications are defined as medications (other than protocol-defined rescue pain medication) taken on or after the start of study drug administration. 
 
 
 
Programmer note:  If a subject has no medications, then put “NONE” in the 2nd column. 
If the medication is Ongoing, then put “Ongoing” in the “End Date / Time” column. 
Use formatted terms as much as possible.  If you have to use codes, then add footnotes to explain the codes. 


Pacira Pharmaceuticals, Inc. 
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Treatment Group: YYY 
Listing 16.4.1 
Study Drug Exposure 
Subject ID 
Study Drug 
Administered? 
Date 
Administered 
Start Time 
Study Drug Administration 
End Time 
Duration (minutes) 
Total 
Volume (mL) 
 
 
 
 
 


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Listing 16.4.2 
Surgery 
 
Treatment Group: YYY 
 
Surgery 
Index Nerve Injected 
Duration 
 
 
At Least One Chest 
Subject ID 
Date 
Start Time 
Stop Time 
(minutes) 
Level 
Side 
Tube Inserted? 
 
 
 
 
 
 


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Listing 16.4.3 
Intensive Care Unit and Last Chest Tube Removal 
 
Treatment Group: YYY  
 
ICU 
Last Chest Tube Removed 
Time 
Time 
   Subject ID  
Start Time  
Admitted  
Discharged  
Date  
Time  
 
 
 
 
 
ICU = Intensive Care Unit. 


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Treatment Group: YYY  
 
 
Listing 16.5.1.1 
Pain Intensity Scores at Rest and with Activity 
 
  
NRS-R 
NRS-A  
 
Actual 
Actual 
Subject ID 
Time Point 
Date 
Time 
Actual Score 
Imputed Score 
Actual Score 
Imputed Score 
 
 
 
 
 
 
NRS-R = numeric rating scale at rest; NRS-A =  numeric rating scale with activity. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 82 of 98 
 
 
 
 
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Listing 16.5.1.2 
AUC of NRS-R Pain Intensity Scores 
wWOCF + LOCF Imputation for the Pain Scores 
 
Treatment Group: YYY  
 
 
  
Subject ID  
Time Interval 
(hours) 
AUC  
 
 
 
 
 
 
AUC = area under the curve calculated using the trapezoidal method; NRS-R = numerical rating scale at rest. 
Scores are based on a numeric rating scale where 0 = no pain and 10 = worst possible pain. 
wWOCF + LOCF = imputation using the worst observation carried forward prior to the use of rescue medication within a medication window and 
last observation carried forward for missing values. 
 
 
 
Programmer note: The Time Intervals should be 0-24, 0-36, 0-48, 0-72, 24-48, and 48-72. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 83 of 98 
 
 
 
 
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Listing 16.5.2 
Postoperative Consumption of Opioid Rescue Pain Medication 
 
  
Treatment Group: YYY  
 
 
Subject ID 
First or Second 
Rescue 
Medication 
Date/Time 
Administered 
Hours from End 
of Surgery 
Amount Taken 
(Units) 
Route 
Converted 
Amount (mg) [1] 
Cumulative 
Amount (mg) 
 
 
 
 
 
 
 
[1] Opioids are converted to a morphine-equivalent amount. 
 
 
 
Programmer note: If subject took no postoperative opioid pain medications, put ’NONE’ in the 2nd column. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 84 of 98 
 
 
 
 
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Listing 16.5.3 
Overall Benefit of Analgesia Score Questionnaire 
 
Treatment Group: YYY  
 
 
 
Date/Time of 
 
 
Current Pain 
Distress and Bother with [2]:  
Satisfaction 
with Pain 
Subject ID 
Time Point 
Assessment 
at Rest [1] 
Vomiting 
Itching 
Sweating 
Freezing 
Dizziness 
Treatment [2] 
Total Score 
 
 
 
 
 
 
 
[1] 0 = Minimal Pain, 4 = Maximal imaginable pain. 
[2] 0 = Not at all, 4 = Very much. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 85 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
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Listing 16.5.4 
Subject Satisfaction with Postsurgical Pain Control 
 
Treatment Group: YYY  
 
 
     Subject ID 
Time Point  
Date of 
Assessment  
Time of 
Assessment 
Assessment  
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
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Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
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26 February 2013 
Page 86 of 98 
 
 
 
 
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Listing 16.5.5 
Sensitivity to Cold 
 
Treatment Group: YYY 
Subject ID 
Time Point 
Date/Time of 
  
Assessment  
 
 
 
 
 
 
 
Sensitivity to Cold 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 87 of 98 
 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
402-C-322 
 
 
Listing 16.5.6 
Predefined Treatment-Emergent Opioid-Related Adverse Events at 72 Hours 
 
  
Treatment Group: YYY  
 
Overt 
Urinary 
Need for 
Subject 
Date of 
Diffuse 
Respiratory 
Retention 
Antiemetic 
ID 
Assessment 
Pruritus 
Depression 
[1] 
Constipation 
Sedation 
Confusion 
Delirium 
Vomiting 
Medication 
 
 
 
 
 
 
[1] Urinary retention was measured by need for postsurgical bladder catheterization. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 88 of 98 
 
 
 
 
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Treatment Group: YYY  
 
 
Listing 16.6.1 
Scheduled Bupivacaine Plasma Concentrations 
 
Dose Time 
Date of 
Time of 
Elapsed Time 
Bupivacaine Plasma 
Subject ID 
[1] 
Sample 
Sample 
Time Point 
(hours) [2] 
Concentration (ng/mL) 
 
 
 
 
 
 
[1] Dose time is the start time of study drug administration. 
[2] Elapsed time is the time the sample was collected relative to the time of dose. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 89 of 98 
 
 
 
 
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Listing 16.6.2 
Bupivacaine Plasma Pharmacokinetic Parameters 
 
Treatment Group: YYY  
 
Cmax 
Tmax 
AUC 0-last 
AUC 0-inf 
t1/2 
   Subject ID  
(ng/mL)  
(hours)  
(h*ng/mL)  
(h*ng/mL)  
(hours)  
 
 
 
 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 90 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
402-C-322 
 
 
Treatment Group: YYY  
 
 
Listing 16.6.3 
Unscheduled Bupivacaine Plasma Concentrations 
 
Dose Time 
Date of 
Time of 
Reason for 
Elapsed Time 
Bupivacaine Plasma 
Subject ID 
[1] 
Sample 
Sample 
Collection 
(hours) [2] 
Concentration (ng/mL) 
 
 
 
 
 
 
[1] Dose time is the start time of study drug administration. 
[2] Elapsed time is the time the sample was collected relative to the time of dose. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 91 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
402-C-322 
 
 
  Treatment Group: YYY  
 
 
Listing 16.7.1.1 
Adverse Events (Part 1 of 2) 
 
 
SOC / 
Preferred Term / 
 
 
Start Date / 
 
 
End Date / 
Solicited From: 
 
 
Relationship 
Subject ID 
Verbatim Term 
Time 
Time 
Neuro. [1] 
ORAE[2] 
Serious 
Severity 
to Study Drug 
Outcome 
 
 
 
 
 
 
SOC = system organ class 
* Indicates that the event is not treatment-emergent. 
[1] Neurological assessment. 
[2] Predefined treatment-emergent opioid-related adverse events questionnaire. 
 
 
 
 
Programmer note: If  the subject has no adverse events, then put ‘NONE’ in the “SOC/Preferred Term/Verbatim Term” column. 
Use formatted terms as much as possible.  If you have to use codes, then add footnotes to explain the codes. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 92 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
402-C-322 
 
 
  Treatment Group: YYY  
 
 
Listing 16.7.1.2 
Adverse Events (Part 2 of 2) 
 
Action Taken with Subject 
SOC / 
Preferred Term / 
Start Date / 
End Date / 
Non- 
Pharmaceutical 
Discontinued 
Subject ID 
Verbatim Term 
Time 
Time 
None 
Medication 
Therapy 
from Study 
Other 
 
 
 
 
 
SOC = system organ class. 
* Indicates that the event is not treatment-emergent. 
 
 
 
 
Programmer note: If  the subject has no adverse events, then put ‘NONE’ in the ”SOC/Preferred Term/Verbatim Term” column. 
Use formatted terms as much as possible.  If you have to use codes, then add footnotes to explain the codes. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 93 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
402-C-322 
 
 
  Treatment Group: YYY  
 
 
Listing 16.7.1.3 
Serious Adverse Events (Part 1 of 2) 
 
 
SOC / 
Preferred Term / 
 
 
Start Date / 
 
 
End Date / 
Solicited From: 
 
 
Relationship 
Subject ID 
Verbatim Term 
Time 
Time 
Neuro. [1] 
ORAE[2] 
Severity 
to Study Drug 
Outcome 
 
 
 
 
 
 
SOC = system organ class. 
* Indicates that the event is not treatment-emergent. 
[1] Neurological assessment. 
[2] Predefined treatment-emergent opioid-related adverse events questionnaire. 
 
 
 
 
Programmer note: If  the subject has no adverse events, then put ‘NONE’ in the ”SOC/Preferred Term/Verbatim Term” column. 
Use formatted terms as much as possible.  If you have to use codes, then add footnotes to explain the codes. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 94 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
402-C-322 
 
 
  Treatment Group: YYY  
 
 
Listing 16.7.1.4 
Serious Adverse Events (Part 2 of 2) 
 
Action Taken with Subject 
SOC / 
Preferred Term / 
Start Date / 
End Date / 
Non- 
Pharmaceutical 
Discontinued 
Subject ID 
Verbatim Term 
Time 
Time 
None 
Medication 
Therapy 
from Study 
Other 
 
 
 
 
 
SOC = system organ class. 
* Indicates that the event is not treatment-emergent. 
 
 
 
 
Programmer note: If  the subject has no adverse events, then put ‘NONE’ in the ”SOC/Preferred Term/Verbatim Term” column. 
Use formatted terms as much as possible.  If you have to use codes, then add footnotes to explain the codes. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
Liposome Bupivacaine 
Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
PCDOC #137836 
26 February 2013 
Page 95 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
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Listing 16.7.1.5 
Deaths 
 
Treatment Group: YYY  
 
 
   Subject ID 
Date 
Primary Cause  
Autopsy 
Performed?  
Date of 
Autopsy  
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
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Page 96 of 98 
 
 
 
 
Pacira Pharmaceuticals, Inc. 
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  Treatment Group: YYY  
 
 
Listing 16.8 
Height, Weight, and Vital Signs 
 
 
Heart Rate 
Blood Pressure (mmHg) 
Subject ID 
Time Point 
Date 
Time 
Height (cm) 
Weight (kg) 
(bpm) 
Systolic 
Diastolic 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
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Treatment Group: YYY  
 
 
Listing 16.9 
Neurological Assessment 
 
Metallic 
Problems 
Numbness 
Taste in 
with 
Problems 
Muscles 
Subject ID 
Time Point 
Date 
Time 
Oriented 
[1] 
Mouth 
Hearing 
with Vision 
Twitching 
 
 
 
 
 
 
[1] Numbness of the lips, the tongue, or around the mouth. 


Pacira Pharmaceuticals, Inc. 
402-C-322 Thoracotomy 
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Statistical Analysis Plan 
DOCUMENT NO. 040-00174.001 
CONFIDENTIAL 
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Page 98 of 98 
 
 
 
 
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Listing 16.10 
Physician’s Satisfaction with Wound Healing 
 
 Treatment Group: YYY  
 
 
     Subject ID 
Time Point  
Date of 
Assessment  
Time of 
Assessment 
Assessment  
 
 
 
 
 


CONFIDENTIAL AND PROPRIETARY 
Page 1 of 8 
 
 
 
Cardiac ECG Clinical Statistical Plan 
 
 
 
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 
 
 
Sponsor Reference: 402-C-322 
 
 
SPONSORED BY 
Pacira Pharmaceuticals, Inc. 
10450 Science Center Drive 
San Diego, CA  92121 
Tel: (858) 625-2424 
 
 
This document is confidential. 
 
 
 
DATE: 30Jul2013 
V2 
 
By: 
Joel Morganroth, M.D. 
Chief Scientist, eResearchTechnology, Inc. 
215 840 4961 (tel/cell) 
610 527 0295 (fax) 
JMorganroth@ert.com 
 
 
 
 
Signature:  


CONFIDENTIAL AND PROPRIETARY 
Page 2 of 8 
 
 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................ 3 
1.1 
Objectives ............................................................................................................. 3 
1.1.1 
Primary Objective ................................................................................................. 3 
1.1.2 
Secondary Objective ............................................................................................. 4 
1.2 
Study Design ......................................................................................................... 4 
1.3 
ECG Selection ...................................................................................................... 4 
1.4 
Analysis of 12-Lead ECGs ................................................................................... 5 
2 
ECG STATISTICAL PLAN ................................................................................. 6 
2.1 
Subject Populations .............................................................................................. 6 
2.2 
Central Tendency Analysis ................................................................................... 6 
2.3 
Outlier Analyses ................................................................................................... 6 
2.4 
Morphological Analysis ........................................................................................ 7 
3 
DEVIATIONS IN ANALYSIS FROM STATISTICAL PLAN AND 
OTHER ISSUES .......................................................................................................... 8 


CONFIDENTIAL AND PROPRIETARY 
Page 3 of 8 
 
 
 
1 
INTRODUCTION 
 
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 explored the safety, efficacy, and pharmacokinetic (PK) profile of 
liposome bupivacaine when administered via a new route – intercostal nerve block. 
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® (bupivacaine 
liposome injectable suspension; Pacira Pharmaceuticals, Inc., San Diego, California) 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 HCl. 
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(e)® (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 
lipid components. However, unlike the other two products, EXPAREL employs a novel 
lipid excipient (dierucoylphosphatidylcholine [DEPC]) in its formulation. 
 
1.1 
Objectives 
 
1.1.1 
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. 


CONFIDENTIAL AND PROPRIETARY 
Page 4 of 8 
 
 
 
 
1.1.2 
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. 
 
1.2 
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. This study is to enroll 180 patients 
in up to 30 sites in the US and Europe. 
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). 
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. 
Exclusion criteria will include 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. 
 
1.3 
ECG Selection 
 
ECGs will be obtained by recording digital 12 lead ECGs on a Holter recorder (MORTARA 
H12+) started at baseline (approximately 1 hour prior to surgery) and will continue for a total of 
72 hours. All subjects will have an ECG extracted at baseline and then post-treatment ECG(s ) 
will be extracted at the determination of the Tmax of bupivacaine for each study participant. 
Subjects who are treated with EXPAREL and have PK blood draws will have a single post- 
treatment ECG collected at actual Tmax. Subjects who are treated with placebo or who do not 
have PK blood draws will have post-treatment ECGs extracted at both the mean and median 
Tmax. The unblinded statistician will supply the mean and median Tmax time points for these 
subjects based on the mean and median Tmax observed in the EXPAREL treated subjects who 
have PK blood draws. 


CONFIDENTIAL AND PROPRIETARY 
Page 5 of 8 
 
 
 
 
1.4 
Analysis of 12-Lead ECGs 
 
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, eResearchTechnology, Inc. (ERT; Philadelphia, PA, USA), will generate a 
10-second, 12-lead digital ECG at baseline and at Tmax (see Section 1.3).  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 captured by the central laboratory and processed via its validated data 
management system, EXPERT.  Interval duration measurements (IDMs) 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 will be 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 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 suggest 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 HR, RR, PR, QRS, QT, QTcF, and QTcB will be examined at 
Tmax. 


CONFIDENTIAL AND PROPRIETARY 
Page 6 of 8 
 
 
 
 
2 
ECG STATISTICAL PLAN 
 
2.1 
Subject Populations 
 
The ECG analysis will be performed on all enrolled subjects with at least one available pre-dose 
Day 1 baseline ECG and one post-dose ECG. 
All data collected will be presented in data listings. Unscheduled ECG data, if available, will not 
be included in formal ECG analysis tables, but will be included in subject data listings. 
Data from subjects excluded from an analysis population will be presented in the data listings, 
but will not be included in the calculation of summary statistics. 
 
2.2 
Central Tendency Analysis 
 
The baseline ECG interval value will be obtained from the ECG extracted prior to study drug 
administration. 
Descriptive statistics (e.g., frequency, percent, mean, standard deviation (SD), median, maximum 
and minimum) will be used to summarize the ECG variables and the corresponding changes 
from the baseline to the ECG(s) obtained at actual Tmax when it is obtained, and when not, both 
the median and mean Tmax values will be used in each subject (see Section 1.3).  This will 
provide a time point analysis which is detailed in the tables separately for placebo and liposome 
bupivacaine. 
 
2.3 
Outlier Analyses 
 
An outlier analysis will supplement the central tendency analysis by determining if there are 
subjects who had an exaggerated effect on any ECG interval that would not be revealed in a 
mean change from baseline central tendency analysis. 
Therefore, the data will be presented as the frequency and percent of subjects with each type of 
outlier.  The following criteria (“study endpoints”) are defined for this analysis (“new” means 
not present at baseline and becomes present on a post-dose ECG time point): 
• Heart rate:  A value for a subject is considered to be an outlier if the heart rate 
measurement at the post-dose time point is <50 bpm and the measure is at least a 25% 
decrease from the subject’s baseline heart rate (i.e., a bradycardic event) or if the heart 
rate measurement at the post-dose time point is >100 bpm and the measure is at least a 
25% increase from the baseline heart rate (i.e., a tachycardic event). 
• PR interval:  A value for a subject is considered to be an outlier if the PR interval at the 
post-dose time point is >200 ms and it is at least a 25% increase from the subject’s 
baseline PR interval. 


CONFIDENTIAL AND PROPRIETARY 
Page 7 of 8 
 
 
 
 
• QRS interval:  A value for a subject is considered to be an outlier if the QRS interval at 
the post-dose time point is >100 ms and it is at least a 25% increase from the subject’s 
baseline QRS interval. 
• QT interval:  A value for a subject is considered to be an outlier if the QT interval at the 
post-dose time point is >500 ms and the subject’s baseline QT interval is 500 ms. 
• QTcF: A value for a subject is considered to be an outlier if the QTcF interval at the 
post-dose time point is >500 ms and the subject’s baseline QTcF interval is 500 ms. 
Outlier values will also be presented if the QTcF interval at the post-dose time point is 
>480 ms when the subject’s baseline QTcF interval is 480 ms and when the post-dose 
time point is >450 ms when the subject’s baseline QTcF interval is 450 ms.  In addition, 
the proportion of subjects with changes from baseline of >30-60 ms and >60 ms will be 
presented. 
• QTcB: A value for a subject is considered to be an outlier if the QTcB interval at the 
post-dose time point is >500 ms and the subject’s baseline QTcB interval is 500 ms. 
Outlier values will also be presented if the QTcB interval at the post-dose time point is 
>480 ms when the subject’s baseline QTcB interval is 480 ms and when the post-dose 
time point is >450 ms when the subject’s baseline QTcB interval is 450 ms.  In addition, 
the proportion of subjects with changes from baseline of >30-60 ms and >60 ms will be 
presented. 
The data will be presented by time point (actual Tmax, mean Tmax and median Tmax) separately for 
liposome bupivacaine and placebo. 
A categorical or outlier analysis will be considered exploratory since the study was not powered 
to pick up unusual individual responses to the potential effects of drugs. Outlier analyses will 
produce data as the percentage of subjects in each treatment group that meet the criteria as 
defined for this analysis.  All outliers will be summarized by treatment group on the basis of 
incidence rates. The outlier summary tables will include counts of subjects. 
 
2.4 
Morphological Analysis 
 
Morphological analyses will be performed with regard to the ECG waveform interpretation as 
defined by the central ECG laboratory’s cardiologist. Changes from baseline to the post-dose 
ECG(s) will be done. 
All findings will be presented in the ECG listings. New onset (presented as percentage of 
subjects meeting the new criteria) for the following variables will be detailed in the tables: 
• Atrial fibrillation or flutter 
• Second degree heart block, 


CONFIDENTIAL AND PROPRIETARY 
Page 8 of 8 
 
 
 
 
• Third degree heart block, 
• Complete right bundle branch block, 
• Complete left bundle branch block, 
• ST segment depression, 
• ST segment elevation, 
• T wave abnormalities (negative T waves only), 
• Myocardial infarction pattern, and 
• Any new abnormal U waves. 
The data will be presented in the tables by time point (actual Tmax, mean Tmax and median Tmax) 
separately for the liposome bupivacaine and placebo groups as detailed above for the central 
tendency analyses. 
 
3 
DEVIATIONS IN ANALYSIS FROM STATISTICAL PLAN AND OTHER 
ISSUES 
 
Deviations of the actual final statistical analysis from the statistical plan will be described and 
justified in the final report.