Conditions: Dental Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 166
Healthy volunteers: no

Brief summary:
This is a Phase 3, randomized, double-blind, placebo-controlled study in subjects scheduled to undergo elective bilateral third molar extraction under local anesthesia. At least one lower mandibular third molar must involve full or partial bony impaction confirmed by visual or radiographic evidence.

Detailed description:
Subjects will be screened within 30 days prior to surgery.

Randomized subjects will receive a dental nerve block with lidocaine 2% with epinephrine 1:100,000 before undergoing bilateral third molar extraction under local anesthesia. In addition to the lidocaine nerve block, the Investigator may choose to add topical benzocaine or intraoperative nitrous oxide.

At the end of surgery, and at least 20 minutes after the lidocaine administration, blinded study drug will be infiltrated to provide postsurgical analgesia. Subjects will be required to remain in the research facility for 96 hours after study drug administration.

Postsurgical efficacy, safety, and pharmacokinetic (PK) assessments will be conducted.

All subjects will return for a follow-up visits on Days 7 and 10. A phone call will be made to each subject on Day 30 for an adverse event (AE) assessment and to inquire as to whether the subject made any unscheduled phone calls or office visits related to pain.

Arms:
arm 1: 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration arm 2: 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration

Interventions: intervention 1: Bupivacaine liposome intervention 2: Placebo
Intervention descriptions: intervention 1: Local administration intervention 2: Local administration

Protocol document:
Prot_000.pdf: 
Pacira Pharmaceuticals, Inc. 
 
 
EXPAREL 
Document: 
Clinical Study Protocol 
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Efficacy, and Pharmacokinetics of Local Administration of 
EXPAREL for Prolonged Postsurgical Analgesia in Subjects 
Undergoing Third Molar Extraction 
NCT Number: 
NCT02517905 
Document Date: 
September 02, 2015 
 


 
 
Clinical Study Protocol 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Efficacy, 
and Pharmacokinetics of Local Administration of EXPAREL for Prolonged Postsurgical 
Analgesia in Subjects Undergoing Third Molar Extraction 
 
 
 
 
 
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-329 
EudraCT No.: Not applicable 
IND No.: 69,198 
Study Phase: 3 
Study Drug: EXPAREL® (bupivacaine liposome injectable suspension) 
Date: 02 September 2015 (Amendment 2)  
27 July 2015 (Amendment 1)  
27 May 2015 (original) 
Study Sites: Multicenter study in the United States 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
Tel: (973) 254-3560 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
2 of 68  
02 September 2015 
SUMMARY OF CHANGES 
Section 2 (Synopsis)  
 Secondary Objectives: 
The text was changed  
from: “The secondary objectives of this study are to assess additional efficacy parameters, 
characterize the pharmacokinetic (PK) profile in this surgical model, and further assess the 
safety profile of EXPAREL.” 
to: “The secondary objectives of this study are to assess additional efficacy parameters, 
characterize the pharmacokinetic (PK) profile in this surgical model, and further assess the 
safety and tolerability of EXPAREL.” 
 Methodology:  
o The sample size was increased from approximately 100 subjects (50 per treatment group) 
to approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 
75 subjects in the placebo group).   
o The randomization was changed from 1:1 to 2:1.   
o The following text was added: “Subjects will be prohibited from smoking cigarettes or 
e-cigarettes from the time of randomization until discharge from the clinical research 
unit.” 
o The interim analysis was removed. 
o A Day 7 follow-up visit was added. 
o The following text was changed 
from: “Adverse events will be recorded from the time the ICF is signed through Day 30.  
If a cardiac or neurological event occurs during the study, an unscheduled PK blood 
sample and ECG should be obtained within 2 hours of the time the event is noted.” 
to: “Adverse events will be recorded from the time the ICF is signed through Day 30.  
If a cardiac event (e.g., myocardial depression, decreased cardiac output, heart block, 
hypotension, bradycardia, ventricular arrhythmia, or cardiac arrest) or a neurological 
event (e.g., persistent anesthesia, paresthesia, weakness, or paralysis) occurs during the 
study, an unscheduled PK blood sample should be obtained and, for cardiac events, an 
ECG should be conducted within 2 hours of the time the event is noted.” 
o The following text was added under postsurgical analgesia: “After 96 hours, the analgesic 
regimen may be adjusted.”  
o The following text was changed 
from: “All postsurgical opioid analgesics administered must be documented through 
96 hours.”  
to: “All postsurgical analgesics administered must be documented through Day 10.” 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
o A Day 7 blood draw for PK analysis was added. 
o The following sentence was deleted: “However, blood samples from subjects randomized 
to the placebo group will not be analyzed.”   
 Number of Subjects Planned:  
The sample size was increased from approximately 100 subjects (50 per treatment group) to 
approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 75 subjects in 
the placebo group).   
 Eligibility Criteria: 
For clarification of exclusion criterion 6, the semicolons were changed to commas.  
 Efficacy Assessments:  
o The NRS pain intensity assessment timepoint of at first request for rescue pain 
medication was changed to immediately prior to each administration of rescue pain 
medication through 96 hours. 
o The final timepoint for the PoSSe scale questionnaire was changed from Day 10 to 
Day 7. 
 Tertiary Efficacy Endpoints:  
o The AUC of the NRS pain intensity scores through 96 hours and Day 10 was changed to 
the AUC of the NRS pain intensity scores through 96 hours. 
o The NRS pain intensity scores at each assessed timepoint and at first request for rescue 
pain medication was changed to the NRS pain intensity scores at each assessed timepoint 
and immediately prior to each administration of rescue pain medication through 96 hours.  
o The sum of the pain intensity scores (SPIS) through 24, 48, 72, and 96 hours was added. 
o The PoSSe scale questionnaire mean total score at 72 hours and on Day 10 was changed 
to the PoSSe scale questionnaire mean total score at 72 hours and on Day 7.  
 Pharmacokinetic Analysis:  
A Day 7 blood draw for PK analysis was added. 
 Safety Assessments:  
A 96-hour timepoint (i.e., time of discharge) was added for vital signs. 
 Statistical Methods:  
The interim analysis text was removed. 
 
Table 1 (Time and Events Schedule of Study Procedures) 
 A column was added for the Day 7 assessments.   
 The timeframe for recording opioid rescue use was changed from 96 hours to Day 10. 
 The Day 10 pain intensity assessment was deleted. 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
 A 96-hour timepoint (i.e., time of discharge) was added for vital signs. 
 The final timepoint for the PoSSe scale questionnaire was changed from Day 10 to Day 7. 
 Footnote 3: “Seated position” was changed to “supine position.” 
 Footnote 4: “NRS pain intensity scores also will be recorded at first request for rescue pain 
medication” was changed to “NRS pain intensity scores also will be recorded immediately 
prior to each administration of rescue pain medication through 96 hours.” 
 Footnote 6: Text was changed  
from: “If a cardiac or neurological event occurs during the study, an unscheduled PK blood 
sample and ECG should be obtained within 2 hours of the time that the event is noted.”   
to: “If a cardiac event (e.g., myocardial depression, decreased cardiac output, heart block, 
hypotension, bradycardia, ventricular arrhythmia, or cardiac arrest) or neurological event 
(e.g., persistent anesthesia, paresthesia, weakness, or paralysis) occurs during the study, an 
unscheduled PK blood sample should be obtained and, for cardiac events, an ECG should be 
conducted within 2 hours of the time that the event is noted.” 
 
Section 3 (Table of Contents) 
The Table of Contents was updated. 
 
Section 4.1 (List of Abbreviations) 
The sum of pain intensity scores (SPIS) was added. 
 
Section 8.2 (Secondary Objectives) 
The text was changed  
from: “The secondary objectives of this study are to assess additional efficacy parameters, 
characterize the pharmacokinetic (PK) profile in this surgical model, and further assess the safety 
profile of EXPAREL.” 
to: “The secondary objectives of this study are to assess additional efficacy parameters, 
characterize the pharmacokinetic (PK) profile in this surgical model, and further assess the safety 
and tolerability of EXPAREL.” 
 
Section 9 (Study Design and Plan) 
 The sample size was increased from approximately 100 subjects (50 per treatment group) to 
approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 75 subjects in 
the placebo group).   
 The randomization was changed from 1:1 to 2:1.   


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
 The following text was added: “Subjects will be prohibited from smoking cigarettes or 
e-cigarettes from the time of randomization until discharge from the clinical research unit.” 
 The interim analysis was removed. 
 A Day 7 follow-up visit was added.   
 The following text was changed 
from: “Adverse events will be recorded from the time the ICF is signed through Day 30.  If a 
cardiac or neurological event occurs during the study, an unscheduled PK blood sample and 
ECG should be obtained within 2 hours of the time the event is noted.” 
to: “Adverse events will be recorded from the time the ICF is signed through Day 30.  If a 
cardiac event (e.g., myocardial depression, decreased cardiac output, heart block, 
hypotension, bradycardia, ventricular arrhythmia, or cardiac arrest) or neurological event 
(e.g., persistent anesthesia, paresthesia, weakness, or paralysis) occurs during the study, an 
unscheduled PK blood sample should be obtained and, for cardiac events, an ECG should be 
conducted within 2 hours of the time the event is noted.” 
 “All postsurgical opioid analgesics administered must be documented through 96 hours” 
was changed to “All postsurgical analgesics administered must be documented through 
Day 10.” 
 The following text was added under postsurgical analgesia: “After 96 hours, the analgesic 
regimen may be adjusted.”   
 A Day 7 blood draw for PK analysis was added. 
 The following sentence was deleted: “However, blood samples from subjects randomized to 
the placebo group will not be analyzed.”   
 
Section 10.2 (Exclusion Criteria) 
For clarification of exclusion criterion 6, the semicolons were changed to commas.  
 
Section 11.1 (Treatment to be Administered) 
The text was changed  
from: “Subjects should only receive rescue pain medication (PO oxycodone 5-10 mg) upon 
request for breakthrough pain, as needed (maximum of every 4 hours).  All postsurgical opioid 
analgesics administered must be documented through 96 hours.  No other analgesic agents, 
including NSAIDs, are allowed during the 96-hour observation period.” 
to: “Subjects should only receive rescue pain medication (PO oxycodone 5-10 mg) upon request 
for breakthrough pain, as needed (maximum of every 4 hours).  No other analgesic agents, 
including NSAIDs, are allowed during the 96-hour observation period.  After 96 hours, the 
analgesic regimen may be adjusted.  All postsurgical analgesics administered must be 
documented through Day 10.”   


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
Section 11.3.1 (Randomization Scheme) 
The following text was changed  
from: “Approximately 100 subjects (50 per treatment group) are planned for enrollment.  
Subjects will be randomized in a 1:1 ratio to receive local administration of a single dose of 
either EXPAREL (133 mg/10 mL) or placebo (normal saline, 10 mL).” 
to: “Approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 75 subjects 
in the placebo group) are planned for enrollment.  Subjects will be randomized in a 2:1 ratio to 
receive local administration of a single dose of either EXPAREL (133 mg/10 mL) or placebo 
(normal saline, 10 mL).” 
 
Section 11.5.1 (Blinding Procedures) 
The following text was added: “The site-specific blinding plan will outline the study treatment 
blinding process that will be followed at the site throughout the study.”    
 
Section 11.5.2 (Unblinding Procedures) 
The first two paragraphs in the section were changed  
from: “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.” 
to: “Subject treatment assignments should not be unblinded during the study by blinded study 
personnel.  The Investigator will have the ability to unblind a subject through the randomization 
system 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.  
Any unblinding performed through the randomization system will be recorded as a transaction 
and the appropriate study personnel will be notified that such a transaction occurred.” 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
Section 11.6.1 (Prior and Concomitant Medications and Therapy) 
Under concomitant medications, the following text was changed  
from: “All medications taken within 3 days prior to study drug administration through Day 30 
will be recorded on the CRF.”     
to: “All medications taken within 30 days prior to study drug administration through Day 30 will 
be recorded on the CRF.” 
 
Section 11.6.3 (Permitted and Restricted Therapy or Medications After Surgery Through 
96 Hours) 
This section was revised  
from:  
Permitted 
Subjects should only receive rescue pain medication (PO oxycodone 5-10 mg) upon request for 
breakthrough pain, as needed (maximum of every 4 hours).  All postsurgical opioid analgesics 
administered must be documented through 96 hours.   
Restricted 
No other analgesics are permitted within 96 hours after surgery.  For study purposes, it is 
important to standardize pain management modalities during the first 96 hours following study 
drug administration.  Therefore, the study staff must adhere closely to the treatment requirements 
noted in the protocol.  After 96 hours, the analgesic regimen may be adjusted for each subject 
individually, as deemed appropriate by the physician responsible for the postsurgical care. 
to: 
Subjects should only receive rescue pain medication (PO oxycodone 5-10 mg) upon request for 
breakthrough pain, as needed (maximum of every 4 hours).  No other analgesics are permitted 
within 96 hours after surgery.   
For study purposes, it is important to standardize pain management modalities during the first 
96 hours following study drug administration.  Therefore, the study staff must adhere closely to 
the treatment requirements noted in the protocol.  After 96 hours, the analgesic regimen may be 
adjusted for each subject individually, as deemed appropriate by the physician responsible for the 
postsurgical care. 
All postsurgical analgesics administered must be documented through Day 10.  
 
Section 12.1 (Efficacy Assessments) 
 The NRS pain intensity assessment at first request for rescue pain medication was changed to 
immediately prior to each administration of rescue pain medication through 96 hours. 
 The Day 10 pain intensity assessment was deleted. 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
 The final timepoint for the PoSSe scale questionnaire was changed from Day 10 to Day 7. 
 
Section 12.2 (Efficacy Endpoints) 
Tertiary efficacy endpoints: 
 The AUC of the NRS pain intensity scores through 96 hours and Day 10 was changed to 
the AUC of the NRS pain intensity scores through 96 hours. 
 “The NRS pain intensity scores at each assessed timepoint and at first request for rescue 
pain medication” was changed to “The NRS pain intensity scores at each assessed 
timepoint and immediately prior to each administration of rescue pain medication 
through 96 hours.”  
 The sum of the pain intensity scores (SPIS) through 24, 48, 72, and 96 hours was added. 
 The PoSSe scale questionnaire mean total score at 72 hours and on Day 10 was changed 
to the PoSSe scale questionnaire mean total score at 72 hours and on Day 7.  
 
Section 12.3 (Pharmacokinetic Analysis) 
 A Day 7 blood draw for PK analysis was added. 
 The following sentence was deleted: “However, blood samples from subjects randomized to 
the placebo group will not be analyzed.”   
 
Section 12.5 (Safety Assessments) 
A 96-hour timepoint (i.e., time of discharge) was added for vital signs. 
 
Section 13.1.3 (Vital Signs) 
“Seated position” was changed to “supine position.” 
 
Section 13.1.4 (Electrocardiogram) 
“Seated position” was changed to “supine position.” 
 
Section 13.1.6 (Postoperative Symptom Severity [PoSSe] Scale Questionnaire) 
The final timepoint for the PoSSe scale questionnaire was changed from Day 10 to Day 7. 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
Section 13.2 (Screening Procedures) 
“Measure vital signs (heart rate and blood pressure) after subject has rested in the seated 
position” was changed to “Measure vital signs (heart rate and blood pressure) after subject has 
rested in a supine position.” 
 
Section 13.3 (Baseline Procedures [Day 1]) 
“Measure vital signs (heart rate and blood pressure) after subject has rested in the seated 
position” was changed to “Measure vital signs (heart rate and blood pressure) after subject has 
rested in a supine position.” 
 
Section 13.5 (Procedures After Surgery Through 96 Hours) 
 The NRS pain intensity assessment timepoint of at first request for rescue pain medication 
was changed to immediately prior to each administration of rescue pain medication through 
96 hours. 
 “Measure vital signs (heart rate and blood pressure) after subject has rested in the seated 
position at 1, 2, and 4 hours” was changed to “Measure vital signs (heart rate and blood 
pressure) after subject has rested in a supine position at 1, 2, 4, and 96 hours (i.e., prior to 
discharge).” 
 The following text was changed 
from: “If a cardiac or neurological event occurs during the study, an unscheduled PK blood 
sample and ECG should be obtained within 2 hours of the time that the event is noted.”   
to: “If a cardiac event (e.g., myocardial depression, decreased cardiac output, heart block, 
hypotension, bradycardia, ventricular arrhythmia, or cardiac arrest) or neurological event 
(e.g., persistent anesthesia, paresthesia, weakness, or paralysis) occurs during the study, 
an unscheduled PK blood sample should be obtained and, for cardiac events, an ECG should 
be conducted within 2 hours of the time that the event is noted.”   
 
Section 13.6 (Day 7 Visit) 
This section was added.  
  
Section 13.7 (Day 10 Visit) 
 
The NRS pain intensity assessment was deleted. 
 
“Record date, time, and amount of all opioid pain medication administered” was deleted. 
 
The PoSSe scale questionnaire on Day 10 was deleted. 


Pacira Pharmaceuticals, Inc. 
 
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EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
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02 September 2015 
 
“Document any unscheduled phone calls or office visits related to pain after discharge” 
was changed to “Document any unscheduled phone calls or office visits related to pain 
since Day 7.” 
 
“Record concomitant medications” was changed to “Record concomitant medications 
including opioid rescue.” 
 
Section 14.1.2 (Recording Adverse Events) 
 The following paragraph was changed: 
from: “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.” 
to: “All AEs will be followed through progression 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 end date 
when the severity changes to moderate.  A new AE record with a moderate severity will be 
created with a start date that is the same as the end date of the mild AE.” 
 The following text was changed 
from: “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.” 
to: “Any condition noted before the subject signs the ICF will be listed as Medical History 
and is considered a pre-existing condition.  If a pre-existing condition changes (i.e., becomes 
more severe or more frequent) at any time after the subject signs the ICF it is considered 
an AE.”   
 The following text was changed 
from: “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.”    
to: “Information recorded on the AE CRF will include the AE term, the date and time of 
onset, severity, seriousness, relationship to study drug, action taken with subject due to AE, 
and the outcome of the AE, including the date and time of resolution, if applicable.” 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
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02 September 2015 
Section 14.2.2 (Reporting Serious Adverse Events) 
The following sentence was deleted: “Additional telephone contact information for Pacira Drug 
Safety/designee can be found in the regulatory binder.” 
 Section 15.3 (Determination of Sample Size) 
The following text was added: “However, the EXPAREL group will randomize approximately 
100 subjects to lower the AE detection threshold for the safety database to 3%.  The sample size 
for placebo was increased due to the additional collection of NRS pain intensity score 
immediately prior to all requests for rescue medication through 96 hours.  The placebo sample 
size was increased to ensure that there are at least 50 subjects treated in both the EXPAREL and 
placebo under the current protocol amendment.  It is expected that the sample size will be 
approximately 175 subjects resulting in a 2:1 ratio of EXPAREL to placebo subjects.” 
 
Section 15.8 (Interim Analysis) 
This section was removed.     
 
Section 16 (References) 
The EXPAREL IB reference was updated from Edition 16 (23 October 2013) to Edition 17 
(12 May 2015).     
 
Section 18 (Appendix 1) 
 The NRS pain intensity assessment timepoint of at first request for rescue pain medication 
was changed to immediately prior to each administration of rescue pain medication through 
96 hours. 
 The Day 10 pain intensity assessment was deleted. 
 
Section 18 (Appendix 3) 
 The final timepoint for the PoSSe scale questionnaire was changed from Day 10 to Day 7. 
 Minor edits were made to the questionnaire. 
 
Section 18 (Appendix 4) 
The following text was added: “If the subject is not oriented, the event should be recorded as 
an AE.” 
 


Pacira Pharmaceuticals, Inc. 
 
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02 September 2015 
1. 
SIGNATURE PAGE 
 
 
 
 
 
 
 
03 September 2015 
 
 James B. Jones, MD, PharmD, FACEP 
Sr. Vice President and Chief Medical Officer 
Date 
 
 
 
 
 
 
 
02 September 2015 
 
 George M. Wagner, Vice President 
Regulatory Affairs and Pharmacovigilance 
 
Date 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine free base, 1.3%, 13.3 mg/mL 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Efficacy, and 
Pharmacokinetics of Local Administration of EXPAREL for Prolonged Postsurgical Analgesia in Subjects 
Undergoing Third Molar Extraction 
Principal Investigators: To be determined 
Study Center(s): At least two study sites in the United States 
Publications (Reference): None 
Objectives:  
Primary objective: The primary objective of this study is to demonstrate the analgesic efficacy of single-dose local 
administration of EXPAREL compared with placebo in subjects following bilateral third molar extraction.   
Secondary objectives: The secondary objectives of this study are to assess additional efficacy parameters, 
characterize the pharmacokinetic (PK) profile in this surgical model, and further assess the safety and tolerability 
of EXPAREL. 
Methodology:  
This is a Phase 3, randomized, double-blind, placebo-controlled study in subjects scheduled to undergo elective 
bilateral third molar extraction (i.e., extraction of all four third molars) under local anesthesia.  At least one lower 
mandibular third molar must involve full or partial bony impaction confirmed by visual or radiographic evidence. 
Approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 75 subjects in the placebo group) 
are planned for enrollment.  Subjects will be randomized in a 2:1 ratio to receive local administration of a single 
dose of either EXPAREL (133 mg/10 mL) or placebo (normal saline, 10 mL). 
Screening 
Subjects will be screened within 30 days prior to surgery.  During the screening visit, subjects will be assessed 
for any past or present medical conditions that in the opinion of the Investigator would preclude them from study 
participation.  After the informed consent form (ICF) is signed, a medical/surgical history, dental examination, 
physical examination, vital sign measurements, urine pregnancy test for women of childbearing potential, urine 
drug screen, and 12-lead electrocardiogram (ECG) will be conducted. 
Day 1 (Day of Surgery) 
On Day 1 prior to surgery, any adverse events (AEs) or changes to concomitant medications since screening will 
be recorded, vital signs will be measured, a drug screen will be conducted, and a urine pregnancy test will be 
conducted for women of childbearing potential.  A pre-dose PK sample will be collected from all subjects eligible 
for randomization.  Randomized subjects will receive a dental nerve block with lidocaine 2% with epinephrine 
1:100,000 before undergoing bilateral third molar extraction under local anesthesia.  In addition to the lidocaine 
nerve block, the Investigator may choose to add topical benzocaine or intraoperative nitrous oxide.   
At the end of surgery and at least 20 minutes after the lidocaine administration, study drug will be infiltrated as 
follows to provide postsurgical analgesia:  


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
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02 September 2015 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine free base, 1.3%, 13.3 mg/mL 
 
Maxilla  At the depth of the posterior buccal vestibule, two points of infiltration submucosal and 
supraperiosteal are identified at the apex of the extracted third molar.  The sites are separated by 6-8 mm and 
1 mL of EXPAREL infiltrated in each site (2 mL on each side), for a total of 4 mL in the maxilla. 
 
Mandible  After readaptation and closure of the mucoperiosteal flap, the external oblique ridge is palpated 
identifying the buccinator muscle attachment.  Four infiltration points separated by 6-8 mm are selected 
along this line.  The needle is inserted approximately 5 mm and 0.5 mL of EXPAREL is infiltrated into the 
muscle at each point (total of 2 mL per side for this step).  At the point of greatest subperiosteal reflection, 
just lateral to the third molar socket, two infiltrations are taken deeper (1.5 cm) and 0.5 mL is infiltrated as 
the needle is withdrawn (total of 1 mL per side for this step).  Thus, the total is 6 mL in the mandible. 
Subjects will be required to remain in the research facility for 96 hours after study drug administration.  Subjects 
will be prohibited from smoking cigarettes or e-cigarettes from the time of randomization until discharge from the 
clinical research unit. 
After the first 30 subjects have completed the study through Day 10, the initial plasma samples from the subjects 
who received EXPAREL will be analyzed.  Following a blinded review of the PK data, the protocol may be 
amended so that subsequent assessment and endpoints are collected beyond the median time to maximum plasma 
concentration (Tmax).   
Postsurgical Safety and Efficacy Assessments  
Postsurgical assessments will include pain intensity scores using the 0-10 point numeric rating scale (NRS); use of 
supplemental opioid rescue medication; neurological assessment; 12-lead ECGs; vital signs; subject’s satisfaction 
with postsurgical pain control; and the postoperative symptom severity (PoSSe) scale questionnaire.  At timepoints 
when multiple assessments coincide, the NRS pain intensity assessment will be conducted first, if applicable.  
All subjects will return for follow-up visits on Days 7 and 10.  A phone call will be made to each subject on 
Day 30 for an AE assessment and to inquire as to whether the subject made any unscheduled phone calls or office 
visits related to pain.   
Adverse events will be recorded from the time the ICF is signed through Day 30.  If a cardiac event (e.g., 
myocardial depression, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmia, or 
cardiac arrest) or a neurological event (e.g., persistent anesthesia, paresthesia, weakness, or paralysis) occurs 
during the study, an unscheduled PK blood sample should be obtained and, for cardiac events, an ECG should be 
conducted within 2 hours of the time the event is noted.  If there is a scheduled PK blood draw and ECG within 
2 hours before or after the event, an additional PK blood draw and ECG are not needed. 
Postsurgical Analgesia  
Subjects should only receive rescue pain medication (oral [PO] oxycodone 5-10 mg) upon request for breakthrough 
pain, as needed (maximum of every 4 hours).  No other analgesic agents, including nonsteroidal anti-inflammatory 
drugs (NSAIDs), are allowed during the 96-hour observation period.  After 96 hours, the analgesic regimen may be 
adjusted.  All postsurgical analgesics administered must be documented through Day 10.   
Pharmacokinetic Assessment  
Blood samples for PK analysis will be obtained at baseline (prior to study drug administration); 15 minutes, 
30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours after the beginning of study drug 
administration; and on Days 7 and 10.  Blood samples will be collected from all subjects to maintain the treatment 
double-blind.   
Number of Subjects (Planned): Approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 
75 subjects in the placebo group) are planned for enrollment into the study.   


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
15 of 68  
02 September 2015 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine free base, 1.3%, 13.3 mg/mL 
Eligibility Criteria: 
Inclusion Criteria: 
1. Male or female, ≥18 years of age at screening.  
2. Scheduled to undergo bilateral third molar extractions (i.e., extraction of all four third molars) under local 
anesthesia.  At least one lower mandibular third molar must involve full or partial bony impaction confirmed 
by visual or radiological evidence.  
3. American Society of Anesthesiology (ASA) physical status 1, 2, or 3. 
4. Female subjects must be either surgically sterile, using a medically acceptable method of birth control, or at 
least 2 years postmenopausal, and must have a documented negative pregnancy test result during screening and 
on Day 1 prior to surgery. 
5. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments. 
Exclusion Criteria: 
1. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics or opioids. 
2. Contraindication to lidocaine, epinephrine, bupivacaine, or oxycodone. 
3. History of significant drug allergy (e.g., anaphylaxis or hepatotoxicity). 
4. Positive test result from the urine drug screen at screening or prior to the surgical procedure.  
5. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study 
drug administration.   
6. History or active psychiatric illness (including major depression, bipolar disorder, or anxiety), Type 1 or 
Type 2 diabetes, severe renal or hepatic impairment, significant cardiovascular disease (including cardiac 
rhythm disturbance), migraine headaches, frequent headaches, other pain conditions, or other medical 
condition that, in the opinion of the Investigator, may increase the risk of surgery or interfere with the 
evaluation of the study drug. 
7. History of infection requiring intravenous (IV) antibiotics within 45 days or oral (PO) antibiotics within 
30 days prior to study drug administration for reasons other than dental prophylaxis.  Subjects must be afebrile, 
without signs or symptoms indicative of active infection. 
8. Use of any of the following medications within the times specified before surgery: long-acting opioid 
medication, NSAIDs, aspirin (except for low-dose aspirin used for cardioprotection), or acetaminophen within 
3 days, or any opioid medication within 24 hours. 
9. Initiation of treatment with any of the following medications within 1 month of study drug administration or if 
the medication(s) are being given to control pain: selective serotonin reuptake inhibitors (SSRIs), selective 
norepinepherine reuptake inhibitors (SNRIs), gabapentin, pregabalin (Lyrica®), or duloxetine (Cymbalta®).  
If a subject is taking one of these medications for a reason other than pain control, he or she must be on a 
stable dose for at least 1 month prior to study drug administration. 
10. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. 
11. Use of any concurrent therapy that could interfere with the evaluation of efficacy or safety, such as any drugs 
which in the Investigator’s opinion may exert significant analgesic properties or act synergistically with the 
investigational product. 
12. 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. 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
16 of 68  
02 September 2015 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine free base, 1.3%, 13.3 mg/mL 
Test Product, Dose, Mode of Administration, and Lot Number:  
Name: EXPAREL® (bupivacaine liposome injectable suspension)  
Active Ingredient: Bupivacaine 1.3%, 13.3 mg/mL 
Dosage: Single administration of EXPAREL 133 mg in 10 mL 
Lot Number: To be determined 
Mode of Administration: Infiltration  
Meal Relationship: None 
Test Product, Dose, Mode of Administration, and Lot Number: 
Name: Placebo  
Active Ingredient: Normal saline 
Dosage: Single dose of 10 mL 
Lot Number: Commercial product to be procured by the study site 
Mode of Administration: Infiltration 
Meal Relationship: None 
Duration of Subject Participation in Study:   
Participation will begin upon signing of the ICF.  No more than 30 days should pass between signing the ICF and 
surgery.  A follow-up telephone call will occur on Day 30 (±4 days).  Therefore, each subject may participate in 
the study for a maximum of 64 days. 
Efficacy Assessments (timepoints may change based on the mean Tmax from the first 30 subjects):  
The following efficacy measurements will be conducted at the times specified after the beginning of study drug 
administration: 
 
Date, time of administration, and amount of all opioid rescue medication taken through 96 hours. 
 
Pain intensity scores using the NRS at 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours, 
immediately prior to each administration of rescue pain medication through 96 hours (see Appendix 1). 
 
Subject satisfaction with postsurgical pain control (using a 5-point Likert scale) at 24, 48, 72, and 96 hours, 
and on Day 10 (see Appendix 2). 
 
Postoperative symptom severity (PoSSe) scale questionnaire at 72 hours and on Day 7 (see Appendix 3). 
 
Unscheduled phone calls or office visits related to pain after discharge from the facility through Day 30. 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
17 of 68  
02 September 2015 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine free base, 1.3%, 13.3 mg/mL 
Efficacy Endpoints:  
Primary efficacy endpoint is the area under the curve (AUC) of the NRS pain intensity scores through 48 hours. 
Secondary efficacy endpoints: 
The following secondary endpoints will be analyzed in the following order using a hierarchical, fixed-sequence 
stepwise testing procedure: 
1. The AUC of the NRS pain intensity scores through 24 hours. 
2. The AUC of the NRS pain intensity scores through 72 hours. 
3. Percentage of opioid-free subjects through 24 hours. 
4. Percentage of opioid-free subjects through 48 hours. 
5. Percentage of opioid-free subjects through 72 hours. 
Tertiary efficacy endpoints: 
 
AUC of the NRS pain intensity scores through 96 hours. 
 
Sum of pain intensity scores (SPIS) through 24, 48, 72, and 96 hours. 
 
The NRS pain intensity scores at each assessed timepoint and immediately prior to each administration of 
rescue pain medication through 96 hours.  
 
The AUC of the NRS pain intensity scores from 24-48 and 48-72 hours. 
 
Percentage of pain-free subjects at each assessed timepoint using the NRS pain intensity score. 
 
Percentage of opioid-free subjects through 96 hours. 
 
Time to first opioid rescue medication. 
 
Integrated rank assessment using the NRS pain intensity score at 48 hours and the total amount of 
postsurgical opioids consumed through 48 hours (Silverman 1993). 
 
Overall assessment of the subject’s satisfaction with postsurgical pain control (using a 5-point Likert scale) 
at 24, 48, 72, and 96 hours, and on Day 10. 
 
PoSSe scale questionnaire mean total score at 72 hours and on Day 7. 
 
Number of unscheduled phone calls or office visits related to pain through Day 30. 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
18 of 68  
02 September 2015 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine free base, 1.3%, 13.3 mg/mL 
Pharmacokinetic Analysis:  
Pharmacokinetic parameters will be estimated from plasma bupivacaine measurements using non-compartmental 
analysis, based on the sampling schedule at baseline (prior to study drug administration); 15 minutes, 30 minutes, 
1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours after the beginning of study drug 
administration; and on Days 7 and 10.   
The following parameters will be determined:  
 
Area under the plasma concentration-versus-time curve (AUC) 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-∞). 
 
Maximum plasma concentration (Cmax). 
 
Time to maximum plasma concentration (Tmax). 
 
The apparent terminal elimination rate constant (λz). 
 
The apparent terminal elimination half-life (t1/2el). 
Safety Assessments:  
The following safety assessments will be conducted at the specified timepoints after the beginning of study drug 
administration:  
 
Neurological assessment at baseline (prior to study drug administration); 15 minutes, 30 minutes, 1, 2, 4, 8, 
12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours after the beginning of study drug administration; 
and on Day 10 (see Appendix 4). 
 
Cardiac assessment (i.e., 12-lead ECGs) at baseline (prior to study drug administration); 15 minutes, 
30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours after the beginning of study 
drug administration; and on Day 10.   
 
Vital signs (resting heart rate and blood pressure) at baseline (approximately 1 hour prior to surgery) and 
1, 2, 4, and 96 hours (i.e., time of discharge).  
 
Adverse events from the time the ICF is signed through Day 30.   
Safety Endpoints: 
 
Summary of neurological assessments. 
 
Change from baseline in ECG data closest to the median Tmax. 
 
Change from baseline in vital signs (resting heart rate and blood pressure) at each assessed timepoint.  
 
Incidence of treatment-emergent AEs (TEAEs) through Day 30. 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
19 of 68  
02 September 2015 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
(973) 254-3560 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine free base, 1.3%, 13.3 mg/mL 
Statistical Methods:  
A comprehensive statistical analysis plan will be developed for this study.  Demographic and baseline 
characteristics will be summarized descriptively by treatment group.  Efficacy data will be summarized by 
treatment group.  EXPAREL will be compared with placebo using analysis of variance (ANOVA) with treatment 
as the main effect for the primary efficacy endpoint of AUC of the NRS pain intensity scores through 48 hours.  
Other efficacy endpoints will be analyzed using ANOVA, chi-square tests, and log-rank tests, as appropriate.   
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.  If the first test is 
significant at the 0.05 level, then, and only then, the next secondary efficacy measure will be tested, and so forth.  
The results will be declared statistically significant at the 0.05 significance level. 
Safety endpoints will be summarized descriptively by treatment group.  The PK parameters will be calculated 
using non-compartmental analysis and summarized for the EXPAREL group. 


Pacira Pharmaceuticals, Inc. 
 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
 
20 of 68 
        02 September 2015 
Table 1. 
Time and Events Schedule of Study Procedures  
 
 
Screen 
Visit 
Day 1 15 
min 
30 
min 1h 
2h 
4h 
6h 
8h 
12h 18h 24h 30h 36h 42h 48h 54h 60h 66h 72h 84h 96h D7 D10 D30 
Time Window Within 
30 days 
 
±5 
min 
±5 
min 
±5 
min 
±15 
min 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±30 
min ±1h ±1h ±1h ±1h ±2h ±2h ±2h ±2h ±4h ±4h ±4h ±1d ±1d ±4d 
Obtain signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform dental examination1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination including height and 
weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for women of childbearing 
potential  
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs3  
X 
X2 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Neurological assessment 
 
X2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
12-lead electrocardiogram 
X 
X2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Randomize subject and prepare study drug 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform dental nerve block with lidocaine 2% 
with epinephrine 1:100,000 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study drug; record start and stop 
time 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct NRS pain intensity assessment4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Record times and amounts of opioid rescue 
medication administered5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject satisfaction with postsurgical pain 
control 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Complete PoSSe scale questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Collect scheduled PK blood sample 
 
X2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Document any unscheduled phone calls or office 
visits related to pain after hospital discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Record concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record AEs (starting at signing of ICF)6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pacira Pharmaceuticals, Inc. 
 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
 
21 of 68 
        02 September 2015 
Abbreviations: AE = adverse event; ICF = informed consent form; NRS = numeric rating scale; PK = pharmacokinetic; PoSSe = postoperative symptom severity. 
* Postsurgical efficacy assessments will be conducted at the timepoints specified after the beginning of study drug administration.  At timepoints when multiple assessments coincide, the NRS pain 
intensity assessment will be conducted first, if applicable. 
1   Or on Day 1 prior to surgery. 
2   Prior to surgery. 
3  Vital signs (heart rate and blood pressure) will be measured after subject has rested in a supine position. 
4 NRS pain intensity scores also will be recorded immediately prior to each administration of rescue pain medication through 96 hours. 
5 Subjects should only receive opioid rescue medication (oral oxycodone 5-10 mg) upon request for breakthrough pain, as needed (maximum of every 4 hours).  During the 96-hour observation 
period, no other analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), are allowed.  After 96 hours, the analgesic regimen may be adjusted.    
6 If a cardiac event (e.g., myocardial depression, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmia, or cardiac arrest) or neurological event (e.g., persistent 
anesthesia, paresthesia, weakness, or paralysis) occurs during the study, an unscheduled PK blood sample should be obtained and, for cardiac events, an ECG should be conducted within 2 hours 
of the time that the event is noted.  If there is a scheduled PK blood draw and ECG within 2 hours before or after the event, an additional PK blood draw and ECG are not needed. 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
22 of 68  
02 September 2015 
3. 
TABLE OF CONTENTS  
SUMMARY OF CHANGES ...........................................................................................................2 
1. 
SIGNATURE PAGE ..................................................................................................12 
2. 
SYNOPSIS .................................................................................................................13 
3. 
TABLE OF CONTENTS ...........................................................................................22 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................26 
4.1. 
List of Abbreviations ..................................................................................................26 
4.2. 
Definition of Terms ....................................................................................................27 
5. 
ETHICS ......................................................................................................................28 
5.1. 
Institutional Review Board/Independent Ethics Committee ......................................28 
5.2. 
Ethical Conduct of the Study ......................................................................................28 
5.3. 
Subject Information and Consent ...............................................................................28 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE .................29 
7. 
INTRODUCTION ......................................................................................................30 
7.1. 
Indication ....................................................................................................................30 
7.2. 
Current Therapies/Treatments ....................................................................................30 
7.3. 
EXPAREL (bupivacaine liposome injectable suspension) .........................................31 
7.4. 
Summary of Human Experience with EXPAREL ......................................................31 
8. 
OBJECTIVES .............................................................................................................33 
8.1. 
Primary Objectives .....................................................................................................33 
8.2. 
Secondary Objectives .................................................................................................33 
9. 
STUDY DESIGN AND PLAN ..................................................................................34 
9.1. 
Study Design ...............................................................................................................34 
9.1.1. 
Duration of the Study and Subject Participation ........................................................35 
9.1.2. 
Study Stopping Rules .................................................................................................36 
9.2. 
Discussion of Study Design ........................................................................................36 
10. 
STUDY POPULATION .............................................................................................37 
10.1. 
Inclusion Criteria ........................................................................................................37 
10.2. 
Exclusion Criteria .......................................................................................................37 
10.3. 
Removal of Subjects from Therapy or Assessment ....................................................38 
10.3.1. 
Withdrawal Secondary to Adverse Events .................................................................38 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
23 of 68  
02 September 2015 
10.3.2. 
Voluntary or Study Investigator Withdrawal .............................................................38 
11. 
TREATMENTS ..........................................................................................................39 
11.1. 
Treatment to be Administered ....................................................................................39 
11.1.1. 
Administration Technique ..........................................................................................39 
11.1.2. 
Study Drug Administration Considerations................................................................39 
11.2. 
Identity of Investigational Product(s) .........................................................................40 
11.2.1. 
Description of EXPAREL ..........................................................................................40 
11.2.2. 
Description of Reference Product ...............................................................................40 
11.2.3. 
Description of Diluents ...............................................................................................40 
11.3. 
Method of Assigning Subjects to Treatment ..............................................................40 
11.3.1. 
Randomization Scheme ..............................................................................................40 
11.3.2. 
Randomization Procedures .........................................................................................40 
11.3.3. 
Replacement of Subjects .............................................................................................40 
11.4. 
Selection of Doses in the Study ..................................................................................41 
11.5. 
Blinding ......................................................................................................................41 
11.5.1. 
Blinding Procedures ....................................................................................................41 
11.5.2. 
Unblinding Procedures ...............................................................................................42 
11.6. 
Prior and Concomitant Therapy and Medications ......................................................42 
11.6.1. 
Prior and Concomitant Medications and Therapy ......................................................42 
11.6.2. 
Permitted and Restricted Therapy or Medications During Surgery ...........................43 
11.6.3. 
Permitted and Restricted Therapy or Medications After Surgery Through 
96 Hours After Surgery ..............................................................................................43 
11.7. 
Treatment Compliance ................................................................................................43 
11.8. 
Accountability of Study Drug .....................................................................................43 
12. 
STUDY ENDPOINTS AND MEASUREMENTS ....................................................44 
12.1. 
Efficacy Assessments .................................................................................................44 
12.2. 
Efficacy Endpoints ......................................................................................................44 
12.3. 
Pharmacokinetic Analysis ..........................................................................................45 
12.4. 
Pharmacokinetic Endpoints ........................................................................................45 
12.5. 
Safety Assessments .....................................................................................................46 
12.6. 
Safety Endpoints .........................................................................................................46 
12.7. 
Appropriateness of Measures .....................................................................................46 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
24 of 68  
02 September 2015 
13. 
STUDY PROCEDURES ............................................................................................47 
13.1. 
Instructions for Conducting Procedures and Measures ..............................................47 
13.1.1. 
Pain Intensity Assessments .........................................................................................47 
13.1.2. 
Neurological Assessment ............................................................................................47 
13.1.3. 
Vital Signs ..................................................................................................................47 
13.1.4. 
Electrocardiogram .......................................................................................................47 
13.1.5. 
Subject Satisfaction with Postsurgical Pain Control ..................................................47 
13.1.6. 
Postoperative Symptom Severity (PoSSe) Scale Questionnaire ................................48 
13.2. 
Screening Procedures ..................................................................................................48 
13.3. 
Baseline Procedures (Day 1) ......................................................................................48 
13.4. 
Intraoperative Procedures (Day 1) ..............................................................................49 
13.5. 
Procedures After Surgery Through 96 Hours .............................................................49 
13.6. 
Day 7 Visit ..................................................................................................................50 
13.7. 
Day 10 Visit ................................................................................................................50 
13.8. 
Day 30 Phone Call ......................................................................................................50 
14. 
ADVERSE EVENT REPORTING ............................................................................51 
14.1. 
Adverse Events ...........................................................................................................51 
14.1.1. 
Definitions ..................................................................................................................51 
14.1.2. 
Recording Adverse Events .........................................................................................51 
14.1.3. 
Severity of Adverse Events ........................................................................................52 
14.1.4. 
Relationship of Adverse Events to Study Drug ..........................................................52 
14.1.5. 
Outcome of Adverse Events .......................................................................................53 
14.1.6. 
Action Taken with Subject due to an Adverse Event .................................................53 
14.2. 
Serious Adverse Events ..............................................................................................54 
14.2.1. 
Definition of a Serious Adverse Event .......................................................................54 
14.2.2. 
Reporting Serious Adverse Events .............................................................................54 
15. 
STATISTICAL METHODS .......................................................................................56 
15.1. 
Study Hypothesis ........................................................................................................56 
15.2. 
Study Endpoints ..........................................................................................................56 
15.3. 
Determination of Sample Size ....................................................................................56 
15.4. 
Analysis Populations ..................................................................................................56 
15.5. 
Handling Subject Dropouts and Discontinuations ......................................................57 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
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15.6. 
Statistical Analyses .....................................................................................................57 
15.6.1. 
Baseline Characteristics ..............................................................................................57 
15.6.2. 
Study Compliance .......................................................................................................57 
15.6.3. 
Efficacy Analyses .......................................................................................................57 
15.6.4. 
Pharmacokinetic Analyses ..........................................................................................58 
15.6.5. 
Safety Analyses ..........................................................................................................59 
15.7. 
Significance Testing ...................................................................................................59 
16. 
REFERENCES ...........................................................................................................60 
17. 
INVESTIGATOR AGREEMENT .............................................................................61 
18. 
APPENDICES ............................................................................................................62 
Appendix 1: Subject’s Reported Pain (Numeric Rating Scale) ..................................................63 
Appendix 2: Subject Satisfaction with Postsurgical Pain Control (Likert  Scale) ......................64 
Appendix 3: Postoperative Symptom Severity (PoSSe) Scale Questionnaire ............................65 
Appendix 4: Neurological Assessment .......................................................................................68 
 
LIST OF TABLES 
Table 1. 
Time and Events Schedule of Study Procedures ........................................................20 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
4.1. 
List of Abbreviations 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ASA 
American Society of Anesthesiologists 
AUC 
Area under the curve 
AUC0-tlast 
Area under the plasma concentration-time curve from the time of administration 
to the time of the last quantifiable concentration  
AUC0-∞ 
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 
Ctlast 
Time of the last quantifiable concentration 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
NRS 
Numeric rating scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PCA 
Patient-controlled analgesia 
PK 
Pharmacokinetic 
PO 
Oral 


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PoSSe 
Postoperative symptom severity 
PTEA 
Pretreatment adverse event 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SNRI 
Selective norepinephrine reuptake inhibitor 
SPIS 
Sum of the pain intensity scores 
SSRI 
Selective serotonin reuptake inhibitor 
λz 
The apparent terminal elimination rate constant 
t1/2el 
The apparent terminal elimination half-life 
TAP 
Transversus abdominis plane 
TEAE 
Treatment-emergent adverse event 
Tmax 
The time maximum plasma concentration  
wWOCF 
Windowed Worst-Observation-Carried-Forward 
US 
United States (of America) 
4.2. 
Definition of Terms 
Pharmacokinetic terms are defined in Section 12.4. 


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5. 
ETHICS 
5.1. 
Institutional Review Board/Independent Ethics Committee 
Prior to screening subjects into this study, each study site will obtain the approval of an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that complies with the 
International 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 or her 
medical care.  Similarly, the Investigator and/or Pacira Pharmaceuticals, Inc. (Pacira) is 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/IECs and regulatory agencies. 


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7. 
INTRODUCTION 
7.1. 
Indication 
EXPAREL® was developed to extend pain relief with a single dose administration without the 
use of indwelling catheters and to decrease the requirement for supplemental opioid medications.  
It is indicated for use as an analgesic injected into the surgical site for postsurgical pain relief. 
Effective postsurgical pain control is a critical element in patient recovery following surgery, 
as the majority of patients may experience significant pain, particularly in the first few days.  
Improved postsurgical pain management contributes to better healing, faster patient mobilization, 
shortened hospital stays, and reduced healthcare costs (American Society of Anesthesiologists 
Task Force on Pain Management 1995). 
7.2. 
Current Therapies/Treatments 
Current modalities of postoperative analgesia include infiltration with local anesthetic agents, 
and wound infiltration with local anesthetics combined with the systemic administration of 
analgesics (multimodal therapy).  Multimodal therapy usually includes opioid medications, 
which have considerable drawbacks including time and resources required for monitoring 
opioid-related side effects.  A reduction in the use of postoperative opioids is desirable to 
decrease the incidence and severity of opioid-induced adverse effects, such as respiratory 
depression, nausea, vomiting, constipation, somnolence, pruritus, and urinary retention.   
There are almost 12 billion units of opioids prescribed in the US every year, almost 2 billion of 
which are from the oral surgery arena.  Third molar extraction is associated with a defined period 
of pain and discomfort that often leads to the need for opioid analgesics.  Unfortunately, this has 
the drawback of subjecting the patient to opioid-related adverse events (AEs); depending on the 
specific event, this can occur in up to 50% of patients (Volkow 2011).  Previous studies with the 
use of EXPAREL have shown significant reduction in pain as well as total opioid consumption 
following both hard and soft tissue surgical procedures, along with a significant increase in many 
studies in median time to first opioid use.  This delay was also associated with fewer opioid 
related adverse effects. 
With over 70 million surgeries performed annually in the US, postoperative pain is a ubiquitous 
condition among our population.  While it is a predictable component of the postoperative 
process, such pain is often poorly managed, resulting in clinical and physiological changes that 
increase morbidity and mortality (inability to ambulate early, etc.), diminish quality of life, 
and extend length of stay, thereby increasing hospital expenditures (Oderda 2007) and reducing 
patient satisfaction.  Effective relief of acute pain with minimal opioid complications, on the 
other hand, may improve clinical outcomes, avoid complications (like delay in regaining bowel 
function or an inability to tolerate liquid and solid oral intake, etc.), and conserve healthcare 
resources.  As such, the Joint Commission on Accreditation of Healthcare Organizations requires 
that all healthcare facilities practice adequate pain management and monitor opioid-related AEs 
(Apfelbaum 2003). 


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Opioid analgesics have long been established to be the most effective agents used for the 
management of moderate to severe postoperative pain, and are currently considered the mainstay 
of treatment.  Opioid-only regimens are common and intravenous (IV) patient-controlled 
analgesia (PCA) is a widely used delivery system for morphine sulfate.  Adverse events related 
to opioid administration (e.g., nausea, vomiting, ileus, confusion), however, represent one 
important reason that there is a need to develop opioid-sparing strategies.  Indeed, fear of 
gastrointestinal side effects such as nausea and vomiting, as well as respiratory depression, 
present major limitations for the widespread use of opioid analgesics (Chernin 2001 and 
Viscusi 2009).  Furthermore, management of opioid-related events often requires medical 
attention (e.g., opioid antagonists, antiemetic agents) and increased pharmacy/nursing time, 
which may raise healthcare expenses (Carroll 1994).   
7.3. 
EXPAREL (bupivacaine liposome injectable suspension) 
Bupivacaine is one of the longer-acting local anesthetics, but even so it has a limited duration 
of action after local administration, usually reported as less than 8 hours.  EXPAREL (Pacira 
Pharmaceuticals, Inc., Parsippany, NJ) 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 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 its use in the US. 
 
DepoFoam, a liposomal extended-release formulation contained in the marketed product 
DepoCyt® (1999).  The form of DepoFoam used in each of the products – DepoCyt and 
EXPAREL – has a slightly different mixture of lipid components.   
7.4. 
Summary of Human Experience with EXPAREL 
Pacira has conducted more than 36 clinical studies and one observational follow-up study to 
investigate EXPAREL.  Across these studies, more than 1800 human subjects received 
EXPAREL at doses ranging from 2 mg to 665 mg (equivalent to 2 mg to 750 mg bupivacaine 
HCl) administered by various routes: local infiltration into the surgical site, subcutaneous, 
perineural (or “nerve block”), and epidural.  The product has been generally well tolerated and, 
in active comparator studies, reported AEs occurred at a similar rate as the corresponding 
bupivacaine HCl controls.   


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Across the entire clinical development program, in doses up to 665 mg, no adverse safety signal 
attributed to either CNS or cardiovascular system was reported with EXPAREL.  Adverse events 
that are occasionally reported with high doses of standard bupivacaine solution have not been 
observed.  In two rigorous QTc studies, EXPAREL did not cause significant QTc prolongation 
even at the highest dose evaluated.   
The robust nature of the efficacy results in the Phase 3 wound infiltration studies (SKY0402-C-
316 and SKY0402-C-317) and the Phase 2/3 nerve block study (402-C-323) was demonstrated 
across subgroups of subjects with various prognostic features and across demographic 
subgroups. 
Following the NDA submission of EXPAREL, numerous clinical studies were conducted in 
which EXPAREL was administered via various routes of administration including infiltration 
into the transversus abdominis plane (TAP) (Sternlicht 2014, Feierman 2014) and intraoperative 
wound infiltration or instillation.  Additionally, as of May 2015, more than one million patients 
have received EXPAREL in the postmarketing setting.  
Please refer to the Investigator’s Brochure for additional information regarding the completed 
studies.  Please see the EXPAREL Full Prescribing Information for complete safety information 
regarding EXPAREL (liposome bupivacaine injectable suspension) in the setting of wound 
infiltration. 
 


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8. 
OBJECTIVES 
8.1. 
Primary Objectives 
The primary objective of this study is to demonstrate the analgesic efficacy of single-dose local 
administration of EXPAREL compared with placebo in subjects following bilateral third molar 
extraction.   
8.2. 
Secondary Objectives 
The secondary objectives of this study are to assess additional efficacy parameters, characterize 
the pharmacokinetic (PK) profile in this surgical model, and further assess the safety and 
tolerability of EXPAREL. 
 


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9. 
STUDY DESIGN AND PLAN 
9.1. 
Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled study in subjects scheduled to 
undergo elective bilateral third molar extraction (i.e., extraction of all four third molars) under 
local anesthesia.  At least one lower mandibular third molar must involve full or partial bony 
impaction confirmed by visual or radiographic evidence. 
Approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 75 subjects in the 
placebo group) are planned for enrollment.  Subjects will be randomized in a 2:1 ratio to receive 
local administration of a single dose of either EXPAREL (133 mg/10 mL) or placebo (normal 
saline, 10 mL). 
Screening 
Subjects will be screened within 30 days prior to surgery.  During the screening visit, subjects 
will be assessed for any past or present medical conditions that in the opinion of the Investigator 
would preclude them from study participation.  After the ICF is signed, a medical/surgical 
history, dental examination, physical examination, vital sign measurements, urine pregnancy test 
for women of childbearing potential, urine drug screen, and 12-lead electrocardiogram (ECG) 
will be conducted.  
Day 1 (Day of Surgery) 
On Day 1 prior to surgery, any AEs or changes in concomitant medications since screening will 
be recorded, vital signs will be measured, a urine drug screen will be conducted for all subjects, 
and a urine pregnancy test will be conducted for women of childbearing potential.  A pre-dose 
PK sample will be collected from all subjects eligible for randomization.  Randomized subjects 
will receive a dental nerve block with lidocaine 2% with epinephrine 1:100,000 before 
undergoing bilateral third molar extraction under local anesthesia.  In addition to the lidocaine 
nerve block, the Investigator may choose to add topical benzocaine or intraoperative nitrous 
oxide.   
At the end of surgery, and at least 20 minutes after the lidocaine administration, study drug will 
be infiltrated as follows to provide postsurgical analgesia:   
 
Maxilla  At the depth of the posterior buccal vestibule, two points of infiltration 
submucosal and supraperiosteal are identified at the apex of the extracted third molar.  
The sites are separated by 6-8 mm and 1 mL of EXPAREL infiltrated in each site (2 mL 
on each side), for a total of 4 mL in the maxilla. 
 
Mandible  After readaptation and closure of the mucoperiosteal flap, the external 
oblique ridge is palpated identifying the buccinator muscle attachment.  Four infiltration 
points separated by 6-8 mm are selected along this line.  The needle is inserted 
approximately 5 mm and 0.5 mL of EXPAREL is infiltrated into the muscle at each point 
(total of 2 mL per side for this step).  At the point of greatest subperiosteal reflection, 
just lateral to the third molar socket, two infiltrations are taken deeper (1.5 cm) and 0.5 


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mL is infiltrated as the needle is withdrawn (total of 1 mL per side for this step).  Thus, 
the total is 6 mL in the mandible. 
Subjects will be required to remain in the research facility for 96 hours after study drug 
administration.  Subjects will be prohibited from smoking cigarettes or e-cigarettes from the time 
of randomization until discharge from the clinical research unit. 
After the first 30 subjects have completed the study through Day 10, the initial plasma samples 
from the subjects who received EXPAREL will be analyzed.  Following a blinded review of the 
PK data, the protocol may be amended so that subsequent assessment and endpoints are collected 
beyond the median time to maximum plasma concentration (Tmax).   
Postsurgical Safety and Efficacy Assessments  
Postsurgical assessments will include pain intensity scores using the 0-10 point numeric rating 
scale (NRS); use of supplemental opioid rescue medication; neurological assessment; 12-lead 
ECGs; vital signs; subject’s satisfaction with postsurgical pain control; and the postoperative 
symptom severity (PoSSe) scale questionnaire (Ruta 2000).  At timepoints when multiple 
assessments coincide, the NRS pain intensity assessment will be conducted first, if applicable.  
All subjects will return for follow-up visits on Days 7 and 10.  A phone call will be made to each 
subject on Day 30 for an AE assessment and to inquire as to whether the subject made any 
unscheduled phone calls or office visits related to pain.   
Adverse events will be recorded from the time the ICF is signed through Day 30.  If a cardiac 
event (e.g., myocardial depression, decreased cardiac output, heart block, hypotension, 
bradycardia, ventricular arrhythmia, or cardiac arrest) or neurological event (e.g., persistent 
anesthesia, paresthesia, weakness, or paralysis) occurs during the study, an unscheduled PK 
blood sample should be obtained and, for cardiac events, an ECG should be conducted within 
2 hours of the time the event is noted.  If there is a scheduled PK blood draw and ECG within 
2 hours before or after the event, an additional PK blood draw and ECG are not needed. 
Postsurgical Analgesia  
Subjects should only receive rescue pain medication (oral [PO] oxycodone 5-10 mg) upon 
request for breakthrough pain, as needed (maximum of every 4 hours).  No other analgesics, 
including nonsteroidal anti-inflammatory drugs (NSAIDs) are allowed during the 96 hour 
observation period.  After 96 hours, the analgesic regimen may be adjusted.  All postsurgical 
analgesics administered must be documented through Day 10.   
Pharmacokinetic Assessment  
Blood samples for PK analysis will be obtained at baseline (prior to study drug administration); 
15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours 
after the beginning of study drug administration; and on Days 7 and 10.  Blood samples will be 
collected from all subjects in order to maintain the treatment double-blind.   
9.1.1. 
Duration of the Study and Subject Participation  
Participation will begin upon signing of the ICF.  No more than 30 days should pass between 
signing the ICF and surgery.  A follow-up telephone call will occur on Day 30 (±4 days).  
Therefore, each subject may participate in the study for a maximum of 64 days. 


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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 
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 
EXPAREL is approved for infiltration into a surgical site.  This multicenter, randomized, double-
blind, placebo-controlled study is designed to evaluate the safety, efficacy, and pharmacokinetics 
of local administration of EXPAREL for prolonged postsurgical analgesia in subjects undergoing 
third molar extraction.  The double blind study design is intended to avoid potential bias 
resulting from subject or Investigator knowledge of the assigned treatment. 
Third molar extraction is a frequently performed surgical procedure that causes considerable 
postsurgical pain, particularly following removal of impacted lower mandibular third molars.  
Standard postoperative analgesia following third molar extraction often includes combination 
opioid analgesics.  In this study, all subjects will receive PO oxycodone, as needed, to control 
breakthrough postsurgical pain. 
Neurological and cardiac assessments will be conducted to rule out bupivacaine toxicity related 
to high plasma exposure.   


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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 at screening.  
2. Scheduled to undergo bilateral third molar extractions (i.e., extraction of all four third 
molars) under local anesthesia.  At least one lower mandibular third molar must involve 
full or partial bony impaction confirmed by visual or radiological evidence.  
3. American Society of Anesthesiology (ASA) physical status 1, 2, or 3. 
4. Female subjects must be either surgically sterile, using a medically acceptable method of 
birth control, or at least 2-years postmenopausal and must have a documented negative 
pregnancy test result during screening and on Day 1 prior to surgery. 
5. Able to provide informed consent, adhere to the study visit schedule, and complete all 
study assessments. 
10.2. 
Exclusion Criteria 
A subject will not be eligible for the study if he or she meets any of the following criteria:  
1. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics or 
opioids. 
2. Contraindication to lidocaine, epinephrine, bupivacaine, or oxycodone. 
3. History of significant drug allergy (e.g., anaphylaxis or hepatotoxicity). 
4. Positive test result from the urine drug screen at screening or prior to the surgical 
procedure.  
5. Currently pregnant, nursing, or planning to become pregnant during the study or within 
1 month after study drug administration.   
6. History or active psychiatric illness (including major depression, bipolar disorder, or 
anxiety), Type 1 or Type 2 diabetes, severe renal or hepatic impairment, significant 
cardiovascular disease (including cardiac rhythm disturbance), migraine headaches, 
frequent headaches, other pain conditions, or other medical condition that, in the opinion 
of the Investigator, may increase the risk of surgery or interfere with the evaluation of 
the study drug. 
7. History of infection requiring IV antibiotics within 45 days or PO antibiotics within 
30 days prior to study drug administration for reasons other than dental prophylaxis.  
Subjects must be afebrile, without signs or symptoms indicative of active infection. 
8. Use of any of the following medications within the times specified before surgery: 
long-acting opioid medication, NSAIDs, aspirin (except for low-dose aspirin used for 
cardioprotection), or acetaminophen within 3 days, or any opioid medication within 
24 hours. 


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9. Initiation of treatment with any of the following medications within 1 month of study 
drug administration or if the medication(s) are being given to control pain: selective 
serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors 
(SNRIs), gabapentin, pregabalin (Lyrica®), or duloxetine (Cymbalta®).  If a subject is 
taking one of these medications for a reason other than pain control, he or she must be 
on a stable dose for at least 1 month prior to study drug administration. 
10. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. 
11. Use of any concurrent therapy that could interfere with the evaluation of efficacy or 
safety, such as any drugs which in the Investigator’s opinion may exert significant 
analgesic properties or act synergistically with the investigational product. 
12. 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. 
10.3. 
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. 
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 study drug, the subject will be asked to complete a final evaluation so that he or she 
can be withdrawn in a safe and orderly manner.  In the final evaluation, vital signs (heart rate and 
blood pressure), neurological assessment, 12-lead ECG, and any changes in the subject's health 
status will be assessed and recorded.   
After termination from the study, the subject may be followed for safety including monitoring of 
AEs through Day 30.   


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11. 
TREATMENTS  
11.1. 
Treatment to be Administered 
Study Drug 
Subjects will receive a single dose of either EXPAREL 133 mg or placebo in 10 mL volume 
according to the randomization schedule.  Study drug administration will be performed in a 
blinded manner (e.g., utilizing a syringe masked by a finger cot). 
Rescue Medication 
Subjects should only receive rescue pain medication (PO oxycodone 5-10 mg) upon request for 
breakthrough pain, as needed (maximum of every 4 hours).  No other analgesic agents, including 
NSAIDs, are allowed during the 96-hour observation period.  After 96 hours, the analgesic 
regimen may be adjusted.  All postsurgical analgesics administered must be documented through 
Day 10.   
11.1.1. 
Administration Technique  
Randomized subjects will receive a nerve block with lidocaine 2% with epinephrine 1:100,000 
before undergoing bilateral third molar extraction under local anesthesia.  In addition to the 
lidocaine nerve block, the Investigator may choose to add topical benzocaine or intraoperative 
nitrous oxide.   
At the end of surgery, and at least 20 minutes after lidocaine administration, study drug 
(EXPAREL or placebo) will be infiltrated as follows to provide postsurgical analgesia:   
Maxilla  At the depth of the posterior buccal vestibule, two points of infiltration submucosal 
and supraperiosteal are identified at the apex of the extracted third molar.  The sites are separated 
by 6-8 mm and 1 mL of EXPAREL infiltrated in each site (2 mL on each side), for a total of 
4 mL in the maxilla. 
Mandible  After readaptation and closure of the mucoperiosteal flap, the external oblique ridge 
is palpated identifying the buccinator muscle attachment.  Four infiltration points separated by 
6-8 mm are selected along this line.  The needle is inserted approximately 5 mm and 0.5 mL 
of EXPAREL is infiltrated into the muscle at each point (total of 2 mL per side for this step).  
At the point of greatest subperiosteal reflection, just lateral to the third molar socket, two 
infiltrations are taken deeper (1.5 cm) and 0.5 mL is infiltrated as the needle is withdrawn 
(total of 1 mL per side for this step).  Thus, the total is 6 mL in the mandible. 
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.   
EXPAREL 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 syringe several times prior to administration is recommended. 


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No agents are to be admixed with EXPAREL.  
11.2. 
Identity of Investigational Product(s) 
11.2.1. 
Description of EXPAREL 
EXPAREL 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.  EXPAREL will be provided in 20 mL, 1.3% (13.3 mg/mL) single-use, clear glass 
vials.  EXPAREL vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F). 
11.2.2. 
Description of Reference Product 
Placebo will consist of normal saline and will be supplied by the study sites.  Subjects in the 
placebo group will receive 10 mL of placebo.  
11.2.3. 
Description of Diluents 
Not applicable. 
11.3. 
Method of Assigning Subjects to Treatment 
11.3.1. 
Randomization Scheme 
Approximately 175 subjects (100 subjects in the EXPAREL 133 mg group and 75 subjects in the 
placebo group) are planned for enrollment.  Subjects will be randomized in a 2:1 ratio to receive 
local administration of a single dose of either EXPAREL (133 mg/10 mL) or placebo (normal 
saline, 10 mL). 
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.  
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 obtain a randomization assignment.  The subject will be considered randomized 
into the study once the study treatment assignment is received. 
11.3.3. 
Replacement of Subjects 
Subjects who are randomized but are withdrawn from the study before receiving study drug or 
do not undergo the surgical procedure 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. 


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11.4. 
Selection of Doses in the Study 
During the clinical development of EXPAREL, single doses ranging from 2 mg to 665 mg have 
been safely administered via various routes.  Pharmacokinetic studies have shown that because 
EXPAREL releases bupivacaine gradually as the lipid structure breaks down, administration of 
EXPAREL 266 mg results in a maximum plasma concentration (Cmax) equivalent to that seen 
with standard bupivacaine HCl 100 mg.  Clinical studies have shown that for wound infiltration a 
total dose of 266 mg (20 mL) of EXPAREL is safe and efficacious.  Due to volume constraints at 
the surgical site, a dose of 133 mg (10 mL) will be utilized in this study. 
11.5. 
Blinding 
11.5.1. 
Blinding Procedures 
EXPAREL 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 a serious AE (SAE), Pacira will not automatically 
unblind the subject’s treatment, unless it is necessary to manage treatment of the SAE.  
Expedited SAEs will be unblinded by Pacira for regulatory reporting purposes. 
At each site, only the individual(s) who are designated 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.  
This documentation (e.g., site-specific blinding plan) will be made available to Pacira for review 
before the site enrolls a subject into the study.  The site-specific blinding plan will outline the 
study treatment blinding process that will be followed at the site throughout the study.  
Assignment of blinded and unblinded responsibilities regarding the preparation of study drug 
should take into account that EXPAREL 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.  The individuals preparing study drug will not 
be allowed to perform any of the study assessments or reveal the assigned study treatment to any 
other members of the study team at any time.  Syringes containing study drug will need to be 
gently inverted several times to re-suspend any settling of the study drug that may have occurred 
prior to administration.  Should administration of the study drug involve extension tubing or a 
butterfly needle, then any visible tubing needs to be covered with aluminum foil to maintain the 
blind. 
The administration of study drug will be recorded using the minimal amount of information 
necessary to avoid unblinding staff who will be participating in blinded procedures. 
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 


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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 
specialized unblinded monitors who will notify Pacira of treatment noncompliance. 
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 through the randomization 
system 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.  
Any unblinding performed through the randomization system will be recorded as a transaction 
and the appropriate study personnel will be notified that such a transaction occurred. 
Any incidence(s) of unblinding will be noted in the clinical study report with a full discussion of 
the events leading to the decision to unblind. 
11.6. 
Prior and Concomitant Therapy and Medications 
11.6.1. 
Prior and Concomitant Medications and Therapy  
Prior medications 
 Long-acting opioid medications, NSAIDs, aspirin (except for low-dose aspirin used for 
cardioprotection), and acetaminophen are not permitted within 3 days of study drug 
administration.   
 No opioid medications are permitted within 24 hours of study drug administration.   
 Initiation of treatment with any of the following medications is prohibited within 1 month 
of study drug administration or if the medication(s) are being given to control pain: 
SSRIs, SNRIs, gabapentin, pregabalin (Lyrica), or duloxetine (Cymbalta).  If a subject is 
taking one of these medications for a reason other than pain control, he or she must be on 
a stable dose for at least 1 month prior to study drug administration. 
 Use of systemic glucocorticosteroids is prohibited within 1 month of enrollment in this 
study. 
 Use of any concurrent therapy that could interfere with the evaluation of efficacy or 
safety is prohibited, including any drugs which in the Investigator’s opinion may exert 
significant analgesic properties or act synergistically with the investigational product. 
 Subjects who have received an investigational product within 30 days before the 
scheduled dose of study medication are not eligible for study participation. 


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Concomitant medications 
All medications taken within 30 days prior to study drug administration through Day 30 will be 
recorded on the CRF.     
11.6.2. 
Permitted and Restricted Therapy or Medications During Surgery 
Permitted 
If needed, additional lidocaine 2% with epinephrine 1:100,000 may be administered as long as 
there is a separation of at least 20 minutes between the last administration of lidocaine and the 
administration of study drug.  In addition to the lidocaine nerve block, the Investigator may 
choose to add topical benzocaine or intraoperative nitrous oxide.   
Restricted 
No agents are to be admixed with EXPAREL.  
11.6.3. 
Permitted and Restricted Therapy or Medications After Surgery Through 
96 Hours After Surgery 
Subjects should only receive rescue pain medication (PO oxycodone 5-10 mg) upon request for 
breakthrough pain, as needed (maximum of every 4 hours).  No other analgesics are permitted 
within 96 hours after surgery.   
For study purposes, it is important to standardize pain management modalities during the first 
96 hours following study drug administration.  Therefore, the study staff must adhere closely to 
the treatment requirements noted in the protocol.  After 96 hours, the analgesic regimen may be 
adjusted for each subject individually, as deemed appropriate by the physician responsible for the 
postsurgical care. 
All postsurgical analgesics administered must be documented through Day 10.   
11.7. 
Treatment Compliance 
Not applicable, since study drug (EXPAREL or placebo) will be administered intraoperatively. 
11.8. 
Accountability of Study Drug 
Any shipment of EXPAREL for the study will contain an investigational drug transmittal and 
receipt form to assist the Investigator or designee (e.g., pharmacist) in maintaining current and 
accurate inventory records.  At a minimum, the Investigator or designee will maintain accurate 
records demonstrating dates and units of drug received, lot numbers, subjects to whom drug was 
administered, and accounts of any drug destroyed accidentally or deliberately.  The Investigator 
must retain vials containing used, unused, or expired EXPAREL for return or destruction, as 
instructed by Pacira, following confirmation of drug accountability data by a study monitor.  
A record of drug return or destruction will be maintained and provided to Pacira.  Inventory 
records must be readily available for inspection by the study monitor and appropriate regulatory 
authorities at any time.  A copy of the inventory records, drug accountability information, and 
notice of return or destruction will be returned to Pacira at the end of the study.  Only authorized 
personnel identified by the Investigator will have the ability to access and administer the 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 
beginning of study drug administration (timepoints may change based on the median Tmax from 
the first 30 subjects): 
 Date, time of administration, and amount of all opioid rescue medication taken through 
96 hours. 
 Pain intensity scores using the NRS at 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48, 
72, and 96 hours, and immediately prior to each administration of rescue pain medication 
through 96 hours (see Appendix 1). 
 Subject satisfaction with postsurgical pain control (using a 5-point Likert scale) at 24, 48, 
72, and 96 hours, and on Day 10 (see Appendix 2). 
 Postoperative symptom severity (PoSSe) scale questionnaire at 72 hours and on Day 7 
(see Appendix 3). 
 Unscheduled phone calls or office visits related to pain after discharge from the facility 
through Day 30. 
12.2. 
Efficacy Endpoints 
The efficacy endpoints listed below will be assessed based on the efficacy measurements 
conducted at the specified timepoints after the beginning of study drug administration. 
Primary efficacy endpoint: 
The primary endpoint is the area under the curve (AUC) of the NRS pain intensity scores 
through 48 hours. 
Secondary efficacy endpoints: 
The following secondary endpoints will be analyzed in the following order using a hierarchical 
fixed-sequence stepwise testing procedure: 
1. The AUC of the NRS pain intensity scores through 24 hours. 
2. The AUC of the NRS pain intensity scores through 72 hours. 
3. Percentage of opioid-free subjects through 24 hours. 
4. Percentage of opioid-free subjects through 48 hours. 
5. Percentage of opioid-free subjects through 72 hours. 
Tertiary efficacy endpoints: 
 
The AUC of the NRS pain intensity scores through 96 hours. 
 
Sum of the pain intensity scores (SPIS) through 24, 48, 72, and 96 hours. 


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 
The NRS pain intensity scores at each assessed timepoint and immediately prior to each 
administration of rescue pain medication through 96 hours.  
 
The AUC of the NRS pain intensity scores from 24-48 and 48-72 hours. 
 
Percentage of pain-free subjects at each assessed timepoint using the NRS pain intensity 
score. 
 
Percentage of opioid-free subjects through 96 hours. 
 
Time to first opioid rescue medication. 
 
Integrated rank assessment using the NRS pain intensity score at 48 hours and the total 
amount of postsurgical opioids consumed through 48 hours (Silverman 1993). 
 
Overall assessment of the subject’s satisfaction with postsurgical pain control (using a 
5-point Likert scale) at 24, 48, 72, and 96 hours, and on Day 10. 
 
PoSSe scale mean total score at 72 hours and on Day 7. 
 
Number of unscheduled phone calls or office visits related to pain through Day 30. 
12.3. 
Pharmacokinetic Analysis  
Blood samples for PK analysis will be obtained at baseline (prior to study drug administration); 
15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours 
after the beginning of study drug administration; and on Days 7 and 10.  Blood samples will be 
collected from all subjects in order to maintain the treatment double-blind.     
12.4. 
Pharmacokinetic Endpoints 
Pharmacokinetic parameters will be estimated from the plasma bupivacaine measurements using 
non-compartmental analysis.  The following parameters will be determined: 
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 log-linear 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 maximum plasma concentration (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 at the times specified after the beginning of 
study drug administration: 
 Neurological assessment at baseline (prior to study drug administration); 15 minutes, 
30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours; and on 
Day 10 (see Appendix 4).   
 Cardiac assessment (i.e., 12-lead ECG) at baseline (prior to study drug administration); 
15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 
96 hours; and on Day 10.   
 Vital signs (resting heart rate and blood pressure) at baseline (approximately 1 hour prior 
to surgery), and 1, 2, 4, and 96 hours (i.e., prior to discharge). 
 Adverse events from the time the ICF is signed through Day 30. 
12.6. 
Safety Endpoints 
The following safety endpoints will be assessed based on the safety measurements conducted at 
the specified timepoints: 
 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 median Tmax. 
 Change from baseline in vital signs (resting heart rate and blood pressure) at each 
assessed timepoint. 
 Incidence of treatment-emergent AEs (TEAEs) through Day 30. 
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.   
 


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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 safety, efficacy, and PK assessments conducted after baseline will be timed from the 
beginning of study drug administration.   
At timepoints when multiple assessments coincide, the NRS pain intensity assessments will be 
conducted first, if applicable.   
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.  Postsurgical is defined as after the end of surgery.   
Subjects will remain in the research facility for 96 hours after study drug administration; 
therefore, postsurgical analgesia and collection of study data through the primary endpoint will 
take place under the supervision of study staff. 
13.1.1. 
Pain Intensity Assessments 
Pain intensity will be assessed using the NRS (see Appendix 1).  To assess pain intensity, 
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. 
13.1.2. 
Neurological Assessment 
The neurological assessment will include the subject’s orientation.  Additionally, the subject will 
be asked whether he or she is experiencing any numbness of the lips, the tongue, or around the 
mouth; a metallic taste in the mouth; problems with hearing; problems with vision; or muscles 
twitching (see Appendix 4).   
13.1.3. 
Vital Signs 
Vital signs (heart rate and blood pressure) will be measured after the subject has rested in a 
supine position.  The subject will remain in a supine position during the assessment.   
13.1.4. 
Electrocardiogram 
The 12-lead ECGs will be conducted after the subject has rested in a supine position for 
5 minutes.   
13.1.5. 
Subject Satisfaction with Postsurgical Pain Control 
The subject’s satisfaction with postsurgical pain control will be assessed using the Likert Scale 
at 24, 48, 72, and 96 hours, and on Day 10 (see Appendix 2). 


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13.1.6. 
Postoperative Symptom Severity (PoSSe) Scale Questionnaire 
The PoSSe scale questionnaire will be completed at 72 hours and on Day 7 (see Appendix 3). 
13.2. 
Screening Procedures  
 
Explain study purpose and procedures. 
 
Obtain signed ICF. 
 
Assess eligibility. 
 
Record relevant medical/surgical history, demographics, and baseline characteristics. 
 
Record concomitant medications. 
 
Perform dental examination. 
 
Perform physical examination including height and weight. 
 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position. 
 
Conduct 12-lead ECG. 
 
Perform urine pregnancy test for women of childbearing potential. 
 
Perform urine drug screen. 
 
Record AEs starting at signing of the ICF. 
13.3. 
Baseline Procedures (Day 1) 
 
Confirm eligibility. 
 
Update relevant medical history. 
 
Perform urine pregnancy test for women of childbearing potential before study drug 
administration. 
 
Perform urine drug screen. 
 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position. 
 
Perform neurological assessment (see Appendix 4). 
 
Conduct 12-lead ECG. 
 
Collect baseline (pre-dose) blood sample for PK analysis prior to study drug 
administration. 
 
Record changes to concomitant medications since screening. 
 
Record AEs. 
 
Randomize subject and prepare study drug. 


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13.4. 
Intraoperative Procedures (Day 1) 
 
Administer dental nerve block with lidocaine 2% with epinephrine 1:100,000. 
 
Perform bilateral third molar extraction under local anesthesia.   
 
At the end of surgery, administer study drug according to the randomization schedule. 
 
Record start and stop time of study drug administration. 
 
Record start and stop times of surgery. 
 
Record concomitant medications. 
 
Record AEs and any treatment(s) for the events.   
13.5. 
Procedures After Surgery Through 96 Hours 
 
Collect scheduled blood samples for PK analysis at 15 minutes, 30 minutes, 1, 2, 4, 8, 12, 
18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours.   
 
Administer rescue medication (PO oxycodone 5-10 mg) upon request for breakthrough 
pain, as needed (maximum of every 4 hours).  
 
Record date, time, and amount of all opioid rescue medication administered. 
 
Record subject’s assessment of pain intensity using the NRS at the following timepoints: 
15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours, and immediately prior 
to each administration of rescue pain medication, if applicable (see Appendix 1). 
 
Perform neurological assessment at 15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 
42, 48, 54, 60, 66, 72, 84, and 96 hours (see Appendix 4).   
 
Conduct 12-lead ECG at 15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 
60, 66, 72, 84, and 96 hours.   
 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position at 1, 2, 4, and 96 hours (i.e., prior to discharge).  
 
Obtain overall rating of subject satisfaction with postsurgical pain control using the 
Likert scale at 24, 48, 72, and 96 hours (see Appendix 2). 
 
Have subject complete the PoSSe scale questionnaire at 72 hours (see Appendix 3). 
 
Record concomitant medications. 
 
Record AEs and any treatment(s) for the events. 
 
If a cardiac event (e.g., myocardial depression, decreased cardiac output, heart block, 
hypotension, bradycardia, ventricular arrhythmia, or cardiac arrest) or neurological event 
(e.g., persistent anesthesia, paresthesia, weakness, or paralysis) occurs during the study, 
an unscheduled PK blood sample should be obtained and, for cardiac events, an ECG 
should be conducted within 2 hours of the time that the event is noted.  If there is a 
scheduled PK blood draw and ECG within 2 hours before or after the event, an additional 
PK blood draw and ECG are not needed. 
 
Discharge subject after the 96-hour assessments have been completed. 


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13.6. 
Day 7 Visit 
 
Collect scheduled blood sample for PK analysis.   
 
Document any unscheduled phone calls or office visits related to pain after hospital 
discharge. 
 
Have subject complete the PoSSe scale questionnaire (see Appendix 3). 
 
Record concomitant medications including opioid rescue. 
 
Record AEs and any treatment(s) for the events.  
13.7. 
Day 10 Visit 
 
Collect scheduled blood sample for PK analysis.   
 
Perform neurological assessment (see Appendix 4).   
 
Conduct 12-lead ECG.   
 
Document any unscheduled phone calls or office visits related to pain since Day 7. 
 
Obtain overall rating of subject satisfaction with postsurgical pain control using the 
Likert scale (see Appendix 2). 
 
Record concomitant medications including opioid rescue. 
 
Record AEs and any treatment(s) for the events.  
13.8. 
Day 30 Phone Call 
 
Document any unscheduled phone calls or office visits related to pain since Day 10. 
 
Record concomitant medications. 
 
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 signs the ICF, including frequency or pattern changes for a fluctuating 
condition (e.g., migraine) is considered an AE.   
An AE that occurs after the ICF is signed and before the start of the study drug administration is 
identified as a pretreatment AE (PTAE).  An AE that occurs after the administration of the study 
treatment is considered a TEAE.   
Definition of Adverse Reaction: Any AE caused by a drug.  Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Definition of Suspected Adverse Reaction: Any AE for which there is a reasonable possibility 
that the drug caused the AE.  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. 
14.1.2. 
Recording Adverse Events 
It is the responsibility of the Investigator to document all AEs (i.e., PTAEs and TEAEs) with an 
onset after the subject signs the ICF.  For the purpose of this study, all AEs that occur through 
Day 30 after surgery must be recorded regardless of whether or not they are considered related to 


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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 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 end date when 
the severity changes to moderate.  A new AE record with a moderate severity will be created 
with a start date that is the same as the end date of the mild AE.   
Any condition noted before the subject signs the ICF will be listed as Medical History and is 
considered a pre-existing condition.  If a pre-existing condition changes (i.e., becomes more 
severe or more frequent) at any time after the subject signs the ICF it is considered an AE.  
Note: A change in treatment for a pre-existing condition (e.g., new high blood pressure 
medication), does not necessarily indicate an AE. 
Information recorded on the AE CRF will include the AE term, the date and time of onset, 
severity, seriousness, relationship to study drug, action taken with subject due to AE, and the 
outcome of the AE, including the date and time of resolution, if applicable.   
14.1.3. 
Severity of Adverse Events 
In general, the severity of an AE should be categorized using the following guidelines:  
Mild: 
An AE that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate: 
An AE that is discomforting and interferes with normal everyday 
activities. 
Severe: 
An AE that prevents normal everyday activities. 
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. 
Unlikely:  
A clinical event with a temporal relationship to study drug 
administration which makes a causal relationship improbable and in 
which other drugs, chemicals, or underlying disease provide a 
plausible explanation; 
Possible: 
A clinical event with a reasonable time sequence to administration 
of the study drug but which could also be explained by a concurrent 
disease or other drugs or chemicals; 


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Probable: 
A clinical event with a reasonable time sequence to administration 
of the study drug unlikely to be attributed to a concurrent disease or 
other drugs or chemicals and which follows a clinically reasonable 
response on withdrawal (dechallenge); or 
Definite:  
The pharmacological properties of the study drug(s) or of the 
substance class, and the course of the AE after dechallenge and, if 
applicable, after rechallenge, and/or specific test indicate 
involvement of the study drug(s) in the occurrence/worsening of the 
AE, and no indication of other causes exists. 
14.1.5. 
Outcome of Adverse Events 
The Investigator will assess the outcome of the AE after careful medical consideration, on a 
case-by-case basis.  General guidelines are provided below: 
Recovered/Resolved: 
The event resolved and the subject recovered from the AE. 
Recovered/Resolved 
with Sequelae: 
The initial event resolved, but has a continuing abnormal condition 
as a result of the AE. 
Not Recovered/ 
Not Resolved: 
At the time of last assessment, the event was ongoing, with an 
undetermined outcome.  Note: ongoing AEs are not to be considered 
resolved as a result of death. 
Recovering/Resolving: 
At the time of last assessment, the event was decreasing in 
frequency, severity, etc., and a resolution was expected. 
Fatal: 
The AE directly caused death. 
Unknown: 
There was an inability to access the subject or the subject’s records 
to determine the outcome (e.g., subject withdrew consent or was 
lost to follow-up). 
14.1.6. 
Action Taken with Subject due to an Adverse Event 
The Investigator will provide any actions taken regarding the subject (e.g., treatment, diagnostic 
tests, laboratory tests, or therapy) for each reported AE. 
 
None. 
 
Medication. 
 
Non-pharmaceutical therapy.  (The specific therapy used must be recorded in the 
CRF.) 
 
Discontinued from study. 
 
Other.  (The specific action taken must be recorded.) 


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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 the subject signs the ICF through Day 30, 
whether or not related to EXPAREL, must be reported by the Investigator or designee to Pacira 
Drug Safety within 24 hours of discovery by either email (drugsafety@pacira.com) or fax 


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(973-201-0649).  In addition, the Investigator or designee is encouraged to contact the Medical 
Monitor to discuss the case, as needed, at 908-342-1840.   
Investigators should not wait to receive additional information to fully document the event 
before notifying Pacira Drug Safety or designee of the SAE.  The fax or email report 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 patient-identifying information redacted prior to forwarding to Pacira.  
In the event of a fatal or life-threatening SAE, any required follow-up must be provided to Pacira 
Drug Safety or designee immediately.  The Investigator will follow all SAEs until resolved or the 
condition stabilizes and further follow-up is not warranted. 
If the Investigator is made aware of any SAEs after Day 30, these should also be reported to 
Pacira Drug Safety or designee provided the SAE is considered related to EXPAREL.  The site 
would then provide a completed SAE form within 1 business day and the event would be 
followed until resolution, or until adequate stabilization is met.  


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15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be developed for this study.   
15.1. 
Study Hypothesis 
The primary null hypothesis is: 
H0: The means of the AUC of the NRS pain intensity scores through 48 hours are not different 
between the EXPAREL and placebo groups. 
The alternative hypothesis is: 
HA: The mean AUC of the NRS pain intensity scores through 48 hours for the EXPAREL group 
is less than that of 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  
In previous wound infiltrations studies in hemorrhoidectomy and bunionectomy, the difference 
between treatment groups in mean AUC from 0 to 48 hours or NRS pain intensity scores varied 
from 20 to 103.  The standard deviations varied from 100 to 128.  A sample size of 50 in each 
group will have 90% power to detect a difference in means of 66 assuming that the common 
standard deviation is 100 using a two group t-test with a 0.05 two-sided significance level.  
A sample size of 50 in each group will have 90% power to detect a difference in means 
of 86 assuming that the common standard deviation is 130 using a two group t-test with a 
0.05 two-sided significance level. 
However, the EXPAREL group will randomize approximately 100 subjects to lower the AE 
detection threshold for the safety database to 3%.  The sample size for placebo was increased due 
to the additional collection of NRS pain intensity score immediately prior to all requests for 
rescue medication through 96 hours.  The placebo sample size was increased to ensure that there 
are at least 50 subjects treated in both the EXPAREL and placebo under the current protocol 
amendment.  It is expected that the sample size will be approximately 175 subjects resulting in a 
2:1 ratio of EXPAREL to placebo subjects. 
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 undergo 
the planned surgery and will be based on randomized treatment, regardless of actual treatment 
received. 


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Pharmacokinetic: The PK analysis set will include all subjects in the safety analysis set who 
receive EXPAREL, provide sufficient samples to allow for calculation of PK parameters 
required for analysis, and do not have significant protocol deviations that may invalidate or bias 
the results. 
15.5. 
Handling Subject Dropouts and Discontinuations 
For the calculation of the 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 timepoint 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).  Missing scores between two non-missing scores will use linear interpolation to replace 
the missing score. 
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 Measures 
The primary efficacy measure in this study is the AUC of the NRS pain intensity scores through 
48 hours. 
For the AUC of the NRS pain intensity scores through 48 hours, EXPAREL will be compared to 
placebo using analysis of variance (ANOVA) with treatment as the main effect.  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 pain intensity scores, prior to analysis the windowed Worst-
Observation-Carried-Forward (wWOCF) imputation method will be applied.  For subjects who 
take opioid rescue pain medication, their NRS pain intensity scores recorded within the window 
of controlled type of rescue medication (6 hours for PO oxycodone) 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 


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pain intensity scores in the window that are higher than the worst value prior to opioid rescue 
pain medication will not be overwritten.  If no NRS pain intensity score is available prior to the 
first opioid rescue pain medication, the worst observation from all available measurements 
within the same treatment arm will be used instead. 
15.6.3.2  Secondary Efficacy Measures 
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.  If the first test is significant at the 0.05 level, then, and only then, 
the next secondary efficacy measure will be tested, and so forth.  The results will be declared 
statistically significant at the 0.05 significance level. 
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 the integrated rank assessment that uses total amount of postsurgical opioids consumed 
through 48 hours, opioid medications will be converted to an IV morphine equivalent amount.  
All opioids consumed through 48 hours will be included in the analysis. 
Summary statistics for each measure will be shown at each timepoint by treatment group.  
To test for significant differences between EXPAREL and placebo with respect to continuous 
measures of efficacy, an ANOVA with treatment as the main effect will be used.  Based on the 
model, EXPAREL will be compared to placebo and two-sided CIs about the difference will be 
presented. 
Categorical Measures of Efficacy 
For categorizing subjects as pain-free, the NRS pain intensity score must be 0 or 1 at the assessed 
timepoint. 
The proportion of subjects in each category will be calculated and summarized at each timepoint 
by treatment group.  A chi-square test or Wilcoxon Rank Sum test will be used to compare 
EXPAREL to placebo. 
Time to Event Measures of Efficacy 
The time from start of study drug administration to the first use of an opioid rescue medication 
through 96 hours will be summarized with Kaplan-Meier estimates.  A log-rank test will be used 
to compare EXPAREL 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. 


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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).  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  Neurological Assessments 
The proportion of subjects who are oriented at each timepoint 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. 
15.6.5.3  Electrocardiograms 
Descriptive statistics for each ECG parameter for baseline, each timepoint, and change from 
baseline at each timepoint will be summarized for each treatment group. 
15.6.5.4  Vital Signs 
Descriptive statistics for each vital sign for baseline, each timepoint, and change from baseline at 
each timepoint will be summarized for each treatment group. 
15.7. 
Significance Testing 
All tests will be two-sided and based on a significance level of 0.05. 


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16. 
REFERENCES 
American Society of Anesthesiologists Task Force on Pain Management.  Practice guidelines 
for acute pain management in the postoperative setting: A report by the American Society 
for Anesthesiologist Task Force on Pain Management Acute Pain Section.  Anesthesiology. 
1995;82:1071-1081. 
Apfelbaum JL, Chen C, Mehta SS, et al.  Postoperative pain experience: Results from a national 
survey suggests postoperative pain continues to be undermanaged.  Anesth Analg.  
2003;97:535-540. 
Carroll NV, Miederhoff PA, Cox FM, et al.  Costs incurred by outpatient surgical centers in 
managing postoperative nausea and vomiting.  J Clin Anesth.  1994;6:364-369. 
Chernin T.  Painkillers and pill popping.  Drug Topics.  2001;15:31.  Accessed 04 January 2011.  
Available at: http://drugtopics.modernmedicine.com/drugtopics/PainManagement/ 
ArticleStandard/article/detail/118858. 
EXPAREL Full Prescribing Information, December 2014. 
EXPAREL Investigator’s Brochure, Edition 17, 12 May 2015. 
Feierman DE, Kronenfeld M, Gupta PM.  Liposomal bupivacaine infiltration into the transversus 
abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: Results 
from a cohort of 13 patients.  J Pain Res.  2014;7:477-482. 
Oderda GM, Said Q, Evans RS, et al.  Opioid-related adverse drug events in surgical 
hospitalizations: Impact on cost and length of stay.  Ann Pharmacother.  2007;41(3):400-406. 
Ruta DA, Bissias E, Ogston S, et al.  Assessing health outcomes after extraction of third molars: 
The postoperative symptom severity (PoSSe) scale.  Br J Oral Maxillofac Surg.  
2000;38(5):480-487. 
Silverman DG, O’Connor TZ, Brull SJ.  Integrated assessment of pain scores and rescue 
morphine use during studies of analgesic efficacy.  Anesth Analg.  1993;77:168-170. 
Sternlicht A, Shapiro M, Robelen G, et al.  Infiltration of liposome bupivacaine into the 
transversus abdominis plane for postsurgical analgesia in robotic laparoscopic prostatectomy: 
A pilot study.  Local Reg Anesth.  2014;7:69-74. 
Viscusi ER.  New and emerging treatment options for acute postoperative pain in the inpatient 
setting: Barriers to effective pain management.  Medscape Pharmacists.  Accessed 04 January 
2011.  Available at: http://www.medscape.org/viewarticle/713472_2. 
Volkow ND, McLellan TA.  Curtailing diversion and abuse of opioid analgesics without 
jeopardizing pain treatment.  JAMA.  2011:305(13):1346-1347. 
 


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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 (Numeric Rating Scale) 
Subjects will be evaluated for pain using the NRS at 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 
48, 72, and 96 hours after the beginning of study drug administration, and immediately prior to 
each administration of rescue pain medication through 96 hours.   
 
Pain Intensity Scale 
On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, 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: 
Subject Satisfaction with Postsurgical Pain Control (Likert Scale)  
The subject’s satisfaction with postsurgical pain control will be conducted at 24, 48, 72, and 
96 hours after the beginning of study drug administration, and on Day 10. 
 
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 3: 
Postoperative Symptom Severity (PoSSe) Scale Questionnaire 
Subjects will complete the PoSSe scale at 72 hours after the beginning of study drug 
administration and on Day 7. 
PoSSe Scale 
1. EATING 
a. In the last week, has your operation affected your enjoyment of food? 
(Please mark one box) 
No, not at all          Yes, a little     Yes, very much   
 
b. In the last week, for how many days were you unable to open your mouth normally 
because of  your operation? 
(Please mark one box) 
0 days      1-2 days     3-4 days      5-6 days      7 days  
2. SPEECH 
a. In the last week, for how many days was your voice affected because of your operation? 
(Please mark one box) 
0 days      1-2 days      3-4 days      5-6 days      7 days  
 
b. On the worst day of the last week, how badly was your speech affected by your 
operation? 
(Please mark one box) 
Not at all    Slightly    Moderately     Severely    Unable to speak at all  
3. SENSATION 
a. Thinking of the last week, for how many days were your lips or tongue feeling tingling 
because of your operation? 
(Please mark one box) 
 
None at all      1-2 days      3-4 days      5-6 days         7 days  
 
b. Thinking of the last week, for how many days were your lips or tongue feeling numb 
because of your operation? 
(Please mark one box) 
None at all     1-2 days       3-4 days      5-6 days       7 days   
 


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4.  APPEARANCE 
a. Thinking of the last week, for how many days were your face and/or neck bruised 
because of  your operation? 
(Please mark one box) 
None at all      1-2 days      3-4 days       5-6 days       7 days  
 
b. Thinking of the last week, for how many days were your face and/or neck swollen 
because of  your operation? 
(Please mark one box) 
None at all     1-2 days      3-4 days        5-6 days       7 days  
5. PAIN 
a. Thinking of the last week, for how many days did you experience pain from your 
operation? 
(Please mark one box) 
None at all    1-2 days       3-4 days       5-6 days         7 days  
 
b. Thinking of the last week, has the pain from your operation been controlled by 
painkillers? 
(Please mark one box) 
I have had no pain.  
Yes, completely controlled.  
Controlled mostly but still some discomfort.  
Poorly controlled.  
Not controlled at all.  
6. SICKNESS 
a. Thinking of the last week, for how many days did you vomit or feel nauseated? 
(Please mark one box) 
None at all    1-2 days       3-4 days       5-6 days         7 days  
 
b. On the worse day of the last week, how many times did you vomit or feel nauseated? 
(Please mark one box) 
Not at all       One day       2-3 times      More than      All the time 
3 times       (all day long)  
 


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7. INTERFERENCE WITH DAILY ACTIVITIES 
a. In the last week, did the operation prevent you from carrying out work/housework and 
other daily activities? 
(Please mark one box) 
No, not at all.  
I could continue with my work, but my work suffered.  
Yes, for 1 day.  
Yes, for 26 days.  
Yes, for 7 days.  
 
b. In the last week, have your leisure activities been affected by your operation? 
(including sports, hobbies and social life) 
(Please mark one box) 
Not affected by the operation.  
Mildly affected by the operation.  
Moderately affected by the operation.  
Severely affected by the operation.  
The operation prevented any social life at all.  
 
c. Thinking of the last week, how badly did the pain affect your life? 
(Please mark one box) 
Not at all      Slightly       Moderately      Severely        
 
 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL® 
 
Clinical Study Protocol Amendment 2 
 
CLN-PRO-0133.003 
 
 
CONFIDENTIAL 
68 of 68  
02 September 2015 
Appendix 4: 
Neurological Assessment 
A neurological assessment will be conducted at baseline (prior to study drug administration); 
15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours 
after the beginning of study drug administration; and on Day 10. 
 
The examination will include the subject’s orientation.    
 Is the subject oriented? 
  Yes  
  No  
 
If the subject is not oriented, the event should be recorded 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 not related to the use of a hearing aid? 
 
  Yes  
  No 
 
 Are you having problems with your vision not related to the use of eye glasses? 
 
  Yes  
  No 
 
 Are your muscles twitching?  
 
 
 
 
 
 
 
  Yes  
  No 
 
If the subject answers “yes” to any of these questions, the event should be recorded as an AE.  
 

SAP_001.pdf: 
Pacira Pharmaceuticals, Inc. 
 
 
EXPAREL 
Document: 
Statistical Analysis Plan 
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Efficacy, and Pharmacokinetics of Local Administration of 
EXPAREL for Prolonged Postsurgical Analgesia in Subjects 
Undergoing Third Molar Extraction 
NCT Number: 
NCT02517905 
Document Date: 
Original: November 12, 2015 
Addendum: February 29, 2016 
 


 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Efficacy, and Pharmacokinetics of Local Administration of EXPAREL 
for Prolonged Postsurgical Analgesia in Subjects Undergoing Third Molar 
Extraction 
 
 
 
Protocol No.: 
402-C-329 
IND No.: 
69,198  
Study Phase: 
3  
Study Drug: 
EXPAREL (bupivacaine liposome injectable suspension) 
Date/Version: 12 November 2015, Final 1.0 
Prepared by: 
James Nezamis, MS 
Senior Director, Biostatistics 
Pacira Pharmaceuticals 
Sponsor: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 973-254-3560 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira 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-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
1. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
C-Section 
Cesarean Section 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
ICF  
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IV 
Intravenous 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MED 
Morphine Equivalent Dose 
n 
Sample Size 
NRS 
Numerical Rating Scale 
PACU 
Post-Anesthesia Care Unit 
PK 
Pharmacokinetics 
PO 
Per Oral (by mouth) 
PoSSe 
Postoperative symptom severity questionnaire 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
TEAE 
Treatment-Emergent Adverse Event 
TLFs 
Tables, Listings, Figures 
WHO-DD 
World Health Organization Drug Dictionary 
wWOCF 
Windowed Worst Observation Carried Forward 
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2. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting of 
the clinical study 402-C-329 titled “A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety, Efficacy, and Pharmacokinetics of Local Administration of EXPAREL for 
Prolonged Postsurgical Analgesia in Subjects Undergoing Third Molar Extraction”.  
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 
Trials1.  All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
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 report (CSR), 
regulatory submissions, or manuscripts.  Post-hoc exploratory analyses not necessarily identified 
in this SAP may be performed to further examine study data.  Any post-hoc, unplanned, or 
exploratory analyses performed will be clearly identified as such in the final CSR. 
The following documents related to clinical study Protocol 402-C-329 were reviewed in 
preparation of this SAP: 
• Protocol Amendment 1 issued 27 July 2015. 
• Protocol Amendment 2 issued 2 September 2015. 
• Case report forms (CRFs). 
• ICH Guidance on Statistical Principles for Clinical Trials (E9). 
• FDA protocol feedback received 18 August 2015. 
The reader of this SAP is encouraged to also read the clinical protocol and other identified 
documents for details on the planned conduct of this study.  Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analyses. 
 
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3. 
STUDY OBJECTIVES 
The primary objective of this study is to demonstrate the analgesic efficacy of single-dose local 
administration of EXPAREL® (bupivacaine liposome injectable suspension)) compared with 
placebo in subjects following bilateral third molar extraction.   
The secondary objectives of this study are to assess additional efficacy parameters, characterize 
the pharmacokinetic (PK) profile in this surgical model, and further assess the safety profile of 
EXPAREL.  
 
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4. 
STUDY OVERVIEW 
This is a Phase 3, randomized, double-blind, placebo-controlled study in subjects scheduled to 
undergo elective bilateral third molar extraction (i.e., extraction of all four third molars) under 
local anesthesia.  At least one lower mandibular third molar must involve full or partial bony 
impaction confirmed by visual or radiographic evidence. 
Approximately 175 subjects (at least 100 in the EXPAREL group and 50 in the placebo group) 
are planned for enrollment.  Subjects enrolled under Amendment 1 were randomized in a 1:1 
ratio.  Due to FDA feedback Amendment 2 changed the randomization ratio to 2:1 (EXPAREL: 
placebo), thus subjects enrolled under Amendment 2 will be randomized in a 2:1 ratio to receive 
local administration of a single dose of either EXPAREL (133 mg/10 mL) or placebo (normal 
saline, 10 mL).  
The timing of all assessments is in the Time and Events Schedule of study procedures (Section 
10) and further described in the protocol. 
Screening 
Subjects will be screened within 30 days prior to surgery.  During the screening visit, subjects 
will be assessed for any past or present medical conditions that in the opinion of the Investigator 
would preclude them from study participation.  
Day 1 (Day of Surgery) 
On Day 1 prior to surgery, any AEs or changes in concomitant medications since screening will 
be recorded, vital signs will be measured, a urine drug  screen will be conducted for all subjects, 
and a urine pregnancy test will be conducted for women of childbearing potential.  A pre-dose 
PK sample will be collected from all subjects eligible for randomization.  Randomized subjects 
will receive a dental nerve block with lidocaine 2% with epinephrine 1:100,000 before 
undergoing bilateral third molar extraction under local anesthesia  
At the end of surgery, and at least 20 minutes after the lidocaine administration, a total of 10 mL 
of study drug will be infiltrated [4 mL (2 mL per side) into the maxilla and 6 mL (3 mL per side) 
into the mandible].  
Subjects will be required to remain in the research facility for 96 hours after study drug 
administration. 
Postsurgical Safety and Efficacy Assessments  
Postsurgical assessments will include pain intensity scores using the 0-10 point numeric rating 
scale (NRS, note that NRS assessments for this study are at rest) at scheduled timepoints and 
prior to each request for rescue medication; use of supplemental opioid rescue medication; vital 
signs; subject’s satisfaction with postsurgical pain control; and the postoperative symptom 
severity (PoSSe) scale questionnaire (Ruta 2000).   
All subjects will return for a follow-up visit on Days 7 and 10.  A phone call will be made to 
each subject on Day 30 for an AE assessment and to inquire as to whether the subject made any 
unscheduled phone calls or office visits related to pain.   
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Adverse events will be recorded from the time the ICF is signed through Day 30.  If a cardiac or 
neurological event occurs during the study, an unscheduled PK blood sample and ECG should be 
obtained within 2 hours of the time the event is noted.  If there is a scheduled PK blood draw 
within 2 hours before or after the event, an additional draw is not needed. 
Postsurgical Analgesia  
Subjects should only receive rescue pain medication (oral [PO] oxycodone 10 mg) upon request 
for breakthrough pain, as needed.  No other analgesics, including nonsteroidal anti-inflammatory 
drugs (NSAIDs) are allowed during the 96 hour observation period.  All postsurgical opioid 
analgesics administered must be documented through 96 hours.   
Pharmacokinetic Assessment  
Blood samples for PK analysis will be obtained at baseline (prior to study drug administration); 
15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84, and 96 hours 
after the beginning of study drug administration; and on Days 7 and 10.  Blood samples will be 
collected from all subjects in order to maintain the treatment double-blind.  However, blood 
samples from subjects randomized to the placebo group will not be analyzed. 
 
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5. 
DEFINITIONS 
Study Day 
Study Day is calculated as the date of event minus the date of surgery plus one (1), if the date of 
event is on or after the date of surgery, thus day of surgery is Day 1.  Study Day is based on the 
calendar dates, thus days before the date of surgery have negative values while those on or after 
the date of surgery are positive.  However for those events that have times associated with them, 
if the event occurs on the day of surgery but before time 0, Study Day will be -1; Study Day will 
be 1 for those events occurring on the day of surgery but start after time 0. 
Treatment-emergent Adverse Event 
Treatment-emergent adverse events (TEAEs) are those with onset between the start datetime of 
study drug administration and end of study (Study Day 30±3 days). 
Time 0 (zero) 
Time 0 is defined as the date and time of the end of surgery for all end points except AEs and 
bupivacaine plasma concentrations.  For AEs and PK sampling times 0 is defined as the date and 
time of the start of study drug administration. 
Pain-free 
Pain-free is defined as a NRS score of 0 or 1 with no rescue medication use prior to that 
assessment. 
Time Periods 
All schedule times have a window associated with them (see Time and Events Schedule for 
individual timepoint windows).  Various time frames are used in the data analyses which are 
dependent on these windows.  The table below defines the actual elapsed times with allowance 
for the windows that can be included in the window. 
Defined time frame (hrs) 
Acceptable elapsed times (hrs) 
0-24 
[0 to 25] 
0-48 
[0 to 50] 
0-72 
[0 to 76] 
0-96 
[0 to 100] 
0-Day 10 
[0 to 264] 
24-48 
[23 to 50] 
48-96 
[46 to 100] 
If there are two or more data points that fit the time window the data point that occurs the latest 
in the window should be used.  For example when selecting the data point for the 48 hour 
timepoint, if a subject has data points collected at 47 and 49 hours then the 49 hour timepoint 
should be used.  In this example the 49 hour timepoint record will be used as the end and start of 
all time intervals, thus the 0-48 hour interval will end using the 49 hour record and the 48-72 
hour interval will start using the same 49 hour record. 
Topline Result Tables 
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Topline result tables are to be expedited for Pacira review after database lock.  The topline tables 
for this study are: 
• 
14.1-1: Summary of Subject Disposition 
• 
14.2-1.1.1: Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Primary Efficacy Analysis 
Set - Multiple Imputation Results 
• 
14.2-1.1.2: Sensitivity Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Secondary 
Efficacy Analysis Set - Multiple Imputation Results 
• 
14.2-1.1.3: Sensitivity Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Primary Efficacy 
Analysis Set – Mixed Model Repeated Measures Results 
• 
14.2-2.1: Analysis of AUC of NRS Pain Intensity Scores through 24 hours - Primary Efficacy Analysis Set 
- Multiple Imputation Results 
• 
14.2-2.2: Summary of AUC of NRS Pain Intensity Scores through 24 hours - Primary Efficacy Analysis 
Set - Analysis of Variance Model Results - Multiple Imputation Results 
• 
14.2-3.1: Analysis of AUC of NRS Pain Intensity Scores through 72 hours - Primary Efficacy Analysis Set 
- Multiple Imputation Results 
• 
14.2-3.2: Summary of AUC of NRS Pain Intensity Scores through 72 hours - Primary Efficacy Analysis 
Set - Analysis of Variance Model Results - Multiple Imputation Results 
• 
14.2-5.1: Analysis of Opioid-Free Subjects through 24 hours - Primary Efficacy Analysis Set 
• 
14.2-5.2: Analysis of Opioid Free Subjects through 48 hours - Primary Efficacy Analysis Set 
• 
14.2-5.3: Analysis of Opioid Free Subjects through 72 hours - Primary Efficacy Analysis Set 
• 
14.3-2.2: Summary of Potentially Clinically Meaningful Abnormal Electrocardiogram Results – Central 
Read - Safety Analysis Set 
• 
14.3-3.2: Summary of Potentially Clinically Significant Abnormal Vital Signs – Safety Analysis Set 
• 
14.3-4.1.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
• 
14.3-4.2.2: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) - Safety 
Analysis Set 
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Statistical Analysis Plan 
 
6. 
ANALYSIS SETS 
Safety Analysis Set 
The safety analysis set will include all subjects who receive study drug and will be based on the 
actual treatment received.  
Efficacy Analysis Sets 
Under the protocol, the efficacy analysis set will include all subjects in the safety analysis set 
who undergo the planned surgery and will be based on the randomized treatment, regardless of 
actual treatment received.  However Amendment 2 changee the pain score collection around 
rescue medication use, thus subjects enrolled under Amendment 1 and Amendment 2 have 
differences in efficacy data collection.  Subjects enrolled under Amendment 1 collected pain 
scores only before the first use of rescue medication while those enrolled under Amendment 2 
collected pain scores prior to each use of rescue medication.  This has direct impact on the 
derivation of the primary efficacy endpoint.  Under Amendment 2 the sample size was increased 
to accommodate the FDA request of at least 100 subjects on EXPAREL and to ensure an 
adequate number of subjects in both treatment groups to enable an efficacy analyses based solely 
on those subjects enrolled under Amendment 2.  Thus two efficacy analysis sets are defined for 
this study, primary and secondary efficacy analysis sets. 
The primary efficacy analysis set will include all subjects enrolled under Amendent 2 in the 
safety analysis set who undergo the planned surgery.  This will be the analysis set used for the 
decision on efficacy.   
The secondary efficacy analysis set will include all subjects enrolled under either amendment in 
the safety analysis set who undergo the planned surgery.  This analyses set will be used for a 
sensitivity analysis to ensure that the protocol amendment did not change the efficacy results.  
When adjusting pain scores for rescue medication use, subjects enrolled under Amendment 1 
will use the highest score prior to the first rescue medication request to impute pain scores 
obtained in the rescue medication window. 
In both efficacy analyses sets subjects will be analyzed as randomized, regardless of treatment 
recieved. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects in the safety analysis set who receive EXPAREL, 
provide sufficient samples to allow for calculation of PK parameters required for analysis, and 
do not have significant protocol deviations that may invalidate or bias the results. 
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Statistical Analysis Plan 
 
7. 
STATISTICAL METHODS OF ANALYSIS 
7.1. General Principles 
The statistical analyses will be reported using summary tables, and figures.  All analyses and 
tabulations will be performed using SAS Version 9.1 or later.  Continuous variables will be 
summarized using descriptive statistics (sample size [n], mean, standard deviation [SD], 
minimum, median, and maximum).  Categorical variables will be tabulated with number and 
percentage of subjects.  Unless otherwise noted, percentages will be based on the number of 
subjects in the treatment group within the population. 
Individual subject data will be provided in listings.  All listings will be sorted by treatment, site, 
subject and, if applicable, collection date and time. 
Unless otherwise stated summaries will present data across all sites (overall). 
On all figures, the comparator treatment will be represented in black with solid lines and filled 
squares; EXPAREL will be respresented in red with solid lines and dots.   
Plots of the NRS scores will show both observed and imputed scores.  A change in color and line 
type will differentiate the imputed NRS scores.  Imputed values will be represented by blue and 
green symbols and dashed lines for for comparator and EXPAREL respectively.  NRS scores 
obtained immediately prior to rescue will be indicated by a change in symbol.  For comparator 
the symbol should be a triangle, for EXPAREL the symbol is a star.  The following table shows 
the SAS symbol statements: 
Treatment 
NRS Score 
SAS Statement 
Comparator 
Observed 
symbol font=marker interpol=j line=1 value=U color=black 
 
Imputed 
symbol font=marker interpol=j line=3 value=C color=blue 
EXPAREL 
Observed 
symbol font=marker interpol=j line=1 value=W color=red 
 
Imputed 
symbol font=marker interpol=j line=3 value=V color=green 
Note the symbol statement number will be dependent on the sort order of the treatment and NRS 
score group indicator variables. 
Sites with fewer than 5 subjects per treatment arm will be pooled with other sites for analysis.  
Sites will be pooled with other small sites based on the US Census Bureau geogrpahic regions 
(see Table 1).  Sites meeting the criteria for pooling will be pooled with other similar sites within 
their census division.  If the resulting pooled site within a division still doesn’t have enough 
subjects per treatment group, it will be pooled with the site within the division with the smallest 
enrollment that doesn’t meet the pooling criteria.  If all sites within a division are pooled and the 
resulting pooled site still meeting the pooling criteria, the site will be pooled with other small 
sites within the region.  The pooled site with the region still meets the pooling criteria it will be 
pooled with the site with the smallest enrollment from the neighboring regions.   
Table 1: US Census Regions and Divisions 
Region 
Division 
State 
Midwest 
East North Central 
Illinois, Indiana, Michigan, Ohio, Wisconsin 
West North Central 
Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, South Dakota 
Northeast 
Middle Atlantic 
New Jersey, New York, Pennsylvania 
New England 
Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont 
South 
East South Central 
Alabama, Kentucky, Mississippi, Tennessee 
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Statistical Analysis Plan 
 
Table 1: US Census Regions and Divisions 
Region 
Division 
State 
South Atlantic 
Delaware, District of Columbia, Florida, Georgia, Maryland, North Carolina, 
South Carolina, Virginia, West Virginia 
West South Central 
Arkansas, Louisiana, Oklahoma, Texas 
West 
Mountain 
Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, Wyoming 
Subjects who use opioid rescue medication will have the pain scores obtained after rescue 
replaced using pain scores obtained prior to rescue medication use.  Pain scores obtained during 
the window when the opioid medication is effect will be replaced.  For this study the prescribed 
opioid rescue medication is oxycodone.  The duration of effect for various opioid are listed in 
Table 2. 
Table 2: Opioid Windows 
Medication 
Route 
Window Used to Impute NRS 
Oxycodone 
PO 
6 hours 
Morphine 
IV 
4 hours 
Hydromorphone 
IV 
2 hours 
Hydromorphone 
PO 
4 hours 
Hydrocodone 
PO 
6 hours 
PO = oral; IV = intravenous 
If other rescue medications are given then the window will be determined post-hoc.  If a combination 
opioid product is given then the window will be determined by the opioid part of the medication.  Opioids 
given postsurgically with an indication like ‘anesthesia maintenance’ will not be included for imputation 
purposes. 
 
7.1.1. Handling Missing Values 
7.1.1.1. 
Area Under the NRS-Time Curve 
7.1.1.1.1. 
Multiple Imputation Method 
Rubin’s (1987)4 multiple imputation procedure will be applied to replace each missing value 
with a set of plausible values that represent the uncertainty about the right value to impute.  This 
multiple imputation method is being implemented per the advice provided in “the prevention and 
treatment of missing data in clinical trials”5 For calculation of area under the curve (AUC) of 
NRS pain intensity scores, the windowed worst observation carried forward (wWOCF) multiple 
imputation procedure will be used in the following order: 
a) Windowed worst observation carried forward (wWOCF) for rescue medications.   
For sujects who take a rescue medication, their NRS scores recorded within the window of 
controlled type of rescue medication (see Table 2Table 2: Opioid WindowsError! 
Reference source not found.) will be replaced by the ‘worst’ observation.  The worst 
observation will be the highest score from time 0.25 or end of previous rescue window, to 
pain score immediately prior to rescue medication for those subjects with pain score prior 
to each rescue medication (Amendment 2) or, for those subjects with pains scores only 
prior to first rescue medication use (Amendment 1) in the time interval from time 0.25 to 
up to the time of rescue medication.  The NRS score at rescue will be included in this 
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calculation.  Note that NRS scores in the window that are higher than the worst value 
prior to rescue medication will not be overwritten. 
b) After the wWOCF imputation, described in Step a, subject data still missing with a non-
monotone missing pattern (ie, all pain scores between the last non-missing score and last 
timepoint) will have missing scores imputed using the Markov-Chain Monte-Carlo 
(MCMC) method (Schafer 1997)6, which will be applied in the multiple imputation 
procedure for arbitrary missing patterns.  This MCMC method will use 1000 imputation 
datasets with NBITER=2000 and NITER=1000. 
c) The resulting data from Step b will then have the remaining monotone missing patterns, 
hence a parametric regression method on pain (Rubin 1987) that assumes multivariate 
normality will be applied for this multiple imputation procedure.  
   
d) The AUC and SPIS at various time intervals will be derived from the imputed NRS 
scores resulting from Step c.    
e) The endpoints derived in Step d will be analyzed as described in Section 7.6.2.1 for each 
imputation. 
f) Rubin’s (1987) synthesizing procedure for the multiple imputed data will be applied to 
synthesize analysis results for each imputation.  SAS PROC MIANALYZE will be used 
for this procedure.  The mean parameter estimates, the asymptotic variance for this mean 
from the imputed data analysis in Step e will be created based on Rubin and Schenker 
method (1986)7. 
For summary statisitics based on multiple imputations, the mean value from each imputation will 
be derived for each subject.  These mean values will then be summarized to obtain the summary 
statistics for reporting. 
SAS pseudo-code for multiple imputations is provided in Section 12  
7.1.1.1.2. 
Single Imputation Method 
The single imputation method was the method used for previously submitted studies.  It is being 
provided in this study as a bridge to the older studies.   
For calculation of area under the curve (AUC) of NRS pain intensity scores, the windowed worst 
observation carried forward (wWOCF) and last observation carried forward (LOCF) imputation 
procedure will be used in the following order: 
a) Windowed worst observation carried forward for rescue medications 
For subjects who take a rescue medication, their NRS scores recorded within the window 
of controlled type of rescue medication (see Table 2) will be replaced by the ‘worst’ 
observation.  The worst observation will be the highest score in the time interval from 
time 0 up to the time of 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 for 
that subject will be used instead. 
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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). 
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. 
f) The AUC and SPIS at various time intervals will be derived from the imputed NRS 
scores resulting from Step e. 
7.1.1.2. 
Integrated Rank Assessment 
No imputation of missing data will be performed for the integrated rank assessment calculation.  
Subjects will missing NRS scores at the timepoints of interest will not be included in the 
summaries.  
7.1.1.3. 
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. 
7.1.1.4. 
Rescue Pain Medication 
For calculation of the total rescue pain medication usage (in morphine dose 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 (18=24-6). 
7.1.1.5. 
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 be assigned the date and time of first dose of 
study treatment. 
• 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. 
i) 
Otherwise, ‘January’ will be assigned. 
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• 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: 
iii) 
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. 
iv) 
Otherwise, ‘00:00’ will be assigned. 
For partial stop date/time: 
• If the year is unknown, then the date assigned will be the date subject discontinued from 
study, time will be set to the last time of the day (‘23:59’). 
• If the month is unknown, then month subject discontinued from study 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’). 
7.1.1.6. 
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 assigned the relationship of ‘definite’.  Tables 
presenting related AEs will include all AEs with relationships of ‘possible’, ‘probable’ or 
‘definite’ as assessed by the investigator 
7.1.1.7. 
Time to Event  
For calculating time to an event when only the hour is reported, the minutes will be set to zero.  
If only date is reported, the time will be set to midnight (00:00). 
7.1.2. Multiplicity Adjustments 
Since no multiple comparisons of the primary efficacy endpoint will be made, no alpha-
adjustments will be made. 
Also, since there is only one primary efficacy endpoint and all other efficacy endpoints are 
considered secondary or tertiary, no alpha-adjustments for the primary response variable will be 
made. 
There are five secondary efficacy endpoints that will be analyzed using a hierarchical fixed-
sequence stepwise testing procedure (See Section 7.6.1.2).  The five secondary efficacy 
endpoints will only be analyzed if the prmary efficacy endpoint is statistically significant at the 
two-sided 0.05 significance level.  To protect the Type 1 error rate, the testing will be performed 
sequentially rejecting secondary endpoints at the two-sided 0.05 significance.  The prior 
secondary endpoint must be rejected before before proceeding to the next.  The five secondary 
endpoints will be tested in the following order: 
1. 
AUC(0.25-24) 
2. 
AUC(0.25-72)  
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3. 
Percentage of opioid-free subjects from end of surgery through 24 hours  
4. 
Percentage of opioid-free subjects from end of surgery through 48 hours 
5. 
Percentage of opioid-free subjects from end of surgery through 72 hours 
Tertiary efficacy endpoints will be summarized but not be analyzed.   
7.1.3. By-Site Analyses 
By-site summaries will present descriptive statistics only; no statistical analyses will be 
performed for individual sites.  By-site summaries will be presented for disposition, 
demographics, primary efficacy endpoint and secondary efficacy endpoints. 
7.2. Subject Disposition 
Subject disposition summaries will include the number of subjects that were: 
• Screened,  
• Randomized 
o Randomized Not treated,  
o Randomized Treated,  
• In the safety analysis set, 
• In the primary efficacy analysis set,  
• In the secondary efficacy analysis set 
• In the PK analysis set, 
• Completed the study as planned, 
• Discontinued from the study, and 
• Reasons for discontinuation from the study. 
Percentages will be reported for the safety, efficacy and PK analysis sets, completed study, 
discontinued from study and reasons for discontinuation.  The denominator for all percentages 
will be the number of subjects randomized. 
Safety and PK analysis sets will be presented as treated.  This may result in percentages greater 
than 100%.  All other data will be presented as randomized. 
Summaries will present the data for each treatment group (EXPAREL, Placebo) and across 
treatment groups (Total).  This summary table will show summaries across all sites and for each 
site separately.  
7.3. Description of Demographics  
The summary of demographics will present: 
• Age (years) – descriptive statistics 
• Sex – n (%) 
• Ethnicity – n (%) 
• Race – n (%) 
• Height (cm) – descriptive statistics 
• Weight (kg) – descriptive statistics 
• Body Mass Index (BMI) (kg/m2) – descriptive statistics 
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Age is calculated from the date the subject signed the ICF and birth.  It is presented as the 
number of years between, rounding down to the nearest integer year. 
The formula for BMI is 𝑤/(ℎ2), where w is weight in kilograms and h is height in meters.  
Weight in pounds will be converted to kilograms using the conversion factor of 2.2046 pounds to 
1 kilogram.  Height in inches will be converted to centimeters using the conversion factor of 2.54 
centimeters to 1 inch.  Height in centimeters will be converted to meters using the conversion 
factor of 100 centimeters to 1 meter. 
Summaries will present the data for each treatment group (EXPAREL, Placebo) and across 
treatment groups (Total).  Summaries will be provided for all (safety, efficacy and PK) analysis 
sets.  This summary table will show summaries across all sites and for each site separately. 
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 term and preferred name. 
Prior medications are defined as medications with a stop datetime prior to end of surgery.  
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 separately using n (%) of subjects for 
each treatment group and across treatment groups by ATC class term and preferred name for the 
safety analysis set.  Subjects may have more than one medication per ATC category and 
preferred name.  At each level of subject summarization, a subject will be counted once if one or 
more medications are reported by the subject at that level.  
A listing mapping the ATC term and preferred name to verbatim term will be presented. 
7.5. Measurements of Treatment Compliance 
Study treatment is administered by a party other than the subject, therefore compliance is 
assured.  Duration of surgery will be summarized by treatment and across treatments. 
7.6. Efficacy Analysis 
Primary and secondary efficacy endpoints will be summarized and analyzed using inferential 
statistics.  Tertiary efficacy endpoints will be summarized, no statistical tests will be performed 
on these endpoints. 
7.6.1. Efficacy Endpoints 
7.6.1.1. 
Primary Efficacy 
The primary endpoint is the AUC of the NRS pain intensity scores through 48 hours 
[AUC(0.25-48)]. 
7.6.1.2. 
Secondary Efficacy 
The following secondary endpoints will be analyzed in the following order using a hierarchical 
fixed-sequence stepwise testing procedure: 
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1. The AUC of the NRS pain intensity scores through 24 hours [AUC(0.25-24)]. 
2. The AUC of the NRS pain intensity scores through 72 hours [AUC(0.25-72)]. 
3. Percentage of opioid-free subjects from end of surgery through 24 hours. 
4. Percentage of opioid-free subjects from end of surgery through 48 hours. 
5. Percentage of opioid-free subjects from end of surgery through 72 hours. 
7.6.1.3. 
Tertiary Efficacy 
• 
The AUC of the NRS pain intensity scores through 96 hours. 
• 
Sum of pain intensity scores (SPIS) through 24, 48, 72, and 96 hours.  
• 
The NRS pain intensity scores at each assessed timepoint and immediately prior to each 
request for rescue pain medication.  
• 
The AUC of the NRS pain intensity scores from 24-48 and 48-72 hours. 
• 
Percentage of pain-free subjects at each assessed timepoint using the NRS pain intensity 
score. 
• 
Percentage of opioid-free subjects through 96 hours. 
• 
Time to first opioid rescue medication. 
• 
Integrated rank assessment using the NRS pain intensity score at 48 hours and the total 
amount of postsurgical opioids consumed through 48 hours (Silverman 1993)8. 
• 
Overall assessment of the subject’s satisfaction with postsurgical pain control (using a 
5-point Likert scale) at 24, 48, 72, and 96 hours, and on Day 10. 
• 
PoSSe scale mean total score at 72 hours and on Day 7. 
• 
Number of unscheduled phone calls or office visits related to pain through Day 30. 
7.6.1.4. 
Opioid Consumption 
Opioids will be converted to IV Morphine Equivalent Dose (MED) using the appropriate 
conversion factor from Table 3 for all summaries.  Total opioid dose (MED) is the sum of all 
opioids taken after surgery up to the timepoint of interest.  Subjects with no opioid use during the 
period in question will be assigned a dose of 0 for analysis. 
 
Table 3: IV Morphine Equivalents 
Medication 
Unit 
Route 
Conversion (Multiplication) Factor 
Oxycodone 
mg 
PO 
0.5 
Opioids taken during the study not on table will be reviewed and conversion facter determined. 
 
7.6.1.5. 
Area Under the Curve 
Area under the pain-time curve is derived using the trapezoidal rule on the pain scores adjusted 
for rescue medication use using the wWOCF imputation methods (see Section 7.1.1.1).  Actual 
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assessment times will be used in deriving AUC.  AUC of pain scores will be calculated from the 
first timepoint after surgery to the timepoint of interest. 
7.6.1.6. 
Sum of Pain Intensity Scores 
The sum of pain intensity scores (SPIS) is the sum of the pain scores from the first timepoint 
after surgery to the timepoint of interest.  The pain scores obtained after wWOCF imputation 
method will be used to derive SPI.  SPIs will be derived for 24, 48, 72 and 96 hours. 
7.6.1.7. 
Integrated Rank Assessment 
Integrated rank assessment is a single score that takes pain rating and rescue medication use into 
account.  Positive values for the integrated rank assessment score indicate less pain or opioid use 
and negative numbers indicate more pain or opioid use.  The score is derived as: 
൤2𝑟−𝑝𝑖−𝑚𝑖
𝑟
൨∗100 
Where: 
• i indicates subject; 
• pi is the rank of the subject’s pain score in the pool of all subjects to be analyzed; 
• mi is the rank of the subject’s total opioid use (in MED) through the time period in 
question in the pool of all subjects to be analyzed; 
• r is the mean rank defined as (N + 1) 2
⁄ ; 
• N is the total number of subjects to be analyzed. 
Subjects with no opioid use will be assigned a dose of 0 for analysis. 
Integrated rank assessment will be calculated at 24, 48 and 72 hour timepoints.  Missing NRS 
scores at timepoints of interest will not be imputed.  Subjects with missing NRS values at the 
timepoint of interest will be excluded from the summary.  If the timepoint of interest falls within 
a rescue medication window, the wWOCF value will be used to derive the integrated rank 
assessment.     
7.6.1.8. 
Postoperative Symptom Severity (PoSSe) Questionnaire 
The PoSSe score is the total score of the weighted responses for each question.  If a response is 
missing to any question in the PoSSe, the total score will not be calculated. 
7.6.1.9. 
Time to First Opioid Rescue Medication Use 
Time to first opioid rescue medication use will be calculated as the time from end of surgery to 
time of event in hours. Missing NRS scores at timepoints of interest will not be imputed.  
Subjects with missing NRS values at the timepoint of interest will be excluded from the 
summary.   
7.6.1.10. Pain-free 
Pain free is defined as an NRS score of 0 or 1 with no rescue medication use prior to that 
assessment. 
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7.6.2. Methods of Analysis 
7.6.2.1. 
Primary Efficacy Analysis 
The primary effiacacy analyses will be conducted for both the primary and secondary efficacy 
analysis sets.  Results from the primary efficacy analysis set will be primary efficacy result; the 
the analyses based on the secondary efficacy analysis set are a sensitivity analysis.   
The primary efficacy variable is the AUC of NRS scores from first postsurgery assessment (0.25 
hours) through 48 hours [AUC(0.25-48)] using the wWOCF to adjust for rescue medication use 
and multiple imputation method to account for missing data described in Section7.1.1.1.1. 
Tests for the treatment effect of EXPAREL versus placebo will be based on the following null 
hypothesis (Ho) and two-sided alternative hypothesis (Ha): 
Ho: μs = μp versus Ha: μs ≠ μp 
where μs and μp are the mean of AUC(0.25-48) for EXPAREL and the mean of AUC(0.25-48) for 
placebo, respectively. A two-sided test will be performed at 5% level of significance.  The 
treatment effect of EXPAREL will be considered significantly better than that of placebo if the 
null hypothesis of no difference is rejected and a difference in mean of AUC(0.25-48) in favor of 
EXPAREL (mean for EXPAREL < mean for placebo) is observed. 
For the primary efficacy variable of AUC(0.25-48), EXPAREL will be compared to placebo 
using analysis of variance (ANOVA) with treatment and site as main effects.  Based on the 
model, the least squares (LS) means, LS mean difference between the two treatment groups, 95% 
confidence interval (CI) for the LS mean difference between the two treatment groups, and 
p-value will be reported. 
Descriptive statistics of the primary efficacy variable will also be shown by site but no statistical 
analyses will be performed by site. 
In addition, an ANOVA model with main effects of treatment and site and the treatment by site 
interaction will be reported to assess the interaction on the primary efficacy analysis.  Additional 
analyses may be performed if the interaction effect is significant (p-value <0.05).  
Sensitivity Analyses 
Mixed Model Repeated Measures 
A mixed model repeated measures analysis will be performed using only the data imputed using 
wWOCF but not imputing any missing values outside of the rescue medication windows.  The 
MMRM model will have fixed effects for treatment and time.  The initial model will be fit with 
the treatment-by-time interaction.  If this interaction is not significant (p-value > 0.05) the final 
model will include the main effects only.  If the interaction is significant (p-value ≤ 0.05) the 
interaction will be investigated to determine if it is qualitative or quantitative.  If the interaction 
is quantitative, the final model will include the interaction term.  If the interaction is qualitative, 
additional analyses may be required.   The treatment effect at 48 hours will be estimated from the 
final model. 
Tipping Point 
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A tipping point analysis will be performed using similar imputation technique as the primary 
AUC calculations (see section 7.1.1.1.1) but adding shift values to the imputation until the 
primary analysis results change direction (SAS pseudo-code below). 
PROC MI DATA=OUTDATA_STEPB OUT=OUTDATA_TIP;  
BY _IMPUTATION_; 
CLASS TREATMENT; 
MONOTONE REG(T1 = TREATMENT / DETAILS); 
MONOTONE REG(T2 = TREATMENT T1 / DETAILS); 
… 
MONOTONE REG(T(n-1) = TREAMENT T1 T2 T3 ... T(n-2) / DETAILS);  
 
MNAR ADJUST(T1 / SHIFT=Q ADJUSTOBS=(TREATMENT=’EXPAREL’)); 
MNAR ADJUST(T2 / SHIFT=Q ADJUSTOBS=(TREATMENT=’EXPAREL’)); 
… 
MNAR ADJUST(T(n-1) / SHIFT=Q ADJUSTOBS=(TREATMENT=’EXPAREL’));  
MNAR ADJUST(Tn / SHIFT=Q ADJUSTOBS=(TREATMENT=’EXPAREL’));  
 
VAR TREATMENT T1 T2 T3 … Tn  
RUN; 
where Q is the value to shift the results. 
If the result from the primary efficacy analysis is statistically significant, the above code will be 
run iteratively for integer values of Q from 1 to 10 analyzing each step of the way until the result 
“tips” from statistically significant to not statistically significant.  If the primary efficacy analysis 
result is not statistically significant, the above code will be run iteratively for integer values from 
-1 to -10 until the result “tips” from not clinically significant to clinically significant.   The value 
of Q that results in the change in significance will be reported along with the analysis results. 
Original Imputation Method 
The AUC of NRS scores from first postsurgery assessment (0.25 hours) through 48 hours 
[AUCo(0.25-48)] will also be derived using the methodology used in previous submission, 
wWOCF + LOCF as described in Section 7.1.1.1.2.  AUC(0.25-48) will be analyzed for the 
primary and secondary analysis sets using an analysis of variance with fixed effect of treatment 
reporting the the least squares (LS) means, LS mean difference between the two treatment 
groups, 95% confidence interval (CI) for the LS mean difference between the two treatment 
groups, and p-value along with descriptive statistics. 
7.6.2.2. 
Secondary Efficacy Analyses 
Secondary endpoints AUC(0.25-24) and AUC(0.25-72) will be analyzed in same manner as the 
primary endpoint for the primary efficacy analysis set. 
The secondary endpoints of percentage of opioid-free subjects through 24, 48 and 72 hours will 
be independently analyzed using a Chi-square test stratified on site for the primary efficacy 
analysis set.  Treatment differences and 95% CIs will be derived using the normal approximation 
to the binomial.  
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7.6.2.3. 
Tertiary Efficacy Analyses 
Tertiary endpoints will be summarized as appropriate (eg, descriptive statistics or tabulations).  
No statistical tests will be performed on these endpoints. 
7.6.2.3.1. 
AUC(0.25-96) 
The NRS AUC(0.25-96) will be summarized (n, mean, SD, median, minimum and maximum) by 
treatment group.  The summary will be based on the data obtained using multiple imputations.   
7.6.2.3.2. 
SPI(0.25-24), SPI(0.25-48), SPI(0.25-72) and SPI(0.25-96) 
The NRS SPI(0.25-24), SPI(0.25-48), SPI(0.25-72) and SPI(0.25-96) will be summarized (n, 
mean, SD, median, minimum and maximum) by treatment group.  The summary will be based 
on the data obtained using multiple imputations. 
7.6.2.3.3. 
Numeric Rating Scale Pain Intensity Scores by Assessment Timepoint 
The NRS pain intensity scores will be summarized (n, mean, SD, median, minimum and 
maximum) at each scheduled assessment timepoint for each treatment group. The summaries and 
figures will be based on the data obtained using multiple imputations. 
The NRS pain intensity scores will also be summarized (n, mean, SD, median, minimum and 
maximum) prior to each rescue medication.  The summary will also include the median, 
minimum and maximum time to rescue for those subjects using rescue medication.  Rescue 
medication will be presented in order of the request for rescue medication, e.g., first request, 
second request and so on.  The time to request for rescue medication may differ widely from 
subject to subject.  Only subject with NRS pain scores prior to rescue will be presented in this 
summary. 
Plots of NRS pain intensity scores over time from baseline to last assessment will be presented 
for the mean (± SD) and individual subjects.  The mean plot will be presented for both the 
observed and imputed mean values.  The mean plot will be based only on the scheduled NRS 
assessment scores.  The subject plots will be show both the scheduled and immediately prior to 
rescue NRS assessment scores.  On the subject plots, scores obtained prior to rescue medication 
use will be differentiated from the scheduled scores.  The subject plots will present the observed 
and imputed scores separately.  The scores will be connected using straightlines. 
7.6.2.3.4. 
Numeric Rating Scale Pain Intensity Scores Partial Area Under the Curve 
The NRS AUC(24-48) and AUC(48-72) will be summarized (n, mean, SD, median, minimum 
and maximum) by treatment group.  The summary will be based on the data obtained using 
multiple imputations. 
7.6.2.3.5. 
Percentage of Pain-free Subjects by Assessment Timepoint 
The number and percentage of subjects ever and never using opioids from end of surgery 
through each NRS assessment timepoint will be tabulated by treatment.  Missing NRS values 
will not be imputed for this summary.  Subjects will be excluded from the summaries where they 
are missing NRS values. 
A bar chart presenting the percentage of pain-free subjects at each assessment timepoint will be 
provided. 
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7.6.2.3.6. 
Percentage of Opioid-free Subjects Through 96 hours 
The number and percentage of subjects ever and never using opioids from end of surgery 
through 96 hours will be tabulated by treatment.  
A bar chart presenting the percentage of opioid-free subjects at 24, 48 and 96 hours will be 
provided. 
7.6.2.3.7. 
Time to First Opioid Rescue Medication 
The number and percentage of subjects ever and never using opioids after surgery through 
72 hours will be presented by treatment.  Subjects who did not take opioids will be censored at 
the time of discharge from the clinic or from the time of withdrawal, whichever is sooner.  The 
25th (first quartile), 50th (median – second quartile) and 75th (third quartile) percentiles, 
minimum and maximum time to first use of opioid rescue medication will be estimated using 
Kaplan-Meier methods.  The quartile and the 95% confidence limits for each quartile will be 
presented by treatment.  This summary will be presented overall and for each site.  
A Kaplan-Meier plot of the time to first rescue medication use will be presented.  
7.6.2.3.8. 
Integrated Rank Assessment 
The integrated rank assessment will be derived through 24, 48 and 72 hours.  Each of these 
integrated rank assessments will be summarized (n, mean, SD, median, minimum and maximum) 
by treatment group.  
7.6.2.3.9. 
Subject Satisfaction with Postsurgical Pain Control 
The numeric value for the response to the subject satisfaction with postsurgical pain control will 
be summarized (n, mean, SD, median, minimum and maximum) by treatment group.  The 
responses ‘extremely dissatisfied’, ‘dissatisfied’, ‘neither satisfied nor dissatisfied’, ‘satisfied’, 
‘extremely satisfied’will be scored 1 through 5 respectively.  The data will also be summarized 
by presenting the number and percentage of subjects by treatment group for each of the five 
categories (i.e., ‘extremely dissatisfied’, ‘dissatisfied’, ‘neither satisfied nor dissatisfied’, 
‘satisfied’, ‘extremely satisfied’) available in the subject satisfaction with postsurgical pain 
control questionnaire. 
A bar chart of the percentage of subjects in each category at each assessment timepoint will be 
presented. 
7.6.2.3.10. 
Postsurgical Symptom Severity (PoSSe) Scale Questionnaire 
The total PoSSE score at 72 hours and Day 7 will be summarized (n, mean, SD, median, 
minimum and maximum) by treatment group.  Individual question scores will be summarized 
(n, mean, SD, median, minimum and maximum) by treatment group at each of the assessment 
timepoints as well. 
The total score is the sum of the individual question values (see Listing 16.2-11.2 for values).  
The total score will be derived only if all questions are answered.  
7.6.2.3.11. 
Number of Pain-Related Unscheduled Phone Calls or Office Visits 
The number of pain-related unscheduled phone calls or office visits will be summarized 
(n, mean, SD, median, minimum and maximum) by treatment group.  The number and 
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percentage of subjects reporting for each number of pain-related unscheduled phone calls or 
visits (0, 1, 2… maximum number observed) will be presented by treatment group. 
7.6.2.3.12. 
Postsurgical Opioid Consumption (Rescue) 
Postsurgical opioid consumption (MED) will be summarized (n, mean, SD, median, minimum 
and maximum) by treatment group for the total dose consumed over the 72 hours after the end of 
surgery.  The number and percentages of the types of opioids used will be presented by treatment 
group.  The number and percentage of subjects using any opioid will be presented by treatment 
for 24, 48 and 72 hours after dosing.  This summary table will show summaries across all sites 
and for each site separately. 
The number of times each subject used rescue medication thru 24, 48 and 72 hours will be 
tabulated across all sites and for each site separately.  
7.7. Safety Analyses 
Safety assessments in this study consist of neurological, ECGs, vital signs and AEs.  Vital signs will be 
collected at screening, baseline (prior to surgery) and 1, 2, 4 and 96 hours after surgery.  Adverse events 
will be collected from the time of informed consent through Day 30.  
7.7.1. Neurological Assessment 
Neurological assessments include orientation (orientated, disoriented, not assessable), numbness 
(of lips, tongue, or around mouth), metallic taste, hearing problems, vision problems and muscle 
twitching.  The number and percentage of subjects will be tabulated for each neurological 
assessment by treatment group at each assessment timepoint.   
7.7.2. Electrocardiograms 
Investigator Read 
Investigator’s interpretation of ECGs will be tabulated by treatment presenting the number and 
percentage of subjects in all of the reported interpretations. 
Central Read 
Electrocardiogram intervals (RR, PR, QRS, QT, QTcB, and QTcF) and heart rate will be 
summarized by treatment at each assessment timepoint. Electrocardiogram interval derivations 
and morphological analysis will be done by a central reader. 
Summaries will present both actual and change-from-baseline results for all ECG parameters.  
Baseline statistics will be presented at each assessment timepoint for those subjects reporting 
data at that timepoint.  The summary will highlight the timepoint closest the median PK Tmax 
observed during the study. 
The ECG data will be assessed for potentially clinically meaningful values (see Table 4). The 
number and percentage of subjects satisfying the potentially clinically significant abnormal 
criteria at any time during the study and at each assessment timepoint will be tabulated.  The 
table will present the number and percentage of subjects meeting the individual criteria (critical 
value, critical change) as well as the composite criteria (critical value and critical change).  To 
satisfy the composite criteria the subject must satisfy both within the same ECG read. 
Table 4: Criteria for Potentially Clinically Meaningful ECG Results 
ECG Parameter 
Unit 
Critical Value 
Critical Change1 
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Heart rate 
Bpm 
> 100 
< 50 
Increase of at least 25 
Decrease of at least 25 
PR Interval 
millisecond 
> 200 
Increase of at least 25 
QRS Interval 
millisecond 
> 100 
Increase of at least 25  
QT Interval 
millisecond 
> 500 
Baseline ≤ 500 
QTcF 
millisecond 
> 500 
>480 
>450 
 
 
Baseline ≤ 500 
Baseline ≤ 480  
Baseline ≤ 450 
>30-60 
>60 
QTcB 
millisecond 
> 500 
>480 
>450 
 
 
Baseline ≤ 500 
Baseline ≤ 480  
Baseline ≤ 450 
>30-60 
>60 
1Change criteria not applicable at baseline or screening. 
Tabulations of the number and percent of subjects with each of the ECG morphologies identified 
by the central reader will be presented by treatment at each assessment timepoint. 
7.7.3. Vital Signs 
Vital signs (resting heart rate and blood pressure) will be summarized by treatment at each 
assessment timepoint.  Summaries will present both actual and change from baseline values.   
Vital signs will also be assessed for potentially clinically significant abnormal values (see Table 
5).  The number and percentage of subjects satisifying the potentially clinically significant 
abnormal criteria will be tabulated by treatment group. The table will present the number and 
percentage of subjects meeting the individual criteria (critical value, critical change) as well as 
the composite criteria (critical value and critical change).  To satisfy the composite criteria the 
subject must satisfy both within the same vital signs collection.  
Table 5: Criteria for Potentially Clinically Significant Abnormal Vital Signs 
Vital Sign 
Unit 
Critical Value 
Critical Change1 
Resting Heart Rate 
beats/minute (bpm) 
High: ≥ 120 
Low: ≤ 50 
Increase of at least 15 
Decrease of at least 15 
Systolic Blood Pressure 
mmHg 
High: ≥ 180 
Low: ≤ 90 
Increase of at least 20 
Decrease of at least 20 
Diastolic Blood  Pressure 
mmHg 
High: ≥ 105 
Low: ≤ 50 
Increase of at least 15 
Decrease of at least 15 
1Change criteria not applicable at baseline or screening.  
7.7.4. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).   
Subjects’ AEs will be considered TEAEs if the onset datetime is between the start datetime of 
study treatment and Day 30.   
If an AE has a partial onset datetime the imputed start and stop dates and times will be used to 
determine treatment-emergence (e.g., stop datetime of AE is before start datetime of study 
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treatment then this is not a TEAE). All AE summaries will present TEAEs only; AEs that are not 
treatment-emergent will be included in listings but not summarized. 
The incidence of subjects reporting TEAEs will be tabulated by the number and percentage of 
subjects reporting the TEAE.  Incidence is defined as a subject reporting at least one TEAE 
within the summary level.  Summary levels are ‘at least one TEAE’, system organ class and 
preferred term.  Subjects will be counted only once within each reporting level on the table.  For 
example if a subject reports a TEAE of headache on two separate occasions, the subject will be 
counted only once in the headache row of the table.  Similarly if a subject reports two separate 
TEAEs within the same system organ class the subject will only be counted once in the summary 
row for that system organ class.  A summary of subjects reporting at least one TEAE during the 
study will also be presented. 
The first row on every TEAE table will be the number and percentage of subjects reporting at 
least one TEAE.  Subsequent rows will be presented in descending order of subject counts for 
the overall treatment group with the most common system organ class first, followed within each 
system organ class by the preferred terms in descending subject count order.  For tables 
presenting the severity or relation to study treatment of AE, the sort order will be determined by 
the overall severity or relation to study treatment subject count (i.e., do not consider severity or 
relation to study treatment in the sort order). 
The following summaries will be presented for the AEs reported by the subjects: 
An overview of all TEAEs and serious TEAEs will present the number and percentage of 
subjects in the following categories: 
• Any TEAE 
o Maximum severity: Mild, Moderate or Severe 
• At least one related TEAE 
• At least one serious TEAE 
• Subjects discontinued due to a TEAE 
• Died on study 
Adverse event tables will present the data by treatment group and across all treatment groups.  
Incidence tables will be created for the following groups of TEAEs: 
• All TEAEs 
• Study drug-related TEAEs 
• TEAEs leading to study withdrawal 
• Study drug-related TEAEs leading to study withdrawal 
• All TEAEs by severity  
• All TEAEs by relationship to study drug 
• All serious TEAEs 
• Study drug-related serious TEAEs 
• Serious TEAEs leading to study withdrawal 
• Study drug-related serious TEAEs leading to study withdrawal 
• Serious TEAEs resulting in death 
• Study drug-related serious TEAEs resulting in death 
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CONFIDENTIAL 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
If there are no AEs to report on any of the above tables, the table should be created with the line 
‘no adverse events were reported’ in the body of the table. 
Adverse events will be considered related if the relationship to study treatment is either 
‘possible’, ‘probable’ or ‘definite’.  
Relation of AE to study treatment will also be assessed by the sponsor.  All AE summaries based 
on related AEs will be produced based on the investigator and sponsor assessment of relatedness 
independently.  A shift table presenting the investigator versus the sponsor assessment of 
relatedness will be presented.  The shift table will display the shift in relatedness assessments for 
at least one AE reported at maximum relatedness across all AEs and for each SOC at the 
maximum relatedness across all AEs within SOC and for each AE preferred term.  Relatedness 
categories from least to most related are ‘Unlikely’, ‘Possible’, ‘Probable’ and ‘Definite’. 
A listing of the mapping of the system organ class and preferred terms to verbatim terms will be 
presented. 
7.7.5. Laboratory Parameters 
Not collected in this study. 
7.8. Pharmacokinetic Analysis 
7.8.1. Pharmacokinetic Parameter Calculation Methods 
Pharmacokinetic parameters will be calculated by noncompartmental analysis method from 
concentration-time data 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 bupivacaine plasma concentrations, concentrations 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.  
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
• 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 Clast, 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 ln(2)/λZ. 
• 
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)=∫
 t
0
dt
t
C
)
(
 
• AUC(0-inf) =∫
 t
0
dt
t
C
)
(
＋∫
∞
t
dt
t
C
)
(
= AUC(0-t)＋Ct/λz. 
• C(t) is last observed quantifiable concentration. 
 
7.8.2. Pharmacokinetic Concentrations and Variables 
The analysis of the PK data will be based on the PK analysis set. 
Bupivacaine plasma concentrations will be listed by treatment group, subject, nominal time, and 
actual time.  Concentrations that are BLOQ will be indicated by BLOQ in this listing.  
Plasma concentrations will be summarized by treatment at each time point.  The following 
descriptive statistics will be presented for plasma concentrations obtained at each nominal time 
point: n, arithmetic mean, SD, %CV, geometric mean, median, minimum and maximum. 
Pharmacokinetic parameters will be summarized for the EXPAREL treatment group.  
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 by treatment in linear and 
semi-logarithmic scale. 
7.9. Interim Analysis 
7.9.1. Pharmacokinetic Review 
After the first 30 subjects have completed the study through Day 10, the plasma samples from 
the subjects who received EXPAREL will be reviewed by an unblinded pharmacokineticist not 
involved in the conduct of the study to determine the median time to the observed maximum 
plasma concentration.  The pharmacokineticist will make a recommendation on the PK sampling 
Document No. <  > 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
times so that subsequent assessment and endpoints are collected through the median time to 
maximum plasma concentration (Tmax) plus at least 24 hours.  This recommendation may 
indicate additional, fewer or no change to the PK sample times.  The study team may, based on 
the pharmacokineticists findings, decide to amended the protocol.  
Document No. <  > 
 
CONFIDENTIAL 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
8. 
SAMPLE SIZE CALCUALTIONS 
In previous wound infiltrations studies in hemorrhoidectomy and bunionectomy, the difference 
between treatment groups in mean AUC(0-48 hours) or NRS pain intensity scores varied from 
20 to 103.  The standard deviations varied from 100 to 128.  A sample size of 50 in each group 
will have 90% power to detect a difference in means of 66 assuming that the common SD is 100 
using a two group t-test with a 0.05 two-sided significance level.  A sample size of 50 in each 
group will have 90% power to detect a difference in means of 86 assuming that the common SD 
is 130 using a two group t-test with a 0.05 two-sided significance level. 
Document No. <  > 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
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. 
 
4 Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons. 
 
5 The National Academies Press. The Prevention and Treatment of Missing Data in Clinical Trials, prepared by the 
Panel on Handling Missing Data in Clinical Trials and Committee on National Statistics,  2010. 
 
6 Schafer, J. L. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman & Hall. 
 
7 Rubin DB, Schenker N.  Multiple imputation for interval estimation from simple random samples with ignorable 
nonresponse.  J Am Stat Assoc 1986;81:366-374. 
 
8 Silverman DG, O’Connor TZ, Brull SJ. Integrated assessment of pain scores and rescue morphine use during 
studies of analgesic efficacy. Anesth Analg. 1993;77:168-170. 
Document No. <  > 
 
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Pacira Pharmaceuticals, Inc.
EXPAREL® 
402-C-329 (Third Molar Extraction) 
Clinical Study Protocol Amendment 2 
 
10. 
TIME AND EVENTS SCHEDULED OF STUDY PROCEDURES 
 
 
Screen 
Visit 
Day 1 
15 
min 
30 
min 1h 
2h 
4h 
6h 
8h 
12h 18h 24h 30h 36h 42h 48h 54h 60h 66h 72h 84h 96h D7 D10 D30 
 
Time Window Within 
30 days 
±5 
min 
±5 
min 
±5 
min 
±15 
min 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±30 
min ±1h ±1h ±1h ±1h ±2h ±2h ±2h ±2h ±4h ±4h ±4h ±1d ±1d ±4d 
Obtain signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform dental examination1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination including height and 
weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for women of childbearing 
potential 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs3 
X 
X2 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Neurological assessment 
 
X2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
12-lead electrocardiogram 
X 
X2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Randomize subject and prepare study drug 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform dental nerve block with lidocaine 2% 
with epinephrine 1:100,000 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study drug; record start and stop 
time 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct NRS pain intensity assessment4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Record times and amounts of opioid rescue 
medication administered5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject satisfaction with postsurgical pain 
control 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Complete PoSSe scale questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Collect scheduled PK blood sample 
 
X2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Document any unscheduled phone calls or office 
visits related to pain after hospital discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Record concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record AEs (starting at signing of ICF)6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLN-PRO-0133.003 
CONFIDENTIAL 
33 of 125 
02 September 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
 
 
 
 
Abbreviations: AE = adverse event; ICF = informed consent form; NRS = numeric rating scale; PK = pharmacokinetic; PoSSe = postoperative symptom severity. 
* Postsurgical efficacy assessments will be conducted at the timepoints specified after the beginning of study drug administration.  At timepoints when multiple assessments 
coincide, the NRS pain intensity assessment will be conducted first, if applicable. 
1 Or on Day 1 prior to surgery. 
2 Prior to surgery. 
3 Vital signs (heart rate and blood pressure) will be measured after subject has rested in a supine position. 
4 NRS pain intensity scores also will be recorded immediately prior to each administration of rescue pain medication through 96 hours. 
5 Subjects should only receive opioid rescue medication (oral oxycodone 5-10 mg) upon request for breakthrough pain, as needed (maximum of every 4 hours).  During 
the 96-hour observation period, no other analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), are allowed.  After 96 hours, the analgesic 
regimen may be adjusted. 
6 If a cardiac event (e.g., myocardial depression, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmia, or cardiac arrest) or neurological 
event (e.g., persistent anesthesia, paresthesia, weakness, or paralysis) occurs during the study, an unscheduled PK blood sample should be obtained and, for cardiac 
events, an ECG should be conducted within 2 hours 
of the time that the event is noted. If there is a scheduled PK blood draw and ECG within 2 hours before or after the event, an additional PK blood draw and ECG are not 
needed. 
 
Document No. <  > 
 
CONFIDENTIAL 
34 of 125 
 12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
11. 
LAYOUT OF TABLES, LISTINGS AND FIGURES 
The following are planned summary tables.  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.   
Tables and listings will have 10 point font size.  Listings font size may be reduced to 9 point if 
needed.  The TLFs will have either Times New Roman, Courier New or SAS Monospace type 
face.  All final TLFs will be provided in both PDF and Word (or RTF) file formats. 
Percentages should not appear if the count is zero.  
Italicized text in the TLF mock-ups indicate notes to programmers and are not to appear on any 
TLF. 
Note headers and footers on mock-ups are reflective of the SAP document and not intended to 
appear on the TLFs. 
On all listings the treatments, in order of appearance, are: EXAPAREL, PLACEBO and, if 
applicable, NOT RANDOMIZED.  Always insert a page break between treatments. 
On all listings sort within treatment by site, subject id with further sorts dependent on listing. 
Table and listing shells follow. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
35 of 125 
 12 November 2015 


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7DEOH 6XPPDU\RI,QFLGHQFHRI7UHDWPHQW(PHUJHQW$GYHUVH(YHQWV7($(VE\6HYHULW\  6DIHW\


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.1-1: Summary of Subject Disposition – All Screened Subjects 
Site: Overall 
 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX] 
n (%) 
Total [N=XX] 
n (%) 
Screened [1] 
 
 
xx 
 
 
 
 
Randomized 
xx 
xx 
xx 
  Not Treated 
xx 
xx 
xx 
  Treated 
xx 
xx 
xx 
 
 
 
 
Safety Analysis Set [2](as treated) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Primary Efficacy Analysis Set [3] (as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Secondary Efficacy Analysis Set [3] (as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
PK Analysis Set [4] (as treated) 
xx (xx.x) 
NA 
xx (xx.x) 
 
 
 
 
Completed Study (as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Discontinued from Study (as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Reasons for Discontinuation (as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Death(as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Adverse Event(as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lack of Efficacy(as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lost to Follow-up(as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Withdrawal by Subject(as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Other(as randomized) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
[1] All subjects who signed the informed consent form  
 
[2] All subjects who received study drug 
[3] Subjects who received study drug and underwent surgery 
[4] Subjects who received EXPAREL and provided sufficient samples for calculation of PK parameters 
Number of subjects randomized is used as denominator for all percentages. 
Subjects randomized to EXPAREL but treated with placebo:  
Subjects randomized to placebo but treated with EXPAREL: 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
39 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Note to programmer: First page will present overall sites; subsequent pages will present each site – one 
site per page. For individual sites the label should be the site number.  For the foonotes “Subjects 
treated with...” if no subjects were mistreated, then put ‘NONE’ after the colon; otherwise list all 
subjects who were mistreated. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
40 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.1-2.1: Summary of Subject Demographics and Baseline Characteristics - Safety Analysis Set 
Site: Overall 
 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
Total [N=XX] 
Age (yrs) 
n 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
Sex 
 
 
 
 
  Female 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Male 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Ethnicity 
 
 
 
 
  Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Race 
 
 
 
 
  American Indian or Alaska Native 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Black or African American 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Hawaiian or Pacific Islander 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Multiple 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Height (cm) 
n 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
Document No. <  > 
 
CONFIDENTIAL 
41 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.1-2.1: Summary of Subject Demographics and Baseline Characteristics - Safety Analysis Set 
Site: Overall 
 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
Total [N=XX] 
Weight (kg) 
n 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
Body Mass Index (kg/m^2) 
n 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: First page will present overall sites; subsequent pages will present each site – one 
site per page. For individual sites the label should be the site number. Use this template also for table: 
Table 14.1-2.2.1: Subject Demographics and Baseline Characteristics – Primary Efficacy Analysis Set  
Table 14.1-2.2.2: Subject Demographics and Baseline Characteristics – Secondary Efficacy Analysis Set  
Table 14.1-2.3: Subject Demographics and Baseline Characteristics - Pharmacokinetics Analysis Set  
 
 
Document No. <  > 
 
CONFIDENTIAL 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.1-3.1: Summary of Duration of Surgery (hours) - Safety Analysis Set 
Site: Overall 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
N 
xx 
xx 
Mean 
xx.x 
xx.x 
Standard Deviation 
x.xx 
x.xx 
Median 
xx 
xx 
Minimum 
xx.x 
xx.x 
Maximum 
xx 
xx 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: First page will present overall sites; subsequent pages will present each site – one 
site per page. For individual sites the label should be the site number.  
 
Use this template also for table: 
Table 14.1-3.2.1: Surgery and Study Drug Exposure – Primary Efficacy Analysis Set  
Table 14.1-3.2.2: Surgery and Study Drug Exposure – Secondary Efficacy Analysis Set 
 
 
 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-1.1.1: Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Primary Efficacy Analysis 
Set - Multiple Imputation Results 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
EXPAREL – Placebo 
 
 
 
 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
 
Least squares mean [1]  
 
xxx.x 
 
xxx.x 
 
xxx.x 
Least squares standard error of mean [1] 
 
xxx.xx 
 
xxx.xx 
 
xxx.xx 
95% confidence interval for treatment difference [1] 
 
 
(xxx.x, xxx.x) 
p-value for treatment difference[1] 
 
 
 
0.xxxx 
 
 
 
 
Note: AUC = area under the curve calculated using the trapezoidal method; 
NRS = numeric rating scale at rest, where 0 = no pain and 10 = worst possible pain; 
Summary statsitics based on the subject mean AUC from the multiple imputations; 
wWOCF + LOCF = imputation using the worst observation prior to use of rescue medication within a medication 
window and last-observation-carried-forward for missing values. 
[1] From an ANOVA with main effects of treatment and site. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: The raw SAS outputs from the procedures used to produce ALL 14.2-1.1 & 14.2-1.2 series 
tables should be saved as a possible appendix to the clinical study report (CSR).  Use this template for 
the following tables: 
 
Table 14.2-1.1.2: Sensitivity Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Secondary 
Efficacy Analysis Set - Multiple Imputation Results 
Table 14.2-1.1.3: Sensitivity Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Primary 
Efficacy Analysis Set – Mixed Model Repeated Measures Results  
 
 
 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-1.1.4: Sensitivity Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Primary 
Efficacy Analysis Set – Tipping Point Analysis - Multiple Imputation Results 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
EXPAREL – Placebo 
 
 
 
 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
 
Least squares mean [1]  
 
xxx.x 
 
xxx.x 
 
xxx.x 
Least squares standard error of mean [1] 
 
xxx.xx 
 
xxx.xx 
 
xxx.xx 
95% confidence interval for treatment difference [1] 
 
 
(xxx.x, xxx.x) 
p-value for treatment difference[1] 
 
 
 
0.xxxx 
 
 
 
 
Tipping Point [2] 
 
 
xx 
 
 
 
 
Note: AUC = area under the curve calculated using the trapezoidal method; 
NRS = numeric rating scale at rest, where 0 = no pain and 10 = worst possible pain; 
Summary statsitics based on the subject mean AUC from the multiple imputations; 
wWOCF + LOCF = imputation using the worst observation prior to use of rescue medication within a medication 
window and last-observation-carried-forward for missing values. 
[1] From an ANOVA with main effects of treatment and site. 
[2] Tipping point is the value added to EXPAREL to reverse the statistical significance observed in the 
primary analysis. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
45 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Note to programmer: The raw SAS outputs from the procedures used to produce ALL 14.2-1.1 & 14.2-1.2 series 
tables should be saved as a possible appendix to the clinical study report (CSR).  Use template 14.2-1.1.1 
for the following tables: 
  
Table 14.2-1.1.5: Sensitivity Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Primary 
Efficacy Analysis Set – wWOCF with LOCF Single Imputation (Historical Imputation) 
 
 
 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-1.2: Summary of AUC of NRS Pain Intensity Scores through 48 hours – Primary Efficacy Analysis 
Set - Analysis of Variance (ANOVA) Model Results - Multiple Imputation Results 
 
Effect 
Model 1 
Main Effects 
Model 2 
Main Effects 
w/ Interaction 
 
 
 
Treatment 
0.xxxx 
0.xxxx 
Site 
0.xxxx 
0.xxxx 
Treatment-by-Site Interaction 
NA 
0.xxxx 
 
 
 
Note: AUC = area under the curve calculated using the trapezoidal method; 
NRS = numeric rating scale at rest, where 0 = no pain and 10 = worst possible pain; 
wWOCF + LOCF = imputation using the worst observation prior to use of rescue medication within a medication 
window and last-observation-carried-forward for missing values. 
Model 1: ANOVA with main effects of treatment and site.  
Model 2: ANOVA with main effects of treatment and site and treatment-by-site interaction. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: The raw SAS outputs from the procedures used to produce ALL 14.2-1.1 & 14.2-1.2 series 
tables should be saved as a possible appendix to the clinical study report (CSR).
Document No. <  > 
 
CONFIDENTIAL 
47 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-1.3: Summary of AUC of NRS Pain Intensity Scores through 48 hours by Site – Primary Efficacy 
Analysis Set - Multiple Imputation Results 
Site 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
XXXX 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
Etc. 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
Note: AUC = area under the curve calculated using the trapezoidal method; 
NRS = numeric rating scale at rest, where 0 = no pain and 10 = worst possible pain;  
Summary statsitics based on the subject mean AUC from the multiple imputations; 
wWOCF + LOCF = imputation using the worst observation prior to use of rescue medication within a medication 
window and last-observation-carried-forward for missing values. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer:  Use mock-ups Table 14.2-1.1.1, 14.2-1.2 and 14.2-1.3 for the following tables 
respectively: 
 
Table 14.2-2.1: Analysis of AUC of NRS Pain Intensity Scores through 24 hours - Primary Efficacy Analysis 
Set - Multiple Imputation Results 
Table 14.2-2.2: Summary of AUC of NRS Pain Intensity Scores through 24 hours - Primary Efficacy Analysis 
Set - Analysis of Variance Model Results - Multiple Imputation Results  
Table 14.2-2.3: Summary of AUC of NRS Pain Intensity Scores through 24 hours by Site - Primary Efficacy 
Analysis Set - Multiple Imputation Results 
Table 14.2-3.1: Analysis of AUC of NRS Pain Intensity Scores through 72 hours - Primary Efficacy Analysis 
Set - Multiple Imputation Results 
Table 14.2-3.2: Summary of AUC of NRS Pain Intensity Scores through 72 hours - Primary Efficacy Analysis 
Set - Analysis of Variance Model Results - Multiple Imputation Results 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Table 14.2-3.3: Summary of AUC of NRS Pain Intensity Scores through 72 hours by Site - Primary Efficacy 
Analysis Set - Multiple Imputation Results 
 
 
Document No. <  > 
 
CONFIDENTIAL 
49 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-4: Summary of SPIS of NRS Pain Intensity Scores - Primary Efficacy Analysis Set - Multiple 
Imputation Results 
SPIS 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
SPIS(0.25-24) 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
SPIS(0.25-48) 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
SPIS(0.25-72) 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
SPIS(0.25-96) 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
Note: SPIS = sum of pain intensity scores; 
NRS = numeric rating scale at rest, where 0 = no pain and 10 = worst possible pain;  
Summary statsitics based on the subject mean SPIS from the multiple imputations; 
wWOCF + LOCF = imputation using the worst observation prior to use of rescue medication within a medication 
window and last-observation-carried-forward for missing values. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
50 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-5.1: Analysis of Opioid-Free Subjects through 24 hours - Primary Efficacy Analysis Set 
Site 
  Time Period 
    Opiod Use 
 
 
 
EXPAREL vs PLACEBO 
Statistic 
EXPAREL [N=XX] Placebo [N=XX] 
Difference [1] 
95% CI [1] 
p-value [2] 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
  0-24 hours 
 
 
 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
Site XXX 
 
 
 
 
 
 
  0-24 hours 
 
 
 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx.x 
(xx.x, xx.x) 
NA 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
Site XXX 
 
 
 
 
 
 
  0-24 hours 
 
 
 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx.x 
(xx.x, xx.x) 
NA 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
[1] Confidence intervals (CI) are based on the normal approximation to the binomial distribution using SAS   
PROC FREQ with RISKDIFFC option. 
[2] From Cochran-Mantel-Haenszel (CMH) test stratified by site. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Note to programmer: Do not split sites across pages. Use mock-up 14.2-5.1 for the following tables: 
 
Table 14.2-5.2: Analysis of Opioid Free Subjects through 48 hours - Primary Efficacy Analysis Set 
Table 14.2-5.3: Analysis of Opioid Free Subjects through 72 hours - Primary Efficacy Analysis Set 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-6.1: Summary of Numerical Rating Scale (NRS) Pain Intensity Scores - By Assessment Timepoint -
Efficacy Analysis Set - Multiple Imputation Results 
 
Assessment Timepoint  
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
15 minute 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
30 minute 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
1 hour 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
X hour 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
Summary statsitics based on the subject mean NRS scores from the multiple imputations. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Timepoints to appear on this table are 15 and 30 minute followed by 1, 2, 4, 8, 12, 24, 
48, 72 and 96 hours. Do not split timepoints across pages. 
 
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402-C-329 (Third Molar Extraction) 
EXPAREL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-6.2: Summary of Numerical Rating Scale (NRS) Pain Intensity Scores at Rescue - Efficacy Analysis 
Set  
 
 
Relative Rescue for Subject  
Parameter 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
 
First Rescue 
NRS Score 
N 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
Standard Deviation 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
Time to Rescue (hrs) 
Median 
xx.x 
xx.x 
 
 
Minimum 
xx 
xx 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
Second Rescue 
NRS Score 
N 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
Standard Deviation 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
Time to Rescue (hrs) 
Median 
xx.x 
xx.x 
 
 
Minimum 
xx 
xx 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
Summary statsitics based on the subject mean NRS scores from the multiple imputations. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Do not split rescue block across pages. 
 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-7.1: Summary of AUC(0.25-96) and AUC(0.25-Day 10) of NRS Pain Intensity Scores - Primary 
Efficacy Analysis Set – Multiple Imputation Results 
 
 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
AUC(0.25-96) 
N 
 
Xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
Xx 
 
xx 
 
Maximum 
 
Xxx 
 
xxx 
 
 
 
 
AUC(0.25-Day 10) 
n 
 
Xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
Xx 
 
xx 
 
Maximum 
 
Xxx 
 
xxx 
 
 
 
 
Note: AUC = area under the curve calculated using the trapezoidal method; 
NRS = numeric rating scale at rest, where 0=no pain and 10=worst possible pain; 
Summary statsitics based on the subject mean AUC scores from the multiple imputations; 
wWOCF + LOCF = imputation using the worst observation prior to use of rescue medication within a medication 
window and last-observation-carried-forward for missing values. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-7.2: Summary of AUC(24-48) and AUC(48-72) of NRS Pain Intensity Scores - Primary Efficacy 
Analysis Set – Multiple Imputation Results 
 
AUC 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
AUC(24-48) 
n 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
AUC(48-72) 
n 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
 
 
 
 
Note: AUC = area under the curve calculated using the trapezoidal method; 
NRS = numeric rating scale at rest, where 0 = no pain and 10 = worst possible pain; 
Summary statsitics based on the subject mean AUC scores from the multiple imputations; 
wWOCF + LOCF = imputation using the worst observation prior to use of rescue medication within a medication 
window and last-observation-carried-forward for missing values. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-8: Tabulation of Pain-Free Subjects at Assessment Time Points - Primary Efficacy Analysis Set 
 
Time Point 
Pain Free 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
 
15 min 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
30 min 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
1 hour 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Etc. 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Pain-free is a NRS score of 0 or 1 with no prior rescue medication use. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Note to programmer: Do not split time point across pages. Time points to appear on this tables are 15 min, 
30 min and 1 hour, 2 hour, 4 hour, 6 hour, 8 hour, 12 hour, 24 hour, 48 hour, 72 hour, 96 hour and Day 10. 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
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Protocol: 402-C-329 
Table 14.2-9: Summary of Time to First Rescue Medication Use (hours) - Primary Efficacy Analysis Set 
Site: Overall 
 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
Rescued 
n (%) 
xx (xx.x) 
xx (xx.x) 
No Rescue (censored) 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Quartiles [1] 
 
 
 
  First (25% rescued) 
Est. (95% CI) 
xxx (xxx,xxx) 
xxx (xxx,xxx) 
  Median (50% rescued) 
Est. (95% CI) 
xxx (xxx,xxx) 
xxx (xxx,xxx) 
  Third (75% rescued) 
Est. (95% CI) 
xxx (xxx,xxx) 
xxx (xxx,xxx) 
Minimum 
Observed 
xxx 
xxx 
Maximum 
Observed 
xxx* 
xxx* 
 
 
 
 
* indicates censored observation 
 
Est. = Point estimate; CI = confidence interval 
[1] Estimates from Kaplan-Meier analysis.  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Note to programmer: First page will present overall sites; subsequent pages will present each site – one 
site per page.  
 
 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-10: Summary of Integrated Rank Assessment of NRS Pain Intensity Scores and Opioid Use - By 
Assessment Timepoint - Primary Efficacy Analysis Set 
Site: Overall 
Assessment Timepoint  
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
24 hours 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
48 hours 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
72 hours 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
Positive numbers indicate less pain or opioid use; negative numbers indicate greater pain or opioid use. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.   
  
 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-11: Summary of Satisfaction with Postsurgical Pain Control Questionnaire Score by Timepoint - 
Primary Efficacy Analysis Set  
Site: Overall 
 
Timepoint 
Score 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
 
24 hour 
Summary  
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
Standard Deviation 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
1: Extremely dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
2: Dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
3: Neither satisfied nor dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
4: Satisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
5: Extremely Satisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. Timepoints to appear on this table are 24, 48, 72 and 96 
hour.  Do not split timepoint across pages. 
 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-12.1: Summary of Postoperative Symptom Severity (PoSSe) Questionnaire - Total Score [1] Summary 
- Primary Efficacy Analysis Set  
Site: Overall 
Timepoint  
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
72 hour 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
Xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
Xx 
 
 
 
 
Day 10 
N 
xx 
Xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
Xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
Xx 
 
 
 
 
[1] Total score is the sum all questions scores for a subject. 
Subjects missing total score in 72 hr:  
Subjects missing total score in Day 10:  
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. If PoSSe total score calculated for all subjects put “none” 
after “Subjects missing total score…”; otherwise list subject numbers after appropriate timepoint.  
 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-12.2: Summary of Postoperative Symptom Severity (PoSSe) Questionnaire - Individual Question 
Score Tabulation - Primary Efficacy Analysis Set  
Site: Overall 
Timepoint 
 Question 
Score 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
72 hour 
 
 
 
 
  1 EATING, in last week: 
 
 
 
 
    1a: Enjoyment of food 
No, not at all 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Yes, a little 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Yes, very much 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
    1b: Days unable to open mouth normally 
0 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
  2 SPEECH, in last week: 
 
 
 
 
    2a: Days voice affected 
0 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
    2b: On worst day how badly speech affected 
Not at all 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Slightly 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Moderately 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Severely 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Unable to speak 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-12.2: Summary of Postoperative Symptom Severity (PoSSe) Questionnaire - Individual Question 
Score Tabulation - Primary Efficacy Analysis Set  
Site: Overall 
Timepoint 
 Question 
Score 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
72 hour (continued) 
 
 
 
 
  3 SENSATION, in last week: 
 
 
 
 
    3a: Days lips or tongue tingled 
None at all 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
     
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
  
 
 
 
 
    3b: Days lips or tongue numb 
None at all 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
  4 APPEARANCE, in last week: 
 
 
 
 
    4a: Days face or neck bruised 
None at all 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
    4b: Days face or neck swollen 
None at all 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-12.2: Summary of Postoperative Symptom Severity (PoSSe) Questionnaire - Individual Question 
Score Tabulation - Primary Efficacy Analysis Set 
Site: Overall 
Timepoint 
 Question 
Score 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
72 hour (continued) 
 
 
 
 
  5 PAIN, in last week: 
 
 
 
 
    5a: Days experience pain 
0 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
    5b: Contolled by painkillers 
Had no pain 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Comletely 
controlled 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Some discomfort 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Poorly controlled 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
No controlled 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
  6 SICKNESS 
 
 
 
 
    6a: Last week, days vomit/nauseated 
0 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1-2 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
3-4 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
5-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
    6b: Worst day, how many times vomit/nauseated 
None 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
One day 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
2-3 times 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
> 3 times 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
All the time 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-12.2: Summary of Postoperative Symptom Severity (PoSSe) Questionnaire - Individual Question 
Score Tabulation - Primary Efficacy Analysis Set  
Site: Overall 
Timepoint 
 Question 
Score 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
72 hour (continued) 
 
 
 
 
  7 INTERFERENCE DAILY ACTIVITIES, in last week 
 
 
 
 
    7a: Prevent work/housework 
Not at all 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Work suffered 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
1 day 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
2-6 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
     
7 days 
n (%) 
XX (XX.X) 
XX (XX.X) 
  
 
 
 
 
    7b: Leisure activities affected 
Not affected 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Mildly 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Moderately 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Severely 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Prevented 
activities 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
    7c: Pain affect life 
 
 
 
 
 
None 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Slightly 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Moderately 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
Severely 
n (%) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  Timepoints to appear on this table are 72 hour and Day 10. 
 
 
 
 
 
Document No. <  > 
 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-13: Summary of Number of Unscheduled Phone Calls or Office Visits Related to Pain - Primary 
Efficacy Analysis Set 
Site: Overall 
 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
Count Summary 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx.x 
xx.x 
 
Median 
xx 
xx 
 
Maximum 
xx 
xx 
 
 
 
 
Count Distribution 
 
 
 
  0  
n (%) 
xx (xx.x) 
xx (xx.x) 
  1 
n (%) 
xx (xx.x) 
xx (xx.x) 
  2 
n (%) 
xx (xx.x) 
xx (xx.x) 
  3 
n (%) 
xx (xx.x) 
xx (xx.x) 
  4 
n (%) 
xx (xx.x) 
xx (xx.x) 
  5 
n (%) 
xx (xx.x) 
xx (xx.x) 
  … 
n (%) 
xx (xx.x) 
xx (xx.x) 
  U 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. Distribution should present all counts up to the highest 
number of visits in the data (U). 
 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-14.1: Summary of Total Rescue Medication Consumption (MED) - Primary Efficacy Analysis Set 
Site: Overall 
Time Period 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
0-24 hrs 
n 
xx 
xx 
     
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
0-48 hrs 
n 
xx 
xx 
     
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
0-72 hrs 
n 
xx 
xx 
     
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
0-96 hrs 
n 
xx 
xx 
     
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-14.2: Summary of the Number of Times Rescue Medication was Used by Subject - Primary Efficacy 
Analysis Set 
Site: Overall 
 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
Count Summary 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Minimum 
xx.x 
xx.x 
 
Median 
xx 
xx 
 
Maximum 
xx 
xx 
 
 
 
 
Count Distribution 
 
 
 
  0  
n (%) 
xx (xx.x) 
xx (xx.x) 
  1 
n (%) 
xx (xx.x) 
xx (xx.x) 
  2 
n (%) 
xx (xx.x) 
xx (xx.x) 
  3 
n (%) 
xx (xx.x) 
xx (xx.x) 
  4 
n (%) 
xx (xx.x) 
xx (xx.x) 
  5 
n (%) 
xx (xx.x) 
xx (xx.x) 
  … 
n (%) 
xx (xx.x) 
xx (xx.x) 
  U 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Present table overall sites and for each site. Distribution should present all counts 
up to the highest number of visits in the data (U). 
 
 
Document No. <  > 
 
CONFIDENTIAL 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-1: Tabulation of Neurological Assessments by Timepoint- Safety Analysis Set  
 
 
 
Timepoint 
Assessment 
Score 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Baseline (Prior to Surgery) 
 
 
 
 
 
 
Numbness of lips, tongue or mouth 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Metallic taste 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Hearing problems 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Vision problems 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Muscle twitching 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
At anytime after baseline 
 
 
 
 
 
 
Numbness of lips, tongue or mouth 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Metallic taste 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Hearing problems 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Vision problems 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Muscle twitching 
No 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  Timepoints to appear on this table are, in order of 
appearance, Baseline (prior to surgery), At anytime after baseline, 15 and 30 minutes and 1, 2, 4, 8, 12, 
18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 84 and 96 hours.  Do not split a timepoint across pages.  For the 
timepoint ‘anytime after baseline’ if there is at least one ‘yes’ at any timepoint but baseline, the 
subject will be a ‘yes’. 
  
 
Document No. <  > 
 
CONFIDENTIAL 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-2.1 Summary of Electrocardiogram Parameters – Central Read - Safety Analysis Set 
Site: Overall 
 
ECG Parameter 
Timepoint 
Value 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Heart Rate (bpm) 
 
 
 
 
 
 
Baseline 
Actual 
n 
xx 
xx 
xx 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
At Median Tmax 
Baseline Actual[1] 
n 
xx 
xx 
xx 
 
  (XX Hour) 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Actual 
n 
xx 
xx 
xx 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n 
xx 
xx 
xx 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
 
[1] Baseline (prior to surgery) for subjects with data at the timepoint. 
QTcF = corrected QT interval using Fridericia’s correction 
QTcB = corrected QT interval using Bazett’s correction 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Document No. <  > 
 
CONFIDENTIAL 
69 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Note to programmer: Only present overall sites. Electrocardiogram intervals are ‘Heart Rate (bpm)’, ‘RR 
Interval (msec)’, ‘PR Interval (msec)’, ‘QRS Interval (msec)‘, ‘QT Interval (msec)‘, ‘QTcF Interval 
(msec)‘, ‘QTcB Interval (msec).’ Timepoints to appear on this table are, in order of appearance, Baseline, 
At Median Tmax (XX Hour), At Subjects’ Tmax, 15 and 30 minutes and 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 
54, 60, 66, 72, 84 and 96 hours.  Don’t split timepoint across pages. Note that the X hour (Tmax) timepoint 
will be a duplicate of X hour summary. 
 
Document No. <  > 
 
CONFIDENTIAL 
70 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-2.2: Summary of Potentially Clinically Meaningful Abnormal Electrocardiogram Results – Central 
Read - Safety Analysis Set 
 
 
ECG Parameter Timepoint 
Criteria 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Heart Rate (bpm) 
 
 
 
 
 
 
Baseline 
< 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Decrease >= 25 
n (%) 
NA 
NA 
NA 
 
 
< 50 & Decrease >= 25 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
 
> 100 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 25 
n (%) 
NA 
NA 
NA 
 
 
> 100 & Increase >= 25 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
Any time after Baseline < 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Decrease >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
< 50 & Decrease >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
 
> 100 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
> 100 & Increase >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
At Median Tmax  
< 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
  (XX hours) 
Decrease >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
< 50 & Decrease >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
 
> 100 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
> 100 & Increase >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
15 minutes 
< 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Decrease >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
< 50 & Decrease >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
 
> 100 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
> 100 & Increase >= 25 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Document No. <  > 
 
CONFIDENTIAL 
71 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Note to programmer: Only present overall sites. Electrocardiogram intervals are ‘Heart Rate (bpm)’, ‘PR 
Interval (msec)’, ‘QRS Interval (msec)‘, ‘QT Interval (msec)‘, ‘QTcF Interval (msec)‘, ‘QTcB Interval 
(msec).’ Timepoints to appear on this table are, in order of appearance, Baseline, Any time after Baseline, 
At Median Tmax (X hour), At Subjects’ Tmax, 15 and 30 minutes and 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 
54, 60, 66, 72, 84 and 96 hours.  Don’t split timepoint across pages. Note that the At Median Tmax (X hour) 
timepoint will be a duplicate of X hour summary. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-2.3: Tabulation Electrocardiogram Morphology Results – Central Read - Safety Analysis Set 
 
Time Point 
Morphology 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Any Time After Baseline 
 
 
 
 
 
No Findings 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
At Least One Finding  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Abnormal U Wave  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
ST Segment Elevation 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
ST Segment Depression 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
T Wave Inversion 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Second or Third Degree Heart Block 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
LBBB 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
RBBB 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Atrial Fibrillation 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Atrial Flutter 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
MI 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
No Findings 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
At Least One Finding  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Abnormal U Wave  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
ST Segment Elevation 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
ST Segment Depression 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
T Wave Inversion 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Second or Third Degree Heart Block 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
LBBB 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
RBBB 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Atrial Fibrillation 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Atrial Flutter 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
MI 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. Electrocardiogram morphology list presented in mock-up may 
not be complete (or may contain items not found during study), the list should only present those 
morphologies found during the study. Timepoints to appear on this table are, in order of appearance, At Any 
Time After Baseline, Baseline, X hour (Tmax), 15 and 30 minutes and 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, 48, 
Document No. <  > 
 
CONFIDENTIAL 
73 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
54, 60, 66, 72, 84 and 96 hours.  Don’t split timepoint across pages. Note that the X hour (Tmax) timepoint 
will be a duplicate of X hour summary. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
74 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-2.4: Tabulation Electrocardiogram Interpretation – Investigator Read - Safety Analysis Set 
 
Time Point 
Interpretation 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Any Time After Baseline 
 
 
 
 
 
Normal 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Not clinically siginificant 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Clinically siginificant 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Baseline 
Normal 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Not clinically siginificant 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Clinically siginificant 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Note to programmer: Only present overall sites. Timepoints to appear on this table are, in order of 
appearance, At Any Time After Baseline, Baseline, X hour (Tmax), 15 and 30 minutes and 1, 2, 4, 8, 12, 18, 
24, 30, 36, 42, 48, 54, 60, 66, 72, 84 and 96 hours.  Don’t split timepoint across pages. Note that the X 
hour (Tmax) timepoint will be a duplicate of X hour summary. 
 
Document No. <  > 
 
CONFIDENTIAL 
75 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-3.1: Summary of Vital Signs – Safety Analysis Set 
Site: Overall 
 
Vital Sign 
Timepoint 
Value 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Resting Heart Rate (bpm) 
 
 
 
 
Baseline 
Actual 
n 
xx 
xx 
xx 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
1 hour 
Baseline Actual[1] 
n 
xx 
xx 
xx 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Actual 
n 
xx 
xx 
xx 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n 
xx 
xx 
xx 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
 
 
 
Minimum 
xx 
xx 
xx 
 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
 
[1] Baseline (prior to surgery) for subjects with data at the timepoint. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. Vital signs are ‘Resting Heart Rate (bpm)’, ‘Systolic Blood 
Pressure (mmHg)’ and ‘Diastolic Blood Pressure (mmHg)’. Timepoints to appear on this table are Baseline, 1, 
2 and 4 hour.  Don’t split timepoint across pages.  
 
Document No. <  > 
 
CONFIDENTIAL 
76 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-3.2: Summary of Potentially Clinically Significant Abnormal Vital Signs – Safety Analysis Set 
Site: Overall 
 
Vital Sign 
Timepoint 
Criteria 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Resting Heart Rate (bpm) 
 
 
 
 
 
Baseline 
<= 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
NA 
NA 
NA 
 
 
<= 50 & Decrease >= 15 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
 
>= 120 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
NA 
NA 
NA 
 
 
>= 120 & Increase >= 15 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
1 hour 
<= 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
<= 50 & Decrease >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 120 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
>= 120 & Increase >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
2 hour 
<= 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
<= 50 & Decrease >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 120 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
>= 120 & Increase >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
4 hour 
<= 50 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
<= 50 & Decrease >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 120 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
>= 120 & Increase >= 15 
n (%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Document No. <  > 
 
CONFIDENTIAL 
77 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-3.2: Summary of Potentially Clinically Significant Abnormal Vital Signs – Safety Analysis Set 
Site: Overall 
 
Vital Sign 
Timepoint 
Criteria 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Systolic Blood Pressure (mmHg) 
 
 
 
 
 
Baseline 
<= 90 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 20 
n (%) 
NA 
NA 
NA 
 
 
<= 90 & Decrease >= 20 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
 
>= 180 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 20 
n (%) 
NA 
NA 
NA 
 
 
>= 180 & Increase >= 20 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
1 hour 
<= 90 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
<= 90 & Decrease >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 180 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>= 180 & Increase >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
2 hour 
<= 90 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
<= 90 & Decrease >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 180 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>= 180 & Increase >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
4 hour 
<= 90 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
<= 90 & Decrease >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 180 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>= 180 & Increase >= 20 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Document No. <  > 
 
CONFIDENTIAL 
78 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-3.2: Summary of Potentially Clinically Significant Abnormal Vital Signs – Safety Analysis Set 
Site: Overall 
 
Vital Sign 
Timepoint 
Criteria 
Statistic 
EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XXX] 
Diatolic Blood Pressure (mmHg) 
 
 
 
 
 
Baseline 
<= 50 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
NA 
NA 
NA 
 
 
<= 50 & Decrease >= 15 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
 
>= 105 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
NA 
NA 
NA 
 
 
>= 105 & Increase >= 15 
n (%) 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
1 hour 
<= 50 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
<= 50 & Decrease >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 105 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>= 105 & Increase >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
2 hour 
<= 50 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
<= 50 & Decrease >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 105 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>= 105 & Increase >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
4 hour 
<= 50 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Decrease >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
<= 50 & Decrease >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
>= 105 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Increase >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>= 105 & Increase >= 15 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Document No. <  > 
 
CONFIDENTIAL 
79 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Table 14.3-4.1.1: Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
Site: Overall 
Number of 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX]  
n (%) 
Total [N=XX] 
n (%) 
 
 
 
 
Subjects with Any TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
  At least one Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
  At least one Serious 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Subjects 
Discontinued 
due 
to 
TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Died on Study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  
 
Document No. <  > 
 
CONFIDENTIAL 
80 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-4.1.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
 
Site: Overall 
System Organ Class 
  Preferred Term 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX]  
n (%) 
Total [N=XX] 
n (%) 
 
 
 
 
Subjects with at least one TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
SOC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
SOC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT2.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT2.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ETC. 
 
 
 
 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA TBD). 
Sorted by descending total incidence by system organ class and preferred term within system organ class. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  Use mock-up Table 14.3-2.1.2 for the following tables: 
 
Table 14.3-4.1.3: Summary of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) - 
Safety Analysis Set  
Table 14.3-4.1.4: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) Leading to Study 
Withdrawal - Safety Analysis Set 
Table 14.3-4.1.5: Summary of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) 
Leading to Study Withdrawal - Safety Analysis Set 
 
For related tables add the following footnote to the table: 
Related TEAEs are those AEs indicated as ‘possible’, ‘probable’ or ‘definite’ related by the investigator 
on the AE CRF. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
81 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-4.1.6: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Severity - Safety 
Analysis Set 
Site: Overall 
System Organ Class 
  Preferred Term 
Severity 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX]  
n (%) 
Total [N=XX] 
n (%) 
 
 
 
 
 
Subjects with at least one 
TEAE 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
SOC1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
  PT1.1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
  PT1.2 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC2 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
  PT2.1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ETC. 
 
 
 
 
 
 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA TBD). 
Sorted by descending total incidence by system organ class and preferred term within system organ class. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 
Document No. <  > 
 
CONFIDENTIAL 
82 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-4.1.7: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Relationship to 
Study Drug - Safety Analysis Set 
Site: Overall 
System Organ Class 
  Preferred Term 
Severity 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX]  
n (%) 
Total [N=XX] 
n (%) 
 
 
 
 
 
Subjects with at least one 
TEAE 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
SOC1 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
  PT1.1 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
  PT1.2 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
SOC2 
Unlikely 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   
Possible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Probable 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Definite 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
ETC. 
 
 
 
 
 
 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA TBD). 
Sorted by descending total incidence by system organ class and preferred term within system organ class. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
83 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
 
Note to programmer: Only present overall sites. 
Note to programmer: Only present overall sites. Use templates 14.3.1-1 through 14.3.1-7 respectively for 
the following tables:  
 
Table 14.3-4.2.1: Overview of Serious Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
Table 14.3-4.2.2: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) - Safety 
Analysis Set 
Table 14.3-4.2.3: Summary of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) - Safety Analysis Set 
Table 14.3-4.2.4: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) Leading to 
Study Withdrawal - Safety Analysis Set 
Table 14.3-4.2.5: Summary of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) Leading to Study Withdrawal - Safety Analysis Set 
Table 14.3-4.2.6: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) Resulting in 
Death - Safety Analysis Set 
Table 14.3-4.2.7: Summary of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) Resulting in Death - Safety Analysis Set 
 
 
Document No. <  > 
 
CONFIDENTIAL 
84 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.3-5.1: Summary of Incidence of Prior Medications - Safety Analysis Set 
Site: Overall 
Anatomical Therapeutic Class (ATC) 
  Preferred Name 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX]  
n (%) 
Total [N=XX] 
n (%) 
 
 
 
 
Subjects taking at least one medication 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
ATC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
ATC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN2.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN2.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ETC. 
 
 
 
 
 
 
 
Medications are coded using World Health Organization Drug Dictionary (WHO-DD) March 2015. 
Sorted by descending total incidence by ATC and preferred name within ATC. 
Prior medications are those stopped before end of surgery. 
Subjects using the same prior medication more than once are counted only once at each summary level. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites.  Use this template for the following tables: 
 
Table 14.3-5.2: Incidence of Concomitant Medications – Safety Analysis Set.  
 
On these tables change the footnote ‘Prior medications are those stopped before end of surgery’ to read 
‘Concomitant medications are those taken between the end of surgery and discharge from study’ on Table 
14.3-5.2. 
Document No. <  > 
 
CONFIDENTIAL 
85 of 125 
12 November 2015 
 


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/LVWLQJ$OO3ULRUDQG&RQFRPLWDQW0HGLFDWLRQV±5DQGRPL]HG6XEMHFWV 
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/LVWLQJ6XEMHFW(OLJLELOLW\ ±,QFOXVLRQ([FOXVLRQ&ULWHULD


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-1: Subject Disposition – All Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Date of 
Last Visit 
End of Study Status 
Specify 
XXX 
XXX-YYYY 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: End of study status for subject who early terminated from the study is the primary 
reason for termination.  If subject discontinued due to an AE then the reason should read ‘ADVERSE EVENT, 
AE # X’. If subject discontinued due to death the reason should read ‘DEATH ON DDMONYYYY’.  For those 
reasons that also collected a specify text, that text belongs in the specify column. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
88 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-2: Randomization and Analysis Sets – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
Randomization Analysis Sets 
 
 
Site 
Subject 
Date and Time 
Number 
Safety 
PK 
Primary 
Efficacy 
Secondary 
Efficacy 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXXXX 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
89 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-3: Demographics – All Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Birth Date 
Age 
(yrs) Sex 
Race 
Ethnicity 
XXX 
XXX-YYYY DDMONYYYY 
XX 
XXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
90 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-4: Surgery – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
Anesthesia Time 
Surgery Time 
All 4 Molars 
Impaction 
Site 
Subject 
Date 
Start 
Stop 
Start 
Stop 
Duration (hr) 
1 16 17 32 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
HH:MM 
HH:MM 
 
XX.X 
XXX 
X 
X 
X 
X 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
HH:MM 
HH:MM 
 
XX.X 
XXX 
X 
X 
X 
X 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
HH:MM 
HH:MM 
 
XX.X 
XXX 
X 
X 
X 
X 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
HH:MM 
HH:MM 
 
XX.X 
XXX 
X 
X 
X 
X 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
HH:MM 
HH:MM 
 
XX.X 
XXX 
X 
X 
X 
X 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
HH:MM 
HH:MM 
 
XX.X 
XXX 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Impaction: F=Fully bony; P=Partially bony; S=Soft tissue; E=Erupted 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-5: Study Drug Administration – Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Date 
Start 
Time 
Stop 
Time 
Molar 
Total Volume 
(mL) 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
1 
X 
 
 
 
 
 
16 
X 
 
 
 
 
 
17 
X 
 
 
 
 
 
32 
X 
 
 
 
 
 
Total 
XX 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
1 
X 
 
 
 
 
 
16 
X 
 
 
 
 
 
17 
X 
 
 
 
 
 
32 
X 
 
 
 
 
 
Total 
XX 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
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Protocol: 402-C-329 
Listing 16.2-6.1: Numeric Rating Scale (NRS) – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
 
Time From Dose 
 
 
 
Site Subject 
Date and Time 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
NRS 
Average 
NRS[1] Comments 
XXX 
XXX-YYYY DDMONYYYYTHH:MM 
0.25 
0.XX 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
0.50 
0.XX 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
1 
X 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
2 
ND 
 
 
XX 
 
 
 
DDMONYYYYTHH:MM 
RESCUE 
X 
 
XX 
NA 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
6 
X 
 
-X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
8 
X 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
12 
XX 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
24 
XX 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
48 
XX 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
X 
XX 
XX 
 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
NRS: 0=No Pain to 10=Worst Pain Imaginable 
 
ND=Not Done  NA=Not Applicable 
[1] Average NRS score from the multiple imputations; RESCUE NRS scores not imputed. 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by NRS collection date and time.  If NRS was taken due to rescue medication 
dosing, put RESCUE in scheduled column and hours from dose in actual column – leave deviation column blank.  
Do not split a subject’s data across pages. 
 
 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-6.2.1: Area Under the Average NRS Score (Multiple Imputations) Curve - Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
AUC(0.25-48) 
AUC(0.25-24) 
AUC(0.25-72) 
AUC(0.25-96) 
AUC(24-48) 
AUC(48-72) 
XXX 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
XXX-YYYY 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
XXXXX.X 
 
 
 
 
 
 
 
 
NRS: 0=No Pain to 10=Worst Pain Imaginable 
 
ND=Not Done 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template for the following table: 
 
Listing 16.2-6.2.2: Area Under the NRS Score (wWOCF+LOCF) - Randomized Subjects 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
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Protocol: 402-C-329 
Listing 16.2-7: Integrated Rank Assessment (IRA) - Randomized Subjects 
Treatment: TTTTTTT 
 
 
48 hr 
24 hr 
72 hr 
Site Subject 
Opioid (MED) 
[Rank] 
NRS 
[Rank] 
IRA 
Opioid (MED) 
[Rank] 
NRS 
[Rank] 
IRA 
Opioid (MED) 
[Rank] 
NRS 
[Rank] 
IRA 
XXX 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
XXX-YYYY 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
XXX.X [XX] 
XX [XX] 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
NRS: 0=No Pain to 10=Worst Pain Imaginable 
 
ND=Not Done 
NRS Rank based on reported values without imputation. 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-8.1: Rescue Medication – Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Date and Time 
Time to 
Rescue (hr) 
Medication 
Dose 
(mg) 
Conversion 
Factor 
Dose 
(MED) Route 
Number 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
XX.X 
Oxycodone 
XX 
0.5 
XX.XX 
PO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time to rescue is time from end of surgery to rescue medication dose. 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-8.2: Rescue Medication Total Dose from End of Surgery through Timepoint – Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
24 hr 
48 hr 
72 hr 
XXX 
XXX-YYYY 
XXXX.XX 
XXXX.XX 
XXXX.XX 
 
XXX-YYYY 
XXXX.XX 
XXXX.XX 
XXXX.XX 
 
XXX-YYYY 
XXXX.XX 
XXXX.XX 
XXXX.XX 
 
XXX-YYYY 
XXXX.XX 
XXXX.XX 
XXXX.XX 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-9: Pain-free Status through Timepoint – Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
24 hr 
48 hr 
72 hr 
96 hr 
XXX 
XXX-YYYY 
XXX 
XXX 
XXX 
XXX 
 
XXX-YYYY 
XXX 
XXX 
XXX 
XXX 
 
XXX-YYYY 
XXX 
XXX 
XXX 
XXX 
 
XXX-YYYY 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
Pain-free is defined as an NRS score ≤ 0 at that timepoint and no prior rescue medication use. 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Pain-free is a YES/NO value.
Document No. <  > 
 
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402-C-329 (Third Molar Extraction) 
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Protocol: 402-C-329 
Listing 16.2-10: Subject Satisfaction with Post-Surgical Pain Control – Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Assessment 
Date and Time 
Rating 
Score 
XXX 
XXX-YYYY 
24 hr 
DDMONYYYYTHH:MM 
EXTREMELY DISSATISFIED 
1 
 
XXX-YYYY 
48 hr 
DDMONYYYYTHH:MM 
DISSATISFIED 
2 
 
XXX-YYYY 
72 hr 
DDMONYYYYTHH:MM 
NEITHER SATISFIED NOR DISSATISFIED 
3 
 
XXX-YYYY 
96 hr 
DDMONYYYYTHH:MM 
SATISFIED 
4 
 
XXX-YYYY 
Day 10 
DDMONYYYYTHH:MM 
EXTREMELY SATISFIED 
5 
 
 
 
 
 
 
XXX 
XXX-YYYY 
24 hr 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
X 
 
XXX-YYYY 
48 hr 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
X 
 
XXX-YYYY 
72 hr 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
X 
 
XXX-YYYY 
96 hr 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
X 
 
XXX-YYYY 
Day 10 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
X 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Possible values for rating and score are indicated in first 5 rows of mock-up. 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-11.1: Postoperative Symptom Severity (PoSSe) Scale Questionnaire – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
Question Score (%) (see Listing 16.2-11.2 for question text & scoring) 
Total 
(%) 
Site Subject 
1a 
1b 
2a 
2b 
3a 
3b 
4a 
4b 
5a 
5b 
6a 
6b 
7a 
7b 
7c 
XXX 
XXX-YYYY X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX 
 
XXX-YYYY X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX XX.XX 
 
XXX-YYYY X.XX 
NA 
X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX X.XX 
NC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NA=Not answered 
 
NC=Not calculated 
Total = sum of all scores; ranging from 0% (least severe) to 100% (most severe). 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page 1 of 2) 
Protocol: 402-C-329 
Listing 16.2-11.2: Postoperative Symptom Severity (PoSSe) Scale Questionnaire – Questions 
 
Eating: 
  1a. In the last week, has your operation affected your enjoyment of food? 
    [0]No, not at all; [5.25] Yes, a little; [10.5] Yes, very much 
  1b. In the last week, for how many days were you unable to open your mouth normally because of your        
      operation? 
    [0]0 days; [2.63]1-2 days; [5.25]3-4 days; [7.88]5-6 days; [10.5] 7 days 
Speech: 
  2a. In the last week, for how many days was your voice affected because of your operation? 
    [0]0 days; [1.25]1-2 days; [2.5]3-4 days; [3.75]5-6 days; [5] 7 days 
  2b. On the worst day of the last week, how badly was your speech affected by your operation? 
    [0]Not at all; [1.25]Slightly; [2.5]Moderately; [3.75]Severely; [5]Unable to speak at all 
Sensation: 
  3a. Thinking of the last week, for how many days were your lips or tongue felling tingling because of  
      your operation? 
    [0]None at all; [2]1-2 days; [4]3-4 days; [6]5-6 days; [8] 7 days 
  3b. Thinking of the last week, for how many days were you lips or tongue felling numb because of your  
      operation? 
    [0]None at all; [2]1-2 days; [4]3-4 days; [6]5-6 days; [8] 7 days 
Appearance: 
  4a. Thinking of the last wekk, for how many days were your face and/or neck bruised because of your  
      operation? 
    [0]None at all; [1.5]1-2 days; [3]3-4 days; [4.5]5-6 days; [6] 7 days 
  4b. Thinking of the last week, for how many days were your face and/or neck swollen because of you  
      operation? 
    [0]None at all; [1.5]1-2 days; [3]3-4 days; [4.5]5-6 days; [6] 7 days 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page 2 of 2) 
Protocol: 402-C-329 
Listing 16.2-11.2: Postoperative Symptom Severity (PoSSe) Scale Questionnaire – Questions 
 
Pain: 
  5a. Thinking of the last week, for how many days did you experience pain from your operation? 
    [0]None at all; [2.38]1-2 days; [4.75]3-4 days; [7.13]5-6 days; [9.5] 7 days 
  5b. Thinking of the last week, has the pain from your operation been controlled by pain killers? 
    [0] I have had no pain; [2.38] Yes, completely controlled;  
    [4.75] Controlled mostly but still some discomfort; [7.13] Poorly controlled;  
    [9.5] Not controlled at all 
Sickness: 
  6a. Thinking of the last week, for how many days did you vomit or feel nauseated? 
    [0]None at all; [1.25]1-2 days; [2.5]3-4 days; [3.75]5-6 days; [5] 7 days 
  6b. On the worse day of the last week, how many times did you vomit of feel nauseated? 
    [0]None at all; [1.25]One day; [2.5]2-3 times; [3.75]More than 3 times;  
    [5]All the time (all day long) 
Interference with daily activities: 
  7a. In the last week, did the operation prefvent you from carrying out work/housework and other daily  
      activities? 
    [0]None at all; [0.83]I could continue with my work, but my work suffered; [1.65]Yes, for 1 day; 
    [2.48]Yes, for 2-6 days; [3.3]Yes, for 7 days 
  7b. In the last week, have your leisure activities been affected by your operation? (including sports,  
      hobbies and social life) 
    [0]Not affected by the operation; [0.83]Mildly affected by the operation;  
    [1.65]Moderately affected by the operation; [2.48]Severely affected by the operation; 
    [3.3]The operation prevented any social life at all 
  7c. Thinking of the last wekk, how badly did the pain affect your life? 
    [0]Not at all; [1.1]Slightly; [2.2]Moderately; [3.3]Severely 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
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402-C-329 (Third Molar Extraction) 
EXPAREL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-12: Day 30 Phone Contact – Pain-Related Calls/Visits – Randomized Subjects 
Treatment: TTTTTTT 
 
 
 
 
Number of pain-related 
Site 
Subject 
Date 
Visit 
Phone calls 
Office Visits 
Total 
XXX 
XXX-YYYY 
DDMONYYYY 
Day 7 
XX 
XX 
 
 
XXX-YYYY 
DDMONYYYY 
Day 10 
XX 
XX 
 
 
XXX-YYYY 
DDMONYYYY 
Day 30 
XX 
XX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
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402-C-329 (Third Molar Extraction) 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-13: Neurological Assessment – Randomized Subjects 
Treatment: TTTTTTTT 
 
 
Date and Time 
Of 
Assessment 
Time From Dose 
Questions 
Site 
Subject 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
1 
2 
3 
4 
5 
6 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
0 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
0.25 
0.XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
0.50 
0.XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
1 
X 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
2 
ND 
 
 
 
 
 
 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
8 
X 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
12 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
18 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
24 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
30 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
36 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
42 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
48 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
54 
XX 
 
-X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
60 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
66 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
84 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
240 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
1) Is subject oriented? 
 
 
2) Do you have numbness of the lips, the tongue or around the mouth? 
3) Do you have a metallic taste in your mouth? 
4) Are you having problems with your hearing not related to the use of a hearing aid? 
5) Are you having problems with your vision no related to the use of eye glasses? 
6) Are your muscles twitching? 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
104 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-14.1: Electrocardiogram Findings – Investigator Assessment – Randomized Subjects 
Treatment: EXPAREL 
 
 
Date and Time of 
Time From Dose 
 
Site Subject 
Dose 
Sample 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
Finding 
XXX 
XXX-YYYY NA 
DDMONYYYYTHH:MM 
Screening 
NA 
 
 
 
 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
0 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
0.25 
0.XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
0.50 
0.XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
1 
X 
X 
 
 
 
 
DDMONYYYYTHH:MM 
2 
ND 
 
 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
-X 
 
 
 
 
DDMONYYYYTHH:MM 
6 
X 
X 
 
 
 
 
DDMONYYYYTHH:MM 
8 
X 
X 
 
 
 
 
DDMONYYYYTHH:MM 
12 
XX 
-X 
 
 
 
 
DDMONYYYYTHH:MM 
18 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
24 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
30 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
36 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
42 
XX 
-X 
 
 
 
 
DDMONYYYYTHH:MM 
48 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
54 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
60 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
66 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
72 
XX 
-X 
 
 
 
 
DDMONYYYYTHH:MM 
84 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
96 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
168 
XX 
X 
 
 
 
 
DDMONYYYYTHH:MM 
240 
XX 
X 
 
 
 
 
 
 
 
 
 
NA=Not applicable 
 
ND=Not done 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
105 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-14.2.1: Electrocardiogram Morphology – Central Read Assessment – Randomized Subjects 
Treatment: EXPAREL 
 
 
 
Time from Dose 
 
Site Subject 
Sample 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
Morphology 
XXX 
XXX-YYYY DDMONYYYYTHH:MM Screening 
NA 
 
 
 
 
DDMONYYYYTHH:MM 
0 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
0.25 
0.XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
0.50 
0.XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
1 
X 
 
X 
 
 
 
DDMONYYYYTHH:MM 
2 
ND 
 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
 
X 
 
 
 
DDMONYYYYTHH:MM 
6 
X 
 
-X 
 
 
 
DDMONYYYYTHH:MM 
8 
X 
 
X 
 
 
 
DDMONYYYYTHH:MM 
12 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
18 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
24 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
30 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
36 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
42 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
48 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
54 
XX 
 
-X 
 
 
 
DDMONYYYYTHH:MM 
60 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
66 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
84 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
168 
XX 
 
X 
 
 
 
DDMONYYYYTHH:MM 
240 
XX 
 
X 
 
 
 
 
 
 
 
 
NA=Not applicable 
 
ND=Not done 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
106 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-14.2.2: Electrocardiogram Intervals – Central Read Assessment – Randomized Subjects 
Treatment: EXPAREL 
 
 
 
Date and Time 
Of 
Sample 
Time From Dose 
Heart 
Rate (bpm) 
Intervals (msec) 
Site Subject 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
RR 
PR 
QRS 
QT 
QTcB QTcF 
XXX 
XXX-YYYY DDMONYYYYTHH:MM Screening 
NA 
 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
0 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
0.25 
0.XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
0.50 
0.XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
1 
X 
 
X 
XX 
XXX* XXX*^ XXX* XXX* XXX* XXX* 
 
 
DDMONYYYYTHH:MM 
2 
ND 
 
 
 
 
 
 
 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
8 
X 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
12 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
18 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
24 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
30 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
36 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
42 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
48 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
54 
XX 
 
-X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
60 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
66 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
84 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
DDMONYYYYTHH:MM 
240 
XX 
 
X 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
NA=Not applicable 
potentially clinically meaningful value=*; change from baseline=^ 
ND=Not done 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
107 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-15: Vital Signs – All Subjects 
Treatment: TTTTTTTT 
SITE: XXX 
Time from Dose 
 
Blood  
Pressure  
 
 
Body 
Mass 
Index 
(m/kg2) 
Subject 
Visit 
Date and Time 
Sched 
(hr) 
Actual 
(hr) 
Devi-
ation 
(mins) 
Heart 
Rate 
(bpm) 
Sys.  
(mmHg) 
Dia.  
(mmHg) 
Height 
(cm) 
Weight 
(kg) 
XXX-YYYY 
Screening DDMONYYYYTHH:MM 
NA 
NA 
NA 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
Day 1 
DDMONYYYYTHH:MM 
0 
X 
X 
XX 
XXX 
XXX 
 
 
 
 
 
DDMONYYYYTHH:MM 
1 
X 
X 
XX 
XXX 
XXX*^ 
 
 
 
 
 
DDMONYYYYTHH:MM 
2 
X 
X 
XX 
XXX*^ 
XXX 
 
 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
-X 
XX* 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
potentially clinically meaningful value=*; change from baseline=^ 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
108 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-16.1: All Adverse Events – All Subjects 
Treatment: TTTTTTT 
Site Subject 
TEAE Data Type 
Data 
XXX 
XXX-YYYY 
N 
Start 
DDMONYYYYTHH:MM 
 
 
 
Stop 
DDMONYYYYTHH:MM 
 
 
 
AE Number 
X 
 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
Severity 
XXXXXXXX 
 
 
 
Relationship to Study Drug XXXXXXXX 
 
 
 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
Outcome 
XXXXXXXXXXXXXX 
 
 
 
Serious 
XXX 
 
 
 
  Serious Cause(s) 
  XXXXXXXXXXXXX 
 
 
 
 
  XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row.  Do not split an AE across pages.  Insert a 
page break between subjects.  This this template for the following listings: 
Listing 16.2-16.2.1: Treatment-emergent Adverse Events – Randomized Subjects  
Listing 16.2-16.2.2: Treatment-emergent Study Drug Related Adverse Events – Randomized Subjects  
Listing 16.2-16.3: All Serious Adverse Events – All Subjects  
Listing 16.2-16.4.1: Treatment-emergent Serious Adverse Events – Randomized Subjects  
Listing 16.2-16.4.2: Treatment-emergent Study Drug Related Serious Adverse Events – Randomized Subjects 
 
 
Document No. <  > 
 
CONFIDENTIAL 
109 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-17.1: All Prior and Concomitant Medications – Randomized Subjects 
Treatment: TTTTTTT 
Site Subject 
Category 
Data Type 
Data 
XXX 
XXX-YYYY 
 
Start 
DDMONYYYYTHH:MM 
 
 
 
Stop 
DDMONYYYYTHH:MM 
 
 
 
Medication Number 
X 
 
 
 
ATC Level 1 
XXXXXXXXXXXXXXXXXX 
 
 
 
  ATC Level 2 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
    ATC Level 3 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
      ATC Level 4 
      XXXXXXXXXXXXXXXXXXXX 
 
 
 
  Preferred Name 
XXXXXXXXXXXXXXXXXXXXX 
 
 
 
    Verbatim 
  XXXXXXXXXXXXXXXXXXXX 
 
 
 
Route 
XXXXXXXX 
 
 
 
Frequency 
XXXXXXXX 
 
 
 
Given for AE or MH? 
XXXXXXXXXXXXXXXXXXXXX AE # XX (or MH # XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC=Anatomical therapeutic class 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If medication is ongoing, put ONGOING in stop row.  Do not split an medication across 
pages.  Insert a page break between subjects.  Values for category column are: CONCOMITANT; 
SURGICAL/ANESTHESIA; NON-MEDICATION; PRIOR.  Use this template for the following listings: 
Listing 16.2-17.2: Prior Medications – Randomized Subjects  
Listing 16.2-17.3: Concomitant Medications – Randomized Subjects 
 
 
 
 
 
 
Document No. <  > 
 
CONFIDENTIAL 
110 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-18: Dental Examination – Randomized Subjects 
Treatment: TTTTTTT 
Site 
Subject 
Performed? 
Date of Exam 
Impaction 
Confirmation 
Date of X-ray 
XXX 
XXX-YYYY 
YES 
DDMONYYYYTHH:MM 
XXXXXXXXXXXX 
DDMONYYYYTHH:MM 
 
XXX-YYYY 
NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Values for performed are YES or NO; impaction confirmation are VISUAL or RADIOLOGICAL. 
 
 
 
Document No. <  > 
 
CONFIDENTIAL 
111 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-19: Medical/Surgical History – Randomized Subjects 
Treatment: TTTTTTT 
 
 
Date 
 
 
 
Site Subject 
Start  
Stop 
Number Classification 
Term 
XXX 
XXX-YYYY 
DDMONYYYY 
DDMONYYYY 
X 
System Organ Class: 
 
 
 
 
 
 
Preferred Term: 
 
 
 
 
 
 
Verbatim: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If ongoing put ONGOING in stop date column. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
112 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-20: Informed Consent – All Subjects 
Treatment: TTTTTTT 
 
 
 
Date 
 
Met Criteria 
Site 
Subject 
Subject  
Initials 
Screening 
Visit 
Signed 
Consent 
ICF Version 
Protocol 
Version 
Inclusion 
Exclusion 
XXX 
XXX-YYYY 
ABC 
DDMONYYYY 
DDMONYYYY 
DDMONYYYY 
AMENDMENT 2 
YES 
YES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
Document No. <  > 
 
CONFIDENTIAL 
113 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-21.1: Subject Eligibility – All Subjects  
Treatment: TTTTTTTTTTTTTT 
 
 
Date of 
 
Site 
Subject 
Informed 
Consent 
Eligibility 
Assessment 
Criteria Failed 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
 
XXX 
XXX-YYYY 
DDMONYYYY DDMONYYYY 
Inclusion: 1, 4  
Exclusion: 8, 10, 12 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If subject was not randomized treatment should be ‘NOT RANDOMIZED’.  Criteria Failed 
may take any or all of the following values: Inclusion 1, 2, 3, 4 or 5 and Exclusion 1 through 12.  Insert 
a page break after each treatment group. 
 
 
 
Document No. <  > 
 
CONFIDENTIAL 
114 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page 1 of 2) 
Protocol: 402-C-329 
Listing 16.2-21.2: Subject Eligibility – Inclusion/Exclusion Criteria  
Inclusion/Exclusion Criteria 
Inclusion 1 
Male or female, ≥18 years of age at screening. 
Inclusion 2 
Scheduled to undergo bilateral third molar extractions (i.e., extraction of all four third 
molars) under local anesthesia. At least one lower mandibular third molar must involve full 
or partial bony impaction confirmed by visual or radiological evidence. 
Inclusion 3 
American Society of Anesthesiology (ASA) physical status 1, 2, or 3.  
Inclusion 4 
Female subjects must be either surgically sterile, using a medically acceptable method of 
birth control, or at least 2 years postmenopausal, and must have a documented negative 
pregnancy test result during screening and on Day 1 prior to surgery.  
Inclusion 5 
Able to provide informed consent, adhere to the study visit schedule, and complete all study 
assessments.  
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name  
 
 
Document No. <  > 
 
CONFIDENTIAL 
115 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page 2 of 2) 
Protocol: 402-C-329 
Listing 16.2-21.2: Subject Eligibility – Inclusion/Exclusion Criteria  
Inclusion/Exclusion Criteria 
Exclusion 1 
History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics or 
opioids.  
Exclusion 2 
Contraindication to lidocaine, epinephrine, bupivacaine, or oxycodone.  
Exclusion 3 
History of significant drug allergy (e.g., anaphylaxis or hepatotoxicity).  
Exclusion 4 
Positive test result from the urine drug screen at screening or prior to the surgical 
procedure.  
Exclusion 5 
Currently pregnant, nursing, or planning to become pregnant during the study or within 1 
month after study drug administration.  
Exclusion 6 
History or active psychiatric illness (including major depression, bipolar disorder, or 
anxiety), Type 1 or Type 2 diabetes, severe renal or hepatic impairment, significant 
cardiovascular disease (including cardiac rhythm disturbance), migraine headaches, frequent 
headaches, other pain conditions, or other medical condition that, in the opinion of the 
Investigator, may increase the risk of surgery or interfere with the evaluation of the study 
drug.  
Exclusion 7 
History of infection requiring intravenous (IV) antibiotics within 45 days or oral (PO) 
antibiotics within 30 days prior to study drug administration for reasons other than dental 
prophylaxis. Subjects must be afebrile, without signs or symptoms indicative of active 
infection.  
Exclusion 8 
Use of any of the following medications within the times specified before surgery: long-
acting opioid medication, NSAIDs, aspirin (except for low-dose aspirin used for 
cardioprotection), or acetaminophen within 3 days, or any opioid medication within 24 hours. 
Exclusion 9 
Initiation of treatment with any of the following medications within 1 month of study drug 
administration or if the medication(s) are being given to control pain: selective serotonin 
reuptake inhibitors (SSRIs), selective norepinepherine reuptake inhibitors (SNRIs), 
gabapentin, pregabalin (Lyrica®), or duloxetine (Cymbalta®). If a subject is taking one of 
these medications for a reason other than pain control, he or she must be on a stable dose 
for at least 1 month prior to study drug administration. 
Exclusion 10 
Current use of systemic glucocorticosteroids within 1 month of enrollment in this study.  
Exclusion 11 
Use of any concurrent therapy that could interfere with the evaluation of efficacy or safety, 
such as any drugs which in the Investigator’s opinion may exert significant analgesic 
properties or act synergistically with the investigational product. 
Exclusion 12 
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.  
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
Document No. <  > 
 
CONFIDENTIAL 
116 of 125 
12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-22: Screening Tests – All Subjects 
Treatment: TTTTTTTTTT 
Site 
Subject 
Visit 
Date 
Pregnancy 
Drug Screen 
XXX 
XXX-YYYY 
Screening 
DDMONYYYY 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
 
 
Day 1 
DDMONYYYY 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
 
 
 
 
 
 
 
XXX-YYYY 
Screening 
DDMONYYYY 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
 
 
Day 1 
DDMONYYYY 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
 
 
 
 
 
 
 
XXX-YYYY 
Screening 
DDMONYYYY 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
 
 
Day 1 
DDMONYYYY 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer:  Possible results for screening tests are: POSITIVE, NEGATIVE, NOT DONE or NOT 
APPLICABLE. 
 
 
Document No. <  > 
 
CONFIDENTIAL 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-23: Deviations – All Subjects 
Treatment: TTTTTTT 
Site Subject 
Date 
Category 
Description 
XXX 
XXX-YYYY 
DDMONYYYY 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 
Document No. <  > 
 
CONFIDENTIAL 
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12 November 2015 
 


Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-24.1: Pharmacokinetic Concentrations – EXPAREL Subjects 
Treatment: EXPAREL 
 
 
Date and Time of 
Time From Dose 
 
Site 
Subject 
Dose 
PK Sample 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(mins) 
Concentration 
(ng/mL) 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
0 
XX 
 
X 
 
BLOQ 
 
 
 
DDMONYYYYTHH:MM 
0.25 
0.XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
0.50 
0.XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
1 
X 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
2 
ND 
 
 
 
 
 
 
DDMONYYYYTHH:MM 
4 
X 
 
-X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
6 
X 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
8 
X 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
12 
XX 
 
-X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
18 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
24 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
30 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
36 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
42 
XX 
 
-X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
48 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
54 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
60 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
66 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
72 
XX 
 
-X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
84 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
96 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
168 
XX 
 
X 
 
XXX.X 
 
 
 
DDMONYYYYTHH:MM 
240 
XX 
 
X 
 
XXX.X 
 
 
 
 
 
 
 
 
BLOQ=below limit of quantitation 
 
ND=Not Done 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: Insert a page break after each subject.  If a sample was not collected – put ND in 
actual column under time from dose.  Sort listing within subject by sample date and time. 
Document No. <  > 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-24.2: Pharmacokinetic Parameters – EXPAREL Subjects 
Treatment: EXPAREL 
Site 
Subject 
AUC(0-inf) 
(ng*hr/mL) 
AUC(0-last)  
(ng*hr/mL) 
Cmax 
ng/mL 
Tmax 
(hr) 
Half-life 
(hr) 
Lamba_z 
(hr) 
XXX 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
XXX-YYYY 
 
NC 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
NC 
 
NC 
 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
 
 
 
 
 
 
 
YYY 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
XXX-YYYY 
 
XXXX.XX 
 
XXXX.XX 
 XXX.X 
 XX.X 
 
X.XXX 
 
X.XXX 
 
 
 
 
 
 
 
 
NC=Not Calculated 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: If a parameter was not calculated – put NC in column. 
 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-25: Unique Adverse Events Terms and Associated Coded Terms 
MedDRA Terms 
SOC 
  Preferred Term 
Verbatim(s) 
SOC1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
  PT1.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
  PT1.2 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
   
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
SOC2 
 
  PT2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
Coded using MedDRA 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by SOC and preferred term in alphabetical order 
 
 
Document No. <  > 
 
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Pacira Pharmaceuticals, Inc. 
402-C-329 (Third Molar Extraction) 
EXPAREL 
Statistical Analysis Plan 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Listing 16.2-26: Unique Medication Terms and Associated Coded Terms 
Who Drug Dictionary Terms 
ACT1 
  ACT2 
    ACT3 
      ACT4 
        Preferred name 
Verbatim(s) 
ATC1 
 
  ATC1.2 
 
        PN1.2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
        PN1.2.2 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
ATC2 
 
  ATC2.2 
 
    ATC2.3 
 
      ATC2.4 
 
        PN2.2.3.4.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
Coded using Who Drug Dictionary 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by ATC1, ATC2, ATC3, ATC4 and preferred name in alphabetical order 
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Statistical Analysis Plan 
 
11.3. List of Figures 
 
Figure 14.2-1.1: Plot of Mean (±SD) NRS Scores over Time with Imputation – Efficacy Analysis Set 
Figure 14.2-1.2: Plot of Mean (±SD) NRS Scores over Time without Imputation – Efficacy Analysis Set 
Figure 14.2-1.3: Plot of Individual Subject NRS Scores Over Time – Efficacy Analysis Set 
Figure 14.2-2: Bar Chart of Percentage of Pain-Free Subjects – Efficacy Analysis Set 
Figure 14.2-3: Bar Chart of Percentage of Opioid-Free Subjects – Efficacy Analysis Set 
Figure 14.2-4: Plot of Time to First Rescue Medication Use – Efficacy Analysis Set 
Figure 14.2-5: Bar Chart of Subject Satisfaction with Postsurgical Pain Control – Efficacy Analysis Set 
 
 
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12. 
MULTIPLE IMPUTATION EXAMPLE PROGRAM CODE 
 
** Note: INPUT_DATA is the dataset that contains the NRS data with the wWOCF imputation performed 
for the rescue pain scores 
**; 
 
** Step 1 use Markov-Chain Monte-Carlo (MCMC) method to create a monotonic missing pattern **; 
** Note the value for the random seed should be fixed so that the results are reproducible  
**; 
PROC MI DATA=INPUT_DATA SEED=M NIMPUTE=1000 OUT=OUTPUT_STEP1; 
BY TREATMENT; 
MCMC IMPUTE=MONOTONE NBITER=2000 NITER=1000; 
VAR TIME_POINT_LIST; 
RUN; 
 
** Step 2 – use regression on output dataset from Step 1 to impute missing values  
 
**; 
** Ti is the variable containing the pain score from time i  
 
 
 
 
**; 
PROC MI DATA=OUTPUT_STEP1 OUT=OUTPUT_STEP2; 
BY _IMPUTATION_; 
CLASS TREATMENT; 
MONOTONE REG(T1 = TREATMENT / DETAILS); 
MONOTONE REG(T2 = TREATMENT T1 / DETAILS); 
… 
MONOTONE REG(T(n-1) = TREAMENT T1 T2 T3 ... T(n-2) / DETAILS);  
MONOTONE REG(Tn = TREAMENT T1 T2 T3 ... T(n-1) / DETAILS); 
VAR TREATMENT T1 T2 T3 … Tn  
RUN; 
 
** Dataset OUTPUT_STEP2 is as an ADaM dataset, include in DEFINE.XML and transfers 
**; 
 
** Step 3 derive endpoint using appropriate techniques by variable _imputation_  
 
**; 
** Endpoints are: AUC(0.25-48), AUC(0.25-24), AUC(0.25-72), SPI(0.25-24), SPI(0.25-48),  
**; 
** SPI(0.25-72) and integrated rank assessment at 24, 48 and 72 hours  
 
 
**; 
 
** Step 4 get summary statistics  
 
 
 
 
 
 
 
**; 
** Summary step 4a get the mean of all imputation endpoint values for each subject 
 
**; 
PROC SUMMARY DATA=OUTPUT_STEP2; 
 
BY TREATMENT USUBJID; 
 
VAR ENDPOINT_VARIABLE; 
 
OUTPUT OUT=SUMMARYSTATSA MEAN=ENDPOINTMEAN; 
RUN; 
 
** Dataset SUMMARYSTATSA is as an ADaM dataset, include in DEFINE.XML and transfers 
**; 
** SUMMARYSTATSA also source for a data listing 
 
 
 
 
 
**; 
 
** Summary step 4b use subject imputation means to derive summary statistics  
 
**; 
PROC SUMMARY DATA=SUMMARYSTATSA; 
 
BY TREATMENT;  
 
VAR ENDPOINTMEAN; 
 
OUTPUT OUT=SUMMARYSTATSB N=N MEAN=MEAN STDDEV=STDDEV MEDIAN=MEDIAN 
 
 
 
MIN=MIN MAX=MAX; 
RUN; 
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Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
 
 
*** Step 5 analyze imputations   
 
 
 
 
 
 
 
**;  
ODS OUTPUT ESTIMATES=MIXEDSTATSA; 
PROC MIXED DATA= OUTPUT_STEP2 METHOD=TYPE3; 
 
BY _IMPUTATION_; 
 
CLASS TREATMENT SITE; 
 
MODEL ENDPOINT_VARIABLE = TREATMENT SITE; 
 
ESTIMATE 'EXPAREL - PLACEBO' TREATMENT 1 -1; 
RUN; 
 
ODS OUTPUT PARAMETERESTIMATES=MIXEDSTATSB; 
PROC MIANALYZE DATA= MIXEDSTATSA ALPHA=0.05 THETA0=0; 
 
MODELEFFECTS ESTIMATE; 
 
STDERR STDERR; 
RUN; 
 
** Step 6 build report from SUMMARYSTATSB and MIXEDSTATSB 
 
 
**; 
 
 
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STATISTICAL ANALYSIS PLAN 
ADDENDUM 
 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Efficacy, and Pharmacokinetics of Local Administration of EXPAREL 
for Prolonged Postsurgical Analgesia in Subject Undergoing Third Molar 
Extraction 
 
Protocol No.: 
402-C-329 
 
IND No.: 
 
69,198 
 
Study Phase: 
 
3 
 
Study Drug: 
 
EXPAREL (bupivacaine liposome injectable suspension) 
 
Date/Version: 
 
Addendum: 29 February 2016 
Original: 12 November 2015 
 
Prepared by: 
 
 
 
James Nezamis, MS 
Senior Director, Biostatistics 
Pacira Pharmaceuticals 
 
Sponsor: 
 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 973-254-3560 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira 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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Statistical Analysis Plan Addendum 
 
CLN-PRO-0150-002 
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1. 
PURPOSE 
The purpose of this SAP addendum is to describe additional analyses not planned as part of the 
original SAP as well as changes to analyses planned in the SAP. 
2. 
CHANGES TO PLANNED ANALYSES 
The SAP indicated a 6 hour imputation window for oxycodone but a 4 hour dosing cycle.  The 
imputation window was changed to 4 hours.  This changed was deemed appropriate based on 
literature and dosing period.  
Site 100 had more than one surgeon performing extractions.  Therefore it was decided to look at 
some of the data at the surgeon level as well as site level.  The following tables will be expanded 
to include surgeon within site summaries for site 100: 
 
Table 14.1-2.1 – Safety Analysis Set  
 
Table 14.1-2.2.1 – Primary Efficacy Analysis Set 
 
Table 14.1-2.2.2 – Secondary Efficacy Analysis Set  
 
Table 14.1-2.3 – Pharmacokinetic Analysis Set 
 
Table 14.1-2.4 – Per-protocol Analysis Set  
 
Table 14.1-3.1 – Safety Analysis Set  
 
Table 14.1-3.2.1 – Primary Efficacy Analysis Set 
 
Table 14.1-3.2.2 – Secondary Efficacy Analysis Set  
 
Table 14.1-3.3 – Per-protocol Analysis Set 
 
Table 14.2-1.3 – Primary Efficacy Analysis Set  
 
Table 14.2-2.3 – Primary Efficacy Analysis Set  
 
Table 14.2-3.3 – Primary Efficacy Analysis Set 
 
Table 14.2-5.1 – Primary Efficacy Analysis Set  
 
Table 14.2-5.2 – Primary Efficacy Analysis Set 
 
Table 14.2-5.3 – Primary Efficacy Analysis Set 
Due to numerous protocol deviations, a per-protocol population was defined. Subjects will be 
excluded from the study 402-C-329 per-protocol population if any of the following criteria are 
true: 
1) One or more of the 12 scheduled NRS assessments are either missing or ‘Not Done’; 
2) At least one rescue medication dose without an NRS assessment within 15 minutes prior to or at the 
time of rescue medication dose; 
3) Three or more doses of oxycodone within any 12 hour period within 96 hours after surgery; 
4) Dental work (oral surgery, tooth repair, fillings) within 14 days of surgery; 
5) Post-traumatic stress disorder; 
6) NSAIDS or other non-protocol allowed analgesic/anti-inflammatory medications within 96 hours 
after surgery; 
7) For subjects randomized to EXPAREL, an 8 hour PK concentration < 100 ng/mL; 
8) Rescue medication received with a NRS pain score immediately prior to rescue medication dose less 
than 4; 
9) Subjects 100-0123, 100-0124, 100-0137, 100-0138, 100-0154, 100-0157, 200-0032, 300-0029 and 
300-0036  were eliminated from the per-protocol population during manual review of the protocol 
deviation log; 
10) Subject excluded from the primary efficacy population. 
 


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Table 14.1-1 will be modified to include the per-protocol analysis set.  Table A indicates the 
template tables (from SAP) to be produced and the table number and title for the per-protocol 
analysis set. 
Table A: Templates and Titles for Per-protocol Efficacy Analysis Set Tables 
SAP Template 
Number 
Per-protocol Analysis Set Table Number and Title 
14.2-1.1.1 
14.2-1.1.6: Analysis of AUC of NRS Pain Intensity Scores through 48 hours – Per-protocol 
Efficacy Analysis Set 
14.2-1.2 
14.2-1.2.1:  Summary of AUC of NRS Pain Intensity Scores through 48 hours – Per-protocol 
Efficacy Analysis Set - Analysis of Variance (ANOVA) Model Results 
14.2-2.2.1:  Summary of AUC of NRS Pain Intensity Scores through 24 hours – Per-protocol 
Efficacy Analysis Set - Analysis of Variance (ANOVA) Model Results 
14.2-3.2.1:  Summary of AUC of NRS Pain Intensity Scores through 72 hours – Per-protocol 
Efficacy Analysis Set - Analysis of Variance (ANOVA) Model Results 
14.2-1.3 
14.2-1.3.1: Summary of AUC of NRS Pain Intensity Scores through 48 hours by Site – Per-protocol 
Efficacy Analysis Set 
14.2-2.3.1: Summary of AUC of NRS Pain Intensity Scores through 24 hours by Site – Per-protocol 
Efficacy Analysis Set 
14.2-3.3.1: Summary of AUC of NRS Pain Intensity Scores through 72 hours by Site – Per-protocol 
Efficacy Analysis Set 
14.2-5.1 
14.2-5.1.1: Analysis of Opioid-Free Subjects through 24 hours – Per-protocol Efficacy Analysis Set 
14.2-5.2.1: Analysis of Opioid-Free Subjects through 48 hours – Per-protocol Efficacy Analysis Set 
14.2-5.3.1: Analysis of Opioid-Free Subjects through 72 hours – Per-protocol Efficacy Analysis Set 
14.2-6.1 
14.2-6.1.1: Summary of Numerical Rating Scale (NRS) Pain Intensity Scores - By Assessment 
Timepoint – Per-protocol Efficacy Analysis Set 
14.2-6.2 
14.2-6.2.1: Summary of Numerical Rating Scale (NRS) Pain Intensity Scores at Rescue – 
Per-protocol Efficacy Analysis Set 
14.2-7.1 
14.2-7.1.1: Summary of AUC(0.25-96) and AUC(0.25-Day 10) of NRS Pain Intensity Scores – 
Per-protocol Efficacy Analysis Set 
14.2-7.2 
14.2-7.2.1: Summary of AUC(24-48) and AUC(48-72) of NRS Pain Intensity Scores Scores – 
Per-protocol Efficacy Analysis Set 


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SAP Template 
Number 
Per-protocol Analysis Set Table Number and Title 
14.2-8 
14.2-8.1: Tabulation of Pain-Free Subjects at Assessment Time Points Scores – Per-protocol 
Efficacy Analysis Set 
14.2-9 
14.2-9.1: Summary of Time to First Rescue Medication Use (hours) Scores – Per-protocol Efficacy 
Analysis Set 
14.2-10 
14.2-10.1: Summary of Integrated Rank Assessment of NRS Pain Intensity Scores and Opioid Use 
Scores – Per-protocol Efficacy Analysis Set 
14.2-11 
14.2-11.1: Summary of Satisfaction with Postsurgical Pain Control Questionnaire Score by 
Timepoint – Per-protocol Efficacy Analysis Set 
14.2-12.1 
14.2-12.1.1: Summary of Postoperative Symptom Severity (PoSSe) Questionnaire - Total Score [1] 
Summary – Per-protocol Efficacy Analysis Set 
14.2-12.2 
14.2-12.2.1: Summary of Postoperative Symptom Severity (PoSSe) Questionnaire - Individual 
Question Score Tabulation – Per-protocol Efficacy Analysis Set 
14.2-13 
14.2-13.1: Summary of Number of Unscheduled Phone Calls or Office Visits Related to Pain – 
Per-protocol Efficacy Analysis Set 
14.2-14.1 
14.2-14.1.1: Summary of Total Rescue Medication Consumption (MED) – Per-protocol Efficacy 
Analysis Set 
14.2-14.2 
14.2-14.2.1: Summary of the Number of Times Rescue Medication was Used by Subject – 
Per-protocol Efficacy Analysis Set 
 
3. 
ADDITIONAL SUMMARIES 
The effect of surgeon will be determined by replacing the site effect in the efficacy analysis of 
variance with surgeon and by summarizing data by surgeon within site as appropriate (see 
Section 2 for additional detail).  Table B indicated the tables and figures to be produced to 
explore the surgeon effect and, if applicable, the corresponding table or figure template with a 
brief description of changes to the planned output. 
Table B: Templates and Titles for Surgeon Tables 
Surgeon Effect Notes 
Table  
These tables will be amended with additional 
information.  The current data planned 
remains on the table.   
14.1-2.1 
14.1-2.2.1 
14.1-2.2.2  
14.1-2.3 
14.1-2.4  


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For site 100 create new pages in the table for 
each surgeon at site 100.  The site 100 page 
will remain as is unchanged. 
14.1-3.1  
14.1-3.2.1 
14.1-3.2.2  
14.1-3.3 
Replace site effect in ANOVA with surgeon 
14.2-1.1.1.S: Analysis of AUC of NRS Pain Intensity Scores 
through 48 hours – Primary Efficacy Analysis Set – Surgeon Effect 
14.2-1.1.6.S: Analysis of AUC of NRS Pain Intensity Scores 
through 48 hours – Per-protocol Efficacy Analysis Set – Surgeon 
Effect 
14.2-1.2.1.S:  Summary of AUC of NRS Pain Intensity Scores 
through 48 hours – Primary Efficacy Analysis Set - Analysis of 
Variance (ANOVA) Model Results – Surgeon Effect 
14.2-1.2.1.S.1:  Summary of AUC of NRS Pain Intensity Scores 
through 48 hours – Per-protocol Efficacy Analysis Set - Analysis of 
Variance (ANOVA) Model Results – Surgeon Effect 
14.2-2.2.S:  Summary of AUC of NRS Pain Intensity Scores 
through 24 hours – Primary Efficacy Analysis Set - Analysis of 
Variance (ANOVA) Model Results – Surgeon Effect 
14.2-2.2.1.S:  Summary of AUC of NRS Pain Intensity Scores 
through 24 hours – Per-protocol Efficacy Analysis Set - Analysis of 
Variance (ANOVA) Model Results – Surgeon Effect 
14.2-3.2.S:  Summary of AUC of NRS Pain Intensity Scores 
through 72 hours – Primary Efficacy Analysis Set - Analysis of 
Variance (ANOVA) Model Results – Surgeon Effect 
14.2-3.2.1.2:  Summary of AUC of NRS Pain Intensity Scores 
through 72 hours – Per-protocol Efficacy Analysis Set - Analysis of 
Variance (ANOVA) Model Results – Surgeon Effect 
Replace site as stratification with surgeon 
14.2-5.1.S: Analysis of Opioid-Free Subjects through 24 hours – 
Primary Efficacy Analysis Set – Surgeon Effect 
14.2-5.1.1.S: Analysis of Opioid-Free Subjects through 24 hours – 
Per-protocol Efficacy Analysis Set – Surgeon Effect 
14.2-5.2.S: Analysis of Opioid-Free Subjects through 48 hours – 
Primary Efficacy Analysis Set 
14.2-5.2.1.S: Analysis of Opioid-Free Subjects through 48 hours – 
Per-protocol Efficacy Analysis Set 


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14.2-5.3.S: Analysis of Opioid-Free Subjects through 72 hours – 
Primary Efficacy Analysis Set 
14.2-5.3.1.S: Analysis of Opioid-Free Subjects through 72 hours – 
Per-protocol Efficacy Analysis Set 
Total lidocaine dose will be summarized (template 14.1-4.1) by treatment, site and surgeon 
within site.  Lidocaine doses are found in dataset CM where CMCAT=SURGICAL 
MEDICATION / ANESTHESIA and CMDECOD=Xylocaine-epinephrine.  Lidocaine was 
dosed 36 mg/carpule (or capsule) and will be converted from carpules/capsules to mg by 
multiplying the number of carpules used by 36. 
Time from last lidocaine injection to first study treatment injection will be summarized (template 
14.1-5.1) by treatment, site and surgeon within site. 
Impacted third molars will be scored for each subject within jaw (maxillary and mandibular) and 
in total.  Each full bony impaction is scored as 10 while partial impacted molars are scored as 1; 
erupted and soft tissue will be scored as 0.  For example if a subject had 1 full bony impaction, 1 
partial impaction, 1 erupted and 1 soft tissue, the subject’s scores would be 10, 1, 0 and 0 
respectively for a total impaction score of 11.  Thus with each jaw the potential outcomes are 0, 
1, 2, 10, 11 and 20 indicating, respectively, no impactions, a single partial bony impaction, two 
partial bony impactions, a single full bony impaction, one partial and one full bony impaction 
and two full bony impactions; and for the subject the potential outcomes are 0, 1, 2, 3, 4, 10, 11, 
12, 13, 20, 21, 22, 30, 31 and 40.  The impaction scores will be tabulated (template 14.1-5.1.1) 
by treatment, location (all, maxillary, mandibular), site and surgeon within site.  Impaction 
scores will be presented from highest to lowest score. 
Tooth impaction will be tabulated (template 14.1-6.2.1) by treatment, location, site and surgeon 
within site.  Locations will be each tooth and maxillary (Tooth 1 and Tooth 16) and mandibular 
(Tooth 17 and Tooth 32). For maxillary and mandibular summaries if a subjects will be counted 
only once in each impaction category in the highest level of impaction reported where impaction 
levels from highest to lowest are 1-full bony, 2-partial bony, 3-soft tissue and 4-erupted.  
Pharamcokinetic concentrations will be summarized (template 14.2-15.1.1) at each scheduled 
timepoint by treatment, site and surgeon within site.  Plots of the mean PK concentration by time 
indicating each surgeon will be produced from this summary. 
Pharamcokinetic parameters will be summarized (template 14.2-15.2.1) at each scheduled 
timepoint by treatment, site and surgeon within site. 


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Table 14.1-4.1: Summary of Total Lidocaine Dose (mg) - by Site and Surgeon within Site - Safety Analysis 
Set 
 
Site 
Statistic 
EXPAREL [N=XX] 
Placebo [N=XX] 
 
 
 
 
Overall 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Median 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
100 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Median 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
100 – Surgeon 1 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Median 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
 
Maximum 
xx 
Xx 
 
 
 
 
100 – Surgeon 2 
N 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
Standard Deviation 
x.xx 
x.xx 
 
Median 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


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Note to programmer: Sites to appear on this table are Overall, 100, 100-surgeon 1, 100-surgeon 2, 200, 
300).  Do not split a site across pages. Use this template also for tables: 
 
Table 14.1-4.2: Summary of Total Lidocaine Dose (mg) - by Site and Surgeon within Site - Primary Efficacy 
Analysis Set  
Table 14.1-4.3: Summary of Total Lidocaine Dose (mg) - by Site and Surgeon within Site - Secondary Efficacy 
Analysis Set  
Table 14.1-4.4: Summary of Total Lidocaine Dose (mg) - by Site and Surgeon within Site - Per-protocol 
Efficacy Analysis Set 
 
Table 14.1-5.1: Summary of Time from Last Lidocaine Dose to First Study Treatment Dose - by Site and 
Surgeon within Site - Safety Analysis Set 
Table 14.1-5.2: Summary of Time from Last Lidocaine Dose to First Study Treatment Dose - by Site and 
Surgeon within Site - Primary Efficacy Analysis Set  
Table 14.1-5.3: Summary of Time from Last Lidocaine Dose to First Study Treatment Dose - by Site and 
Surgeon within Site - Secondary Efficacy Analysis Set  
Table 14.1-5.4: Summary of Time from Last Lidocaine Dose to First Study Treatment Dose - by Site and 
Surgeon within Site - Per-protocol Efficacy Analysis Set 
  
 
 


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(Page X of Y) 
Protocol: 402-C-329 
Table 14.1-6.1.1: Tabulation of Impaction Scores - by Site and Surgeon within Site - Safety Analysis Set 
 
Site 
Location 
Score [1] 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX] 
n (%) 
 
 
 
 
 
Overall 
All 
40 
XX (XX.X) 
XX (XX.X) 
 
 
31 
XX (XX.X) 
XX (XX.X) 
 
 
30 
XX (XX.X) 
XX (XX.X) 
 
 
22 
XX (XX.X) 
XX (XX.X) 
 
 
21 
XX (XX.X) 
XX (XX.X) 
 
 
20 
XX (XX.X) 
XX (XX.X) 
 
 
13 
XX (XX.X) 
XX (XX.X) 
 
 
12 
XX (XX.X) 
XX (XX.X) 
 
 
11 
XX (XX.X) 
XX (XX.X) 
 
 
10 
XX (XX.X) 
XX (XX.X) 
 
 
4 
XX (XX.X) 
XX (XX.X) 
 
 
3 
XX (XX.X) 
XX (XX.X) 
 
 
2 
XX (XX.X) 
XX (XX.X) 
 
 
1 
XX (XX.X) 
XX (XX.X) 
 
 
0 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Maxillary  
20 
XX (XX.X) 
XX (XX.X) 
 
 
11 
XX (XX.X) 
XX (XX.X) 
 
 
10 
XX (XX.X) 
XX (XX.X) 
 
 
2 
XX (XX.X) 
XX (XX.X) 
 
 
1 
XX (XX.X) 
XX (XX.X) 
 
 
0 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Mandibular  
20 
XX (XX.X) 
XX (XX.X) 
 
 
11 
XX (XX.X) 
XX (XX.X) 
 
 
10 
XX (XX.X) 
XX (XX.X) 
 
 
2 
XX (XX.X) 
XX (XX.X) 
 
 
1 
XX (XX.X) 
XX (XX.X) 
 
 
0 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
[1] Sum of the impaction score for each tooth where full bony impaction = 10; partially bony = 1; other = 0 
Score presented from highest to lowest level of impactions. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL 
 
Statistical Analysis Plan Addendum 
 
CLN-PRO-0150-002 
 
 
CONFIDENTIAL 
10 of 14 
29 February 2016 
Note to programmer: Put each site and surgeon within site (Overall, 100, 100-surgeon 1, 100-surgeon 2, 200, 
300) on a separate page.  Use this template also for tables: 
 
Table 14.1-6.1.2: Tabulation of Impaction Scores - by Site and Surgeon within Site - Primary Efficacy 
Analysis Set  
Table 14.1-6.1.3: Tabulation of Impaction Scores - by Site and Surgeon within Site - Secondary Efficacy 
Analysis Set  
Table 14.1-6.1.4: Tabulation of Impaction Scores - by Site and Surgeon within Site - Per-protocol Efficacy 
Analysis Set 
 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL 
 
Statistical Analysis Plan Addendum 
 
CLN-PRO-0150-002 
 
 
CONFIDENTIAL 
11 of 14 
29 February 2016 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.1-6.2.1: Tabulation of Third Molar Impactions - by Site and Surgeon within Site - Safety Analysis 
Set 
 
Site 
Location 
Impaction 
EXPAREL [N=XX] 
n (%) 
Placebo [N=XX] 
n (%) 
 
 
 
 
 
Overall 
Maxillary [1] 
Full bony 
XX (XX.X) 
XX (XX.X) 
 
 
Partial bony 
XX (XX.X) 
XX (XX.X) 
 
 
Soft Tissue 
XX (XX.X) 
XX (XX.X) 
 
 
Erupted 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Mandibular [1] 
Full bony 
XX (XX.X) 
XX (XX.X) 
 
 
Partial bony 
XX (XX.X) 
XX (XX.X) 
 
 
Soft Tissue 
XX (XX.X) 
XX (XX.X) 
 
 
Erupted 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Right Maxillary 
Full bony 
XX (XX.X) 
XX (XX.X) 
 
 
Partial bony 
XX (XX.X) 
XX (XX.X) 
 
 
Soft Tissue 
XX (XX.X) 
XX (XX.X) 
 
 
Erupted 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Left Maxillary  
Full bony 
XX (XX.X) 
XX (XX.X) 
 
 
Partial bony 
XX (XX.X) 
XX (XX.X) 
 
 
Soft Tissue 
XX (XX.X) 
XX (XX.X) 
 
 
Erupted 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Left Mandible 
Full bony 
XX (XX.X) 
XX (XX.X) 
 
 
Partial bony 
XX (XX.X) 
XX (XX.X) 
 
 
Soft Tissue 
XX (XX.X) 
XX (XX.X) 
 
 
Erupted 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Right Mandible  
Full bony 
XX (XX.X) 
XX (XX.X) 
 
 
Partial bony 
XX (XX.X) 
XX (XX.X) 
 
 
Soft Tissue 
XX (XX.X) 
XX (XX.X) 
 
 
Erupted 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
[1] Subject counted only once at the highest level of impaction, presented from highest to lowest. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL 
 
Statistical Analysis Plan Addendum 
 
CLN-PRO-0150-002 
 
 
CONFIDENTIAL 
12 of 14 
29 February 2016 
Note to programmer: Put each site (Overall, 100, 100-Surgeon 1, 100-Surgeon 2, 200, 300) on a separate 
page.  Use this template also for tables: 
 
Table 14.1-6.2.2: Tabulation of Third Molar Impactions - by Site and Surgeon within Site - Primary Efficacy 
Analysis Set  
Table 14.1-6.2.3: Tabulation of Third Molar Impactions - by Site and Surgeon within Site - Secondary 
Efficacy Analysis Set  
Table 14.1-6.2.4: Tabulation of Third Molar Impactions - by Site and Surgeon within Site - Per-protocol 
Efficacy Analysis Set 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL 
 
Statistical Analysis Plan Addendum 
 
CLN-PRO-0150-002 
 
 
CONFIDENTIAL 
13 of 14 
29 February 2016 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-15.1.1: Summary of Pharmacokinetic Concentrations (ng/mL) - by Scheduled Collection Time, Site 
and Surgeon within Site - Pharmacokinetic Analysis Set 
Site: Overall 
Time Point 
Statistic 
EXPAREL [N=XX] 
 
 
 
Prior to Surgery 
n 
 
xx 
 
Mean 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
Median 
 
xxx.x 
 
Minimum 
 
xx 
 
Maximum 
 
xxx 
 
n (%) BLQ 
xx (xx.x) 
 
 
 
15 min 
n 
 
xx 
 
Mean 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
Median 
 
xxx.x 
 
Minimum 
 
xx 
 
Maximum 
 
xxx 
 
n (%) BLQ 
xx (xx.x) 
 
 
 
BLQ = below limit of quantitation 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Do not split time point across pages. Time points to appear on this tables are Prior to 
Surgery, 15 min, 30 min and 1 hour, 2 hour, 4 hour, 8 hour, 12 hour, 18 hour, 24 hour, 30 hour, 36 hour, 42 
hour, 48 hour, 54 hour, 60 hour, 66 hour, 72 hour, 84 hour, 96 hour, Day 7 and Day 10.  Sites are Overall, 
100, 100-Surgeon 1, 100-Surgeon 2, 200 and 300.  Use this template for the following table: 
 
Table 14.2-15.1.2: Summary of Pharmacokinetic Concentrations (ng/mL) - by Scheduled Collection Time, Site 
and Surgeon within Site – Subjects in Pharmacokinetic and Per-protocol Efficacy Analysis Sets 
 
 


Pacira Pharmaceuticals, Inc. 
 
402-C-329 (Third Molar Extraction) 
EXPAREL 
 
Statistical Analysis Plan Addendum 
 
CLN-PRO-0150-002 
 
 
CONFIDENTIAL 
14 of 14 
29 February 2016 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-329 
Table 14.2-15.2.1: Summary of Pharmacokinetic Parameters - by Site and Surgeon within Site - 
Pharmacokinetic Analysis Set 
Site: Overall 
Parameter 
Statistic 
EXPAREL [N=XX] 
 
 
 
Cmax 
n 
 
xx 
 
Mean 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
Median 
 
xxx.x 
 
Minimum 
 
xx 
 
Maximum 
 
xxx 
 
 
 
Tmax  
n 
 
xx 
 
Mean 
 
xxx.x 
 
Standard Deviation 
 
xxx.xx 
 
Median 
 
xxx.x 
 
Minimum 
 
xx 
 
Maximum 
 
xxx 
 
 
 
BLQ = below limit of quantitation 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Do not split a parameter across pages. Parameters to appear on this table, in order of 
appearance, are Cmax, Early(0-2hr) Cmax, Early Tmax, Late (> 2hr) Cmax, Late Tmax, AUC(0-t), AUC(0-inf), 
Lambda_z, Half-life.  Sites are Overall, 100, 100-Surgeon 1, 100-Surgeon 2, 200 and 300.  Use this template 
for the following table: 
 
Table 14.2-15.2.2: Summary of Pharmacokinetic Concentrations (ng/mL) - by Scheduled Collection Time, Site 
and Surgeon within Site – Subjects in Pharmacokinetic and Per-protocol Efficacy Analysis Sets