Clinical trial NCT02713230
Conditions: Pain
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2016-05-09; Completion date: 2017-07-07
Enrollment: 156 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in 155 adult subjects undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with general anesthesia

Detailed description:
On Day 0, eligible subjects will be randomized in a 1:1 ratio to receive a single dose of EXPAREL 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total volume of 20 mL or placebo 20 mL. Study drug (EXPAREL or placebo) will be administered in a blinded manner via an ultrasound guided single-dose brachial plexus block at least 1 hour prior to surgery.

Postsurgical assessments will include pain intensity scores using a 10-cm visual analog scale (VAS); total postsurgical opioid consumption; overall benefit of analgesia score (OBAS) questionnaire; subject satisfaction with overall analgesia using a 5 point Likert scale; neurological assessment; sensory function assessment; motor function assessment; discharge readiness; unscheduled phone calls or office visits related to pain; 12-lead ECGs; vital sign measurements; and clinical laboratory tests. Adverse events will be recorded from the time the informed consent form is signed through postsurgical Day 29.

Follow-up visits will be scheduled for all subjects on postsurgical Days 5 and 10. A follow-up phone call will be made on postsurgical Day 29.

A population Pharmacokinetic (PK) analysis will be utilized to limit the number of blood draws with a sampling schedule of baseline (prior to the nerve block) through hospital discharge. There will be two collection sequences for this study and a subject can only be randomized to one sequence.

Arms: arm 1: 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively arm 2: 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively arm 3: 20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively
Interventions: intervention 1: bupivacaine liposome injectable suspension intervention 2: bupivacaine liposome injectable suspension intervention 3: Placebo
Intervention descriptions: intervention 1: 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline intervention 2: 20 mL EXPAREL (bupivacaine liposome injectable suspension) intervention 3: 20 mL normal saline as single-injection

Protocol documents:
Prot_001.pdf: 
Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
1 of 82 
14 November 2016 
 
 
 
 
 
 
 
 
Clinical Study Protocol 
Amendment 2 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating 
the Efficacy, Safety, and Pharmacokinetics of Brachial Plexus Block with 
EXPAREL for Postsurgical Analgesia in Subjects Undergoing 
Total Shoulder Arthroplasty or Rotator Cuff Repair 
 
 
 
Protocol No.: 402-C-327 
EudraCT No.: 2015-005228-24 
IND No.: 69,198 
Study Phase: Phase 3 
Study Drug: EXPAREL® (bupivacaine liposome injectable suspension) 
Date: 14 November 2016 (Amendment 2) 
15 February 2016 (Amendment 1) 
24 November 2015 (Original) 
Investigator(s) or Study Site(s): Multicenter study in the US and Europe 
Sponsor: Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ  07054 
Telephone: (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. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
2 of 82 
14 November 2016 
 
 
 
1. 
SIGNATURE PAGE 
 
 
 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
3 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy, 
Safety, and Pharmacokinetics of Brachial Plexus Block with EXPAREL for Postsurgical Analgesia in Subjects 
Undergoing Total Shoulder Arthroplasty or Rotator Cuff Repair. 
Principal Investigator(s): To be determined 
Study Center(s): Multicenter study in the US and Europe 
Publications (Reference): None 
Objectives: 
Primary Objective: The primary objective of this study is to evaluate the magnitude and duration of the analgesic 
effect achieved following single-dose injection brachial plexus block with EXPAREL in subjects undergoing 
primary unilateral total shoulder arthroplasty or rotator cuff repair. 
Secondary Objectives: The secondary objectives of this study are to assess the efficacy, safety, and 
pharmacokinetic (PK) profiles of EXPAREL, as well as the onset and duration of sensory and motor function 
blockade, following administration for analgesia in subjects undergoing primary unilateral total shoulder 
arthroplasty or rotator cuff repair. 
Methodology: This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in 
approximately 120 adult subjects undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair 
with general anesthesia. 
Screening 
Subjects will be screened within 30 days prior to study drug administration. During the screening visit, which  
must take place at least 1 day prior to surgery, subjects will be assessed for past or present neurologic, cardiac, and 
general medical conditions that in the opinion of the investigator would preclude them from study participation. 
After the informed consent form (ICF) is signed, the patient’s eligibility for participation in the study will be 
confirmed and demographic and baseline characteristics will be recorded. A medical history, surgical history, 
neurological assessment, sensory and motor function assessments, physical examination, 12-lead 
electrocardiogram (ECG), vital sign measurements, urine drug screen, blood alcohol test, clinical laboratory tests 
(hematology, chemistry, and urinalysis), and urine pregnancy test for women of childbearing potential will be 
conducted. 
Day of Surgery 
On Day 0, eligible subjects will be randomized in a 1:1 ratio to receive a single dose of either EXPAREL 133 mg 
in 10 mL expanded in volume with 10 mL of normal saline for a total volume of 20 mL or placebo 20 mL.  
Subjects may receive acetaminophen/ paracetamol 1000 mg orally (PO) or intravenously (IV) every 8 hours (q8h) 
(maximum total daily dose of 3000 mg) prior to surgery. Study drug (EXPAREL or placebo) will be administered 
in a blinded manner via an ultrasound guided single-dose brachial plexus block at least 1 hour prior to surgery. 
A confirmatory photo of the ultrasound nerve block needle placement will be taken. The type of brachial plexus 
block (i.e., interscalene or supraclavicular) will be documented. The use of opioids (other than ultrashort-acting 
opioids [i.e., fentanyl, sufentanil, or remifentanil]), acetaminophen/paracetamol, ketorolac, or other non-steroidal 
anti-inflammatory drugs (NSAIDs), and local anesthetics other than the study drug will not be permitted 
intraoperatively, except for emergency use to treat an adverse event (AE). 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
4 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Subjects will be required to remain at the hospital facility through 72 hours. 
Postsurgical Rescue Medication 
Subjects should only receive rescue medication upon request for pain control, as needed. Postsurgical rescue 
medication will consist of PO immediate-release oxycodone (initiating at 5-10 mg every 4 hours [q4h] or as needed 
[PRN]). If a subject cannot tolerate PO medication, IV morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) may be 
administered q4h or PRN. Patient-controlled analgesia (PCA) is not permitted. Postsurgically, all subjects will 
receive acetaminophen/paracetamol up to 1000 mg PO or IV q8h unless contraindicated. The total daily dose of 
acetaminophen/paracetamol should not exceed 3000 mg. 
No other analgesic agents, including NSAIDs, are permitted through 72 hours (postsurgical Day 3). After 
72 hours, the analgesic regimen may be adjusted for each subject individually as deemed appropriate by the 
physician responsible for the postsurgical care. 
Postsurgical Assessments  
Postsurgical assessments will include: 
• Pain intensity scores using a 10-cm visual analog scale 
•  Motor function assessment (Appendix 6) 
(VAS; Appendix 1) 
•  Discharge readiness (Appendix 7) 
• Total postsurgical opioid consumption 
•  Unscheduled phone calls or office visits related to 
• Overall benefit of analgesia score (OBAS) 
pain 
questionnaire (Appendix 2) 
•  12-lead ECGs (ECGs must be read within 2 hours) 
• Subject satisfaction with overall analgesia using a 
•  Vital sign measurements 
5-point Likert scale (Appendix 3) 
•  Clinical laboratory tests (hematology, chemistry, 
• Neurological assessment (Appendix 4) 
and urinalysis; Appendix 8) 
• Sensory function assessment (as measured by cold, 
pinprick, and light touch testing; Appendix 5) 
At timepoints when multiple assessments coincide, the pain intensity assessment will be conducted first and the 
blood draw for PK analysis will be conducted second, as applicable. 
Adverse events will be recorded from the time the ICF is signed through postsurgical Day 29. If a cardiac or 
neurological AE of special interest (AESI), fall, or serious AE (SAE) occurs during the study, an unscheduled PK 
blood sample must be collected. In addition, a 12-lead ECG, vital signs, and any appropriate clinical laboratory 
tests must be conducted. If conducted, the ECG must be read within 2 hours. 
Cardiac AESIs include chest pain (angina, myocardial infarction), abnormal/irregular heart rate (bradycardia, 
tachycardia, extrasystoles), and shortness of breath requiring intervention. Neurologic AESIs include altered 
mental status/altered sensorium, rigidity, dysarthria, seizure, tremors, metallic taste, tinnitus, perioral numbness, 
visual disturbance, severe or worsening dizziness, and dizziness beyond 72 hours postdose. Additionally, the 
following events are of special interest if they persist or occur beyond 72-hours postdose: hyperesthesia, muscular 
twitching, and tingling/paresthesia. 
Follow-up visits will be scheduled for all subjects on postsurgical Days 5 and 10. A follow-up phone call will be 
made on postsurgical Day 29 to all subjects who received study drug to assess for AEs. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
5 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Methodology (Cont.): 
Pharmacokinetic Assessment 
A population PK analysis will be utilized to limit the number of blood draws. A total of 7 PK samples will be 
collected from each subject for this study. All subjects will have PK samples taken at baseline and upon arrival at 
the post-anesthesia care unit (PACU). An additional 5 blood samples will be collected at the assigned time 
windows, spanning from 12 hours postdose to hospital discharge. There are two PK collection sequences for this 
study and a subject can only be randomized to one sequence. The PK schedule sequence will be indicated for each 
subject at the time of randomization and will also be noted on the randomization confirmation. Subjects in 
Sequence 1 will have samples taken at 12, 24, 40, 52, and 72 hours. Subjects in Sequence 2 will have samples 
taken at 24, 36, 48, and 60 hours, and at hospital discharge. 
Blood samples for PK analysis may be drawn using a properly maintained indwelling cannula (PICC line) at the 
discretion of the Investigator. Blood samples will be collected from all subjects to maintain the treatment double- 
blind. 
Interim PK Analysis 
A blinded interim PK analysis was completed after 13 subjects completed the assessments through postsurgical Day 
10. All of the plasma samples from the subjects who received EXPAREL were analyzed and the plasma       
samples from the subjects randomized to placebo were analyzed through the 24-hour timepoint. Enrollment 
continued while the interim PK data were analyzed. The goal of this blinded analysis was to determine the 
appropriateness of the PK timepoints selected and make recommendations to keep, remove, or revise them in order 
to fully characterize the PK profile. 
The results of this analysis showed a median time to maximum plasma concentration (Tmax) of 48 hours for the 
133 mg EXPAREL group and a median Tmax of 60 hours for the 266 mg EXPAREL group. These data informed 
the changes to the PK collection schedule contained in this protocol amendment. 
In addition, the safety assessment timepoints, including the neurological exam, vital signs, and ECG were adjusted 
based on the initial interim PK data; a confirmatory blinded PK interim analysis will be conducted once 30 subjects 
have completed the assessments through postsurgical Day 10. 
Number of Subjects (Planned): Approximately 120 subjects (50 subjects randomized to EXPAREL 133 mg, 50 
subjects randomized to placebo, and any subjects enrolled under the original protocol and randomized to 
EXPAREL 266 mg) are planned for enrollment in this study in order to have at least 94 evaluable subjects in the 
EXPAREL 133 mg and placebo treatment groups. 
Eligibility Criteria: 
Inclusion Criteria: 
1. Male or female, at least 18 years of age at screening. 
2. Scheduled to undergo primary unilateral total shoulder arthroplasty or rotator cuff repair. 
3. Subjects scheduled for rotator cuff repair must have a magnetic resonance imaging (MRI) with a reading 
confirming a tear of at least 1 cm. 
4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
6 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
5. Female subject must be surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner 
who is surgically sterile; or practicing double-barrier contraception; or practicing abstinence (must agree to use 
double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or 
combination oral contraceptive approved by the Food and Drug Administration (FDA) for greater than 2 
months prior to screening and commit to the use of an acceptable form of birth control for the duration of the 
study and for 30 days after completion of the study. 
6. Able to demonstrate normal motor function (by obtaining a 5 on the Lovett Scale when exhibiting biceps, 
wrist, and thumb movement) and sensory function (by exhibiting sensitivity to cold, pinprick, and light touch) 
in the location where sensory function will be measured throughout the study: 2 cm superior to the coracoid 
process on the skin overlying the acromioclavicular joint. 
7. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments. 
Exclusion Criteria: 
1. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study 
drug administration. 
2. Planned concurrent surgical procedure. 
3. Concurrent painful physical condition that may require analgesic treatment (such as an NSAID or opioid) in 
the postsurgical period for pain that is not strictly related to the shoulder surgery and which may confound the 
postsurgical assessments (e.g., significant pain from other joints, chronic neuropathic pain). 
4. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics. 
5. Smoking history of greater than 25 pack-years. 
6. Contraindication to any one of the following: bupivacaine, oxycodone, morphine, or hydromorphone. 
7. Use of any of the following medications within the times specified before surgery: long-acting opioid 
medications or NSAIDs (except for low-dose aspirin used for cardioprotection) within 3 days, or any opioid 
medication within 24 hours. 
8. 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. 
9. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. 
10. Use of dexmedetomidine HCl (Precedex®) within 3 days of study drug administration. 
11. History of impaired kidney function, emphysema or other chronic respiratory disease, rheumatoid arthritis, 
coagulopathy, or loss of sensation in extremities. 
12. Impaired kidney function (e.g., serum creatinine level >2 mg/dL [176.8 µmol/L] or blood urea nitrogen level 
>50 mg/dL [17.9 mmol/L]) or impaired liver function (e.g., serum aspartate aminotransferase [AST] level 
>3 times the upper limit of normal (ULN) or serum alanine aminotransferase [ALT] level >3 times the ULN. 
13. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments. 
14. Any chronic neuromuscular deficit effecting the peripheral nerves or muscles of the surgical extremity. 
15. Any chronic condition or disease that would compromise neurological or vascular assessments. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
7 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
16. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of 
the skin or localized carcinoma in situ of the cervix. 
17. Suspected or known history of drug or alcohol abuse within the previous year. 
18. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2. 
19. Previous participation in an EXPAREL study. 
20. 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. 
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 dose of 133 mg (10 mL) expanded in volume with 10 mL of normal saline for a total volume of 20 
mL 
Lot number: To be determined 
Mode of administration: Preoperative brachial plexus block 
Reference Product, Dose, Mode of Administration, and Lot Number: 
Name: Placebo (normal saline) 
Active ingredient: Not applicable 
Dosage: 20 mL 
Lot number: Commercial product to be provided by Pacira 
Mode of administration: Preoperative brachial plexus block 
Duration of Subject Participation in Study: 
Participation will begin at the signing of the ICF. No more than 30 days should pass between signing of the ICF 
and the administration of study drug. The time from study drug administration through the end of participation is 
30 ± 3 days. Therefore, subjects may participate in the study for up to 63 days. 
Efficacy Assessments: 
The following efficacy measurements will be assessed at the times specified after the beginning of the brachial 
plexus block with study drug: 
• 
Pain intensity scores using the VAS at baseline (on Day 0 prior to the nerve block and prior to any 
premedication); upon arrival at the PACU, every 15 minutes while in the PACU, and prior to PACU 
discharge; at 6, 12, 24, 36, 48, 60, and 72 hours; and immediately prior to each administration of rescue 
pain medication through 72 hours (see Appendix 1). 
• 
Date, time of administration, and amount of all opioid rescue medication taken through 72 hours. 
• 
The OBAS questionnaire at 24 and 72 hours, and on postsurgical Day 10 (see Appendix 2). 
• 
Subject satisfaction with overall analgesia (using a 5-point Likert scale) at 24 and 72 hours, and on 
postsurgical Day 10 (see Appendix 3). 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
8 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
• 
Discharge readiness at 12, 24, 36, 48, 60, and 72 hours or until the subjects is determined to be discharge 
ready, whichever occurs first (see Appendix 7). 
• 
Unscheduled phone calls or office visits related. to pain after discharge through postsurgical Day 10 
Efficacy Endpoints: 
The efficacy endpoints listed below will be assessed based on the efficacy measurements conducted at the times 
specified after the beginning of the brachial plexus block with study drug. 
Primary Endpoint: 
The primary endpoint is the area under the curve (AUC) of the VAS pain intensity scores through 48 hours. 
Secondary Endpoints: 
The following secondary endpoints will be analyzed in the following order: 
• 
Total postsurgical opioid consumption (in IV morphine equivalents) through 48 hours. 
• 
Percentage of opioid-free subjects through 48 hours. 
• 
Time to first opioid rescue through 48 hours. 
Tertiary Endpoints: 
• 
The AUC of the VAS pain intensity scores through 12, 24, and 72 hours. 
• 
The AUC of the VAS pain intensity scores from 24-48 and 48-72 hours. 
• 
VAS pain intensity scores at each assessed timepoint. 
• 
Proportion of subjects who are pain free (defined as a VAS pain intensity score of ≤1.5 without prior 
rescue medication use) at each assessed timepoint. 
• 
Sum of the pain intensity scores (SPIS) through 24, 48, and 72 hours. 
• 
SPIS from 24-48 and 48-72 hours. 
• 
Total opioid consumption in IV morphine equivalents through 24 and 72 hours. 
• 
Total opioid consumption in IV morphine equivalents from 24-48 and 48-72 hours. 
• 
Percentage of opioid-free subjects through 24 and 72 hours. 
• 
The OBAS total score at 24 and 72 hours, and postsurgical Day 10. 
• 
Subject satisfaction with overall analgesia (using a 5-point Likert scale) at 24 and 72 hours, and 
postsurgical Day 10. 
• 
Proportion of subjects meeting Modified Postanesthesia Discharge Scoring System (MPADSS) criteria for 
discharge readiness at 12, 24, 36, 48, 60, and 72 hours. 
• 
Number of unscheduled phone calls or office visits related to pain after discharge through postsurgical 
Day 10. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
9 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Pharmacokinetic Assessments: 
A population PK analysis will be utilized to limit the number of blood draws. A total of 7 PK samples for each 
subject will be collected for this study. All subjects will have PK samples taken at baseline and upon arrival at the 
PACU. An additional 5 blood samples will be collected at the assigned time windows shown in Table 2, spanning 
from 12 hours postdose to 72 hours. There are two PK collection sequences for this study and a subject can only be 
randomized to one sequence. The PK schedule sequence will be indicated for each subject at the time of 
randomization and will also be noted on the randomization confirmation. Subjects in Sequence 1 will have   
samples taken at 12, 24, 40, 52, and 72 hours. Subjects in Sequence 2 will have samples taken at 24, 36, 48, and   
60 hours, and at hospital discharge. 
Pharmacokinetic Endpoints: 
The following PK parameters will be determined: 
• 
AUC from time 0 to the last collection time after drug administration (AUC0-tlast). 
• 
Area under the plasma curve-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 measurements will be conducted at the specified timepoints after the beginning of the 
brachial plexus block with study drug: 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis) at baseline (on Day 0 prior to the nerve 
block) and on postsurgical Day 10 (see Appendix 8). 
• 
Vital signs (resting heart rate and blood pressure) at baseline (on Day 0 prior to the nerve block); every 5 
minutes during performance of the block and up to 30 minutes after the end of the injection and then every 
15 minutes until entering the operating room (OR); upon arrival at the PACU; at 6, 9, 12, 24, 36, 40, 44, 
48, 52, 56, 60, and 72 hours; and on postsurgical Days 5 and 10. 
• 
12-lead ECG recordings at baseline (on Day 0 prior to the nerve block); upon arrival at the PACU; at 6, 9, 
12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; and on postsurgical Days 5 and 10. Note: The ECG must 
be read within 2 hours. 
• 
Neurological assessment at baseline (on Day 0 prior to the nerve block); upon arrival at the PACU; at 6, 9, 
12, 24, 36, 40, 44, 48, 52, 56, 60, 72 hours; and on postsurgical Days 5 and 10 (see Appendix 4). 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-327 (Brachial Plexus Block) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
10 of 82 
14 November 2016 
 
 
 
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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
• 
Sensory function assessment (as measured by cold, pinprick, and light touch testing) will be assessed at 
baseline (on Day 0 prior to the nerve block); at approximately 15, 30, and 45 minutes prior to the OR; 
prior to discharge from the PACU; at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours (see Appendix 5). If on 
postsurgical Day 5 there is a sensory deficit, the sensory deficit will be recorded as an AE and the 
physician will assess the subject for other etiologies that may explain the persistent sensory deficit. 
The sensory function will be further assessed on postsurgical Day 10. If the sensory deficit persists on 
postsurgical Day 10, the subject is to return for unscheduled visit(s) at the Investigator's discretion  
through postsurgical Day 29 or until the sensory function has returned to baseline, whichever occurs first. 
• 
Degree of motor nerve block (biceps, wrist, and thumb movement) will be assessed at baseline (on Day 0 
prior to the nerve block); at approximately 15, 30, and 45 minutes prior to the OR; prior to discharge from 
PACU; at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours (see Appendix 6). If on postsurgical Day 5 there is a 
motor deficit, the motor deficit will be recorded as an AE and the physician will assess the subject for 
other etiologies that may explain the persistent motor deficit. The degree of motor nerve block will be 
further assessed on postsurgical Day10. If the motor deficit persists on postsurgical Day 10, the subject is 
to return for unscheduled visit(s) at the Investigator's discretion through postsurgical Day 29 or until the 
motor function has returned to baseline, whichever occurs first. 
• 
Adverse events from the time the ICF is signed through postsurgical Day 29 
Safety Endpoints: 
The following safety endpoints will be assessed based on the safety measurements conducted at the specified 
timepoints: 
• 
Change from baseline in clinical laboratory data at each assessed timepoint. 
• 
Change from baseline in vital sign data (resting heart rate and blood pressure) at each assessed timepoint. 
• 
Change from baseline in ECG data at each assessed timepoint. 
• 
Summary of neurological assessments (proportion of subjects who are oriented, and proportion of 
subjects who have any of the neurologic events). 
• 
Cold sensation at each assessed timepoint. 
• 
Pinprick sensation at each assessed timepoint. 
• 
Light touch sensation at each assessed timepoint. 
• 
Change from baseline in motor function (biceps, wrist, and thumb movement) at each assessed timepoint. 
• 
Incidence of treatment-emergent AEs (TEAEs) and SAEs through postsurgical Day 29. 
Statistical Methods: 
A comprehensive statistical analysis plan (SAP) 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 
and site as the main effects for the primary efficacy endpoint of AUC of the VAS pain intensity scores through  
48 hours. A hierarchical procedure will be used to provide control of the type 1 error across the four key null 
hypotheses, i.e., for the null hypotheses corresponding to the primary treatment group comparison (EXPAREL 
133 mg treatment group versus placebo) in combination with each of the three secondary endpoints of greatest 
interest. Efficacy endpoints may be analyzed using ANOVA, chi-square tests, and Gehan-Wilcoxon tests, as 


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Clinical Study Protocol Amendment 2 
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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 Product: 
EXPAREL (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
appropriate. Safety endpoints will be summarized descriptively by treatment group. The PK parameters will be 
calculated using non-compartmental analysis and summarized for each EXPAREL group. 
Sample Size 
The sample size was calculated based on efficacy as measured by the AUC of the numeric rating scale at rest 
(NRS-R) pain intensity scores through 72 hours from a previously conducted nerve block study. Assuming a 
2-sided 0.05 alpha and a common standard deviation (SD) of 170 and controlling alpha for the two efficacy 
comparisons, a sample size of 47 subjects per treatment group should have at least 80% power to detect a 100-unit 
treatment difference. Approximately 120 subjects (50 subjects randomized to EXPAREL 133 mg, 50 subjects 
randomized to placebo, and any subjects enrolled under the original protocol and randomized to EXPAREL 266 
mg) are planned for enrollment in this study in order to have at least 94 evaluable subjects in the EXPAREL 133 
mg and placebo treatment groups. 


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Table 1:  Time and Events Schedule of Study Procedures (Screening Visit through PACU Discharge) 
 
Screen 
Visit** 
D0 
Preop 
Dosing 
15 min 
30 min 
45 min 
OR 
PACU 
Arrival 
Every 15 
min 
Up to 
PACU 
Discharge 
PACU 
Discharge 
Time Window 
Within 
30 days 
±5 min 
±5 min 
±5 min 
Obtain signed ICF 
X 
Assess/confirm eligibility 
X 
X3 
Record medical and surgical history 
X 
X3 
Record demographics and baseline characteristics 
X 
Conduct pregnancy test for WOCBP 
X 
X3 
Perform physical examination 
X 
Urine drug screen and blood alcohol test1 
X 
X3 
Clinical labs (hematology, chemistry, and urinalysis)2 
X 
X3 
Perform neurological assessment 
X 
X3 
X 
Measure vital signs (heart rate and blood pressure)4 
X 
X3 
From the beginning of dosing, assess vital 
signs every 5 mins up to 30 mins after 
completion of the injection then every 15 
mins (±5 mins) until OR 
X 
Perform 12-lead ECG recordings5 
X 
X3 
X 
Perform sensory function assessment6 
X 
X3 
X 
X 
X 
X 
Conduct motor function assessment7 
X 
X3 
X 
X 
X 
X 
Record VAS pain intensity scores8 
X3 
X 
X 
X 
Collect PK blood sample; record date and time9 
X3 
X 
Randomize subject, prepare study drug 
X3 
Administer blinded study drug via NB at least 1 hour prior to surgery; 
record start and stop times 
X 
Take photo of ultrasound NB needle placement 
X 
Record block type (interscalene or supraventricular) 
X 
Record intraoperative opioids administered & doses 
X 
Record surgery start and stop times 
X 
Complete OBAS questionnaire 
Subject satisfaction with postsurgical pain control 
Assess discharge readiness; record date and time 
Record date and time of actual discharge 
Document any unscheduled phone calls or office visits related to pain after 
discharge 
Record prior and concomitant medications, including all analgesics10 
Record AEs beginning at the time ICF is signed2,4, 5,9 


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Abbreviations: AE = adverse event; d = day; D = day; ECG = electrocardiogram; h = hour(s), ICF = informed consent form; min = minutes; NB = nerve block; OBAS = overall benefit of 
analgesia score; OR = operating room; PACU = post-anesthesia care unit; PK = pharmacokinetic; Preop = preoperative; VAS = visual analog scale; WOCBP = women of childbearing 
potential. 
* 
Postsurgical safety, efficacy, and PK assessments will be conducted at the timepoints specified after the beginning of the brachial plexus block with study drug. 
At timepoints when multiple assessments coincide, the pain intensity assessment will be conducted first and the blood sample for PK analysis will be conducted second, as applicable. 
**    The screening visit must take place at least 1 day prior to surgery. 
1 
A blood alcohol test will be conducted at screening, and an alcohol breath test will be conducted on Day 0. 
2 
Also conduct clinical laboratory tests if a subject experiences an AE of special interest (AESI; i.e., cardiac AE or neurological AE), fall, or a SAE; see footnote 9. 
3 
Prior to the nerve block with study drug. 
4 
Vital signs will be measured after the subject has rested in a supine position for at least 5 minutes.  Also measure vital signs if a subject experiences an AESI (i.e., cardiac AE or 
neurological AE), fall, or an SAE; see footnote 9. 
5 
Also conduct a 12-lead ECG if a subject experiences an AESI (i.e., cardiac AE or neurological AE), or an SAE; see footnote 9. 
6 
Sensory function will be assessed using cold, pinprick, and light touch testing. If sensory deficit is present at 72 hours, the subject will be assessed on day 5. If on postsurgical Day 5 
there is a sensory deficit, the sensory deficit will be recorded as an AE and the physician will assess the subject for other etiologies that may explain the persistent sensory deficit.  If 
there was a sensory function deficit on Day 5, the sensory function will be further assessed on postsurgical Day 10.  If the sensory deficit persists on postsurgical Day 10, the subject is 
to return for unscheduled visit(s) at the Investigator's discretion through postsurgical Day 29 or until the sensory function has returned to baseline, whichever occurs first. 
7 
The motor function assessment (biceps, wrist, and thumb movement) will be assessed using a 0-10 scale of return to motor function. If motor function deficit (Lovett score below 5) is 
present at 72 hours, the subject will be assessed again on day 5. If on postsurgical Day 5 there is a motor deficit, ie, the subject’s Lovett score has not returned to 5, the motor deficit 
will be recorded as an AE and the physician will assess the subject for other etiologies that may explain the persistent motor deficit.  If there was a motor function deficit on Day 5, the 
motor assessment will be further assessed on postsurgical Day 10. If the motor deficit persists on postsurgical Day 10, the subject is to return for unscheduled visit(s) at the 
Investigator's discretion through postsurgical Day 29 or until the motor function has returned to a Lovett score of 5, whichever occurs first. 
8 
The preoperative pain intensity assessment should be conducted prior to administration of any premedication.  Also record VAS pain intensity score immediately prior to each 
administration of rescue pain medication through 72 hours. 
9 
If a cardiac or neurological AESI, fall, or SAE occurs during the study, an unscheduled PK blood sample must be collected.  In addition, a 12-lead ECG, vital signs, and any appropriate 
clinical laboratory tests must be conducted. Cardiac AESIs include chest pain (angina, myocardial infarction), abnormal/irregular heart rate (bradycardia, tachycardia, extrasystoles), 
and shortness of breath requiring intervention.  Neurologic AESIs include altered mental status/altered sensorium, rigidity, dysarthria, seizure, tremors, metallic taste, tinnitus, perioral 
numbness, visual disturbance, severe or worsening dizziness, and dizziness beyond 72 hours postdose.  Additionally, the following events are of special interest if they persist or occur 
beyond 72-hours postdose: hyperesthesia, muscular twitching, and tingling/paresthesia. 
10 
Instruct subject to discontinue prohibited medications.  Record date/time of all medications starting at least 30 days prior to study drug administration through 72 hours after study drug 
administration.  Record all analgesics taken through postsurgical Day 29.  Record medications administered for treatment of an AE through postsurgical Day 29. 


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Table 2: Time and Events Schedule of Study Procedures (6 hours through Day 29) 
 
6h 
9h 
12h 
18h 
24h 
36h 
40h 44h 48h 
52h 
56h 
60h 
72h 
Discharge 
D5 
Visit 
D10 
Visit 
D29 
Call 
Time 
Window 
±30 
min 
±30 
min 
±30 
min 
±30 
min 
±1h 
±1h 
±1h ±1h ±1h 
±2h 
±2h 
±2h 
±2h 
-2h 
±1d 
±1d 
±3d 
Obtain signed ICF 
Assess/confirm eligibility 
Record medical and surgical history 
Record demographics and baseline characteristics 
Conduct pregnancy test for WOCBP 
Perform physical examination 
X 
Urine drug screen and blood alcohol test1 
Clinical labs (hematology, chemistry, and urinalysis)2 
X 
Perform neurological assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Measure vital signs (heart rate and blood pressure)4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perform 12-lead ECG recordings5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perform sensory function assessment6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X6 
Conduct motor function assessment7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
X7 
Record VAS pain intensity scores8 
X 
X 
X 
X 
X 
X 
X 
Collect PK blood sample; record date and time9 
S1 
S1, S2 
S2 
S1 
S2 
S1 
S2 
S1 
S2 
Randomize subject, prepare study drug 
Administer blinded study drug via FNB at least 1 hour prior to 
surgery; record start and stop times 
Take photo of ultrasound NB needle placement 
Record block type (interscalene or supraventricular) 
Record intraoperative opioids administered & doses 
Record surgery start and stop times 
Complete OBAS questionnaire 
X 
X 
X 
Subject satisfaction with postsurgical pain control 
X 
X 
X 
Assess discharge readiness; record date and time 
X 
X 
X 
X 
X 
X 
Record date and time of actual discharge 
X 
X 
Document any unscheduled phone calls or office visits related 
to pain after discharge 
X 
X 
X 
Record prior and concomitant medications, including all 
analgesics10 
Record AEs beginning at the time ICF is signed2,7, 8,9 


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Abbreviations: AE = adverse event; d = day; D = day; ECG = electrocardiogram; h = hour(s), ICF = informed consent form; min = minutes; NB = nerve block; OBAS = overall benefit of 
analgesia score; OR = operating room; PACU = post-anesthesia care unit; PK = pharmacokinetic; Preop = preoperative; S1 = PK sampling sequence 1; S2 = PK sampling sequence 2; VAS 
= visual analog scale; WOCBP = women of childbearing potential. 
* 
Postsurgical safety, efficacy, and PK assessments will be conducted at the timepoints specified after the beginning of the brachial plexus block with study drug. 
At timepoints when multiple assessments coincide, the pain intensity assessment will be conducted first and the blood sample for PK analysis will be conducted second, as applicable. 
**    The screening visit must take place at least 1 day prior to surgery. 
1 
A blood alcohol test will be conducted at screening, and an alcohol breath test will be conducted on Day 0. 
2 
Also conduct clinical laboratory tests if a subject experiences an AE of special interest (AESI; i.e., cardiac AE or neurological AE), fall, or a SAE; see footnote 9. 
3 
Prior to the nerve block with study drug. 
4 
Vital signs will be measured after the subject has rested in a supine position for at least 5 minutes.  Also measure vital signs if a subject experiences an AESI (i.e., cardiac AE or 
neurological AE), fall, or an SAE; see footnote 9. 
5 
Also conduct a 12-lead ECG if a subject experiences an AESI (i.e., cardiac AE or neurological AE), fall, or an SAE; see footnote 9. 
6 
Sensory function will be assessed using cold, pinprick, and light touch testing. .  If sensory deficit is present at 72 hours, the subject will be assessed on day 5. If on postsurgical Day 5 
there is a sensory deficit, the sensory deficit will be recorded as an AE and the physician will assess the subject for other etiologies that may explain the persistent sensory deficit.  If 
there was a sensory function deficit on Day 5, the sensory function will be further assessed on postsurgical Day 10.  If the sensory deficit persists on postsurgical Day 10, the subject is 
to return for unscheduled visit(s) at the Investigator's discretion through postsurgical Day 29 or until the sensory function has returned to baseline, whichever occurs first. 
7 
The motor function assessment (biceps, wrist, and thumb movement) will be assessed using a 0-10 scale of return to motor function. If motor function deficit (Lovett score below 5) is 
present at 72 hours, the subject will be assessed again on day 5. If on postsurgical Day 5 there is a motor deficit, ie, the subject’s Lovett score has not returned to 5, the motor deficit 
will be recorded as an AE and the physician will assess the subject for other etiologies that may explain the persistent motor deficit.  If there was a motor function deficit on Day 5, the 
motor assessment will be further assessed on postsurgical Day 10. If the motor deficit persists on postsurgical Day 10, the subject is to return for unscheduled visit(s) at the 
Investigator's discretion through postsurgical Day 29 or until the motor function has returned to a Lovett score of 5, whichever occurs first 
8 
The preoperative pain intensity assessment should be conducted prior to administration of any premedication.  Also record VAS pain intensity score immediately prior to each 
administration of rescue pain medication through 72 hours. 
9 
If a cardiac or neurological AESI, fall, or SAE occurs during the study, an unscheduled PK blood sample must be collected.  In addition, a 12-lead ECG, vital signs, and any appropriate 
clinical laboratory tests must be conducted. Cardiac AESIs include chest pain (angina, myocardial infarction), abnormal/irregular heart rate (bradycardia, tachycardia, extrasystoles), 
and shortness of breath requiring intervention.  Neurologic AESIs include altered mental status/altered sensorium, rigidity, dysarthria, seizure, tremors, metallic taste, tinnitus, perioral 
numbness, visual disturbance, severe or worsening dizziness, and dizziness beyond 72 hours postdose.  Additionally, the following events are of special interest if they persist or occur 
beyond 72-hours postdose: hyperesthesia, muscular twitching, and tingling/paresthesia. 
10 
Instruct subject to discontinue prohibited medications.  Record date/time of all medications starting at least 30 days prior to study drug administration through 72 hours after study drug 
administration.  Record all analgesics taken through postsurgical Day 29.  Record medications administered for treatment of an AE through postsurgical Day 29. 


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Table 3: Time and Events Schedule of Study Procedures – Scheduled Pharmacokinetic Samples Blood Draws 
 
 
 
 
 
*Dis. = hospital discharge, regardless of day. 
Note: If a cardiac AE or neurological AESI, fall, or SAE occurs during the study, an unscheduled PK blood sample must be collected.  In addition, a 12-lead ECG, vital signs, and any 
appropriate clinical laboratory tests must be conducted. If conducted, the ECG must be read within 2 hours. Cardiac AESIs include chest pain (angina, myocardial infarction), 
abnormal/irregular heart rate (bradycardia, tachycardia, extrasystoles), and shortness of breath requiring intervention. Neurologic AESIs include altered mental status/altered sensorium, 
rigidity, dysarthria, seizure, tremors, metallic taste, tinnitus, perioral numbness, visual disturbance, severe or worsening dizziness, and dizziness beyond 72 hours postdose.  Additionally, the 
following events are of special interest if they persist or occur beyond 72-hours postdose: hyperesthesia, muscular twitching, and tingling/paresthesia. 
6h 
9h 
12h 
18h 
24h 
36h 
40h 
44h 
48h 
52h 
56h 
60h 
72h 
Dis.* 
Time Window 
±30 
min 
±30 
min 
±30 
min 
±30 
min 
±1h 
±1h 
±1h 
±1h 
±1h 
±2h 
±2h 
±2h 
±2h 
-2hr 
Sequence 1 (S1):  Collect PK blood sample; record date and time 
S1 
S1 
S1 
S1 
S1 
Sequence 2 (S2):  Collect PK blood sample; record date and time 
S2 
S2 
S2 
S2 
S2 


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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ...................................................................................................... 2 
2. 
SYNOPSIS ..................................................................................................................... 3 
3. 
TABLE OF CONTENTS ............................................................................................. 17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 22 
4.1. 
List of Abbreviations .................................................................................................... 22 
4.2. 
Definition of Terms ...................................................................................................... 23 
5. 
ETHICS ........................................................................................................................... 24 
5.1. 
Institutional Review Board/Independent Ethics Committee ....................................... 24 
5.2. 
Ethical Conduct of the Study ..................................................................................... 24 
5.3. 
Subject Information and Consent ................................................................................. 24 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE ................. 25 
7. 
INTRODUCTION ........................................................................................................ 26 
7.1. 
Indication ...................................................................................................................... 26 
7.2. 
Current Therapies/Treatments ...................................................................................... 26 
7.3. 
EXPAREL (bupivacaine liposome injectable suspension) .......................................... 27 
7.4. 
Summary of Human Experience with EXPAREL ....................................................... 27 
7.4.1. 
Wound Infiltration New Drug Application (NDA) ..................................................... 27 
7.4.2. 
Nerve Block Supplemental NDA ................................................................................. 29 
7.5. 
Postmarketing ............................................................................................................... 31 
8. 
OBJECTIVES ............................................................................................................... 32 
8.1. 
Primary Objectives ....................................................................................................... 32 
8.2. 
Secondary Objectives ................................................................................................... 32 
9. 
STUDY DESIGN AND PLAN .................................................................................... 33 
9.1. 
Study Design................................................................................................................. 33 
9.2. 
Discussion of Study Design ......................................................................................... 36 
10. 
STUDY POPULATION .............................................................................................. 38 
10.1. 
Inclusion Criteria .......................................................................................................... 38 
10.2. 
Exclusion Criteria ......................................................................................................... 38 
10.3. 
Removal of Subjects from Therapy or Assessment ..................................................... 39 
10.3.1. 
Withdrawal Secondary to Adverse Events ................................................................. 40 


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10.3.2. 
Voluntary or Study Investigator Withdrawal ............................................................... 40 
11. 
TREATMENTS ............................................................................................................ 41 
11.1. 
Treatment to be Administered ...................................................................................... 41 
11.1.1. 
Administration Technique ............................................................................................ 41 
11.1.2. 
Study Drug Administration Considerations ................................................................. 42 
11.2. 
Identity of Investigational Product(s) ........................................................................... 42 
11.2.1. 
Description of EXPAREL ............................................................................................ 42 
11.2.2. 
Description of Reference Product ................................................................................ 42 
11.2.3. 
Description of Diluents ................................................................................................ 42 
11.3. 
Method of Assigning Subjects to Treatment ............................................................... 42 
11.3.1. 
Randomization Scheme ................................................................................................ 42 
11.3.2. 
Randomization Procedures ........................................................................................... 42 
11.3.3. 
Replacement of Subjects ............................................................................................ 43 
11.4. 
Selection of Doses in the Study ................................................................................. 43 
11.5. 
Blinding ........................................................................................................................ 43 
11.5.1. 
Blinding Procedures ..................................................................................................... 43 
11.5.2. 
Unblinding Procedures ................................................................................................. 44 
11.6. 
Prior and Concomitant Therapy and Medications ....................................................... 44 
11.6.1. 
Before Study Drug Administration .............................................................................. 44 
11.6.2. 
During Surgery .......................................................................................................... 45 
11.6.3. 
After Surgery ............................................................................................................. 45 
11.7. 
Treatment Compliance ................................................................................................. 46 
11.8. 
Accountability of Study Drug .................................................................................... 46 
12. 
STUDY ENDPOINTS AND MEASUREMENTS ..................................................... 47 
12.1. 
Efficacy Assessments ................................................................................................... 47 
12.2. 
Efficacy Endpoints ....................................................................................................... 47 
12.3. 
Pharmacokinetic Analysis ............................................................................................ 48 
12.4. 
Pharmacokinetic Endpoints ....................................................................................... 48 
12.5. 
Safety Assessments ...................................................................................................... 49 
12.6. 
Safety Endpoints ........................................................................................................... 50 
12.7. 
Appropriateness of Measures ....................................................................................... 50 
13. 
STUDY PROCEDURES .............................................................................................. 51 
13.1. 
Instructions for Conducting Procedures and Measures ............................................... 51 


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13.1.1. 
Pain Intensity Assessment ............................................................................................ 51 
13.1.2. 
Overall Benefit of Analgesia Score Questionnaire ...................................................... 51 
13.1.3. 
Subject Satisfaction with Postsurgical Pain Control .................................................. 51 
13.1.4. 
Neurological Assessment ............................................................................................. 51 
13.1.5. 
Sensory Function Assessment ...................................................................................... 52 
13.1.6. 
Motor Nerve Block Assessment ................................................................................ 52 
13.1.7. 
Clinical Laboratory Tests ............................................................................................. 53 
13.1.8. 
Vital Signs .................................................................................................................... 53 
13.1.9. 
Physical Examination ................................................................................................... 53 
13.1.10. 
Electrocardiograms ....................................................................................................... 53 
13.1.11. 
Adverse Events of Special Interest .............................................................................. 54 
13.2. 
Screening Procedures ................................................................................................... 54 
13.3. 
Baseline Procedures (Day 0 - Prior to Study Drug Administration) ........................... 55 
13.4. 
Baseline Procedures (Time 0) ...................................................................................... 56 
13.5. 
Approximately 15, 30, and 45 Minutes After Beginning of Study Drug 
Administration .............................................................................................................. 56 
13.6. 
Intraoperative Procedures ............................................................................................. 56 
13.7. 
Upon Arrival at the Post-Anesthesia Care Unit ........................................................... 56 
13.8. 
Postsurgical Assessments through Hour 72 ............................................................... 57 
13.9. 
Postsurgical Day 5 Visit ............................................................................................... 58 
13.10. 
Postsurgical Day 10 Visit ............................................................................................. 59 
13.11. 
Unscheduled Visit(s) .................................................................................................... 59 
13.12. 
Postsurgical Day 29 Phone Call ................................................................................... 59 
14. 
ADVERSE EVENT REPORTING .............................................................................. 60 
14.1. 
Adverse Events .......................................................................................................... 60 
14.1.1. 
Definitions .................................................................................................................... 60 
14.1.2. 
Recording Adverse Events ......................................................................................... 60 
14.1.3. 
Severity of Adverse Events ........................................................................................ 61 
14.1.4. 
Relationship of Adverse Events to Study Drug ......................................................... 61 
14.1.5. 
Outcome of Adverse Events ...................................................................................... 62 
14.1.6. 
Action Taken with Subject due to an Adverse Event ................................................ 62 
14.2. 
Serious Adverse Events ............................................................................................. 63 
14.2.1. 
Definition of a Serious Adverse Event......................................................................... 63 


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14.2.2. 
Reporting Serious Adverse Events ............................................................................... 64 
15. 
STATISTICAL METHODS ........................................................................................ 65 
15.1. 
Study Hypothesis .......................................................................................................... 65 
15.2. 
Study Endpoints ............................................................................................................ 65 
15.3. 
Determination of Sample Size ................................................................................... 65 
15.4. 
Analysis Populations .................................................................................................... 65 
15.5. 
Handling Subject Dropouts and Discontinuations ....................................................... 65 
15.6. 
Statistical Analyses ....................................................................................................... 66 
15.6.1. 
Baseline Characteristics................................................................................................ 66 
15.6.2. 
Study Compliance ...................................................................................................... 66 
15.6.3. 
Efficacy Analyses ......................................................................................................... 66 
15.6.4. 
Pharmacokinetic Analyses ........................................................................................... 67 
15.6.5. 
Safety Analyses ............................................................................................................ 67 
15.7. 
Significance Testing ................................................................................................... 68 
15.8. 
Interim Pharmacokinetic Analysis ............................................................................... 68 
15.8.1. 
Sample Size Reestimation Interim Analysis ................................................................ 68 
16. 
REFERENCES ............................................................................................................. 70 
17. 
INVESTIGATOR AGREEMENT ............................................................................... 72 
18. 
APPENDICES .............................................................................................................. 73 
Appendix 1: Subject’s Reported Pain Intensity .......................................................................... 74 
Appendix 2: Overall Benefit of Analgesia Score (OBAS) Questionnaire ................................... 75 
Appendix 3: Subject Satisfaction with Postsurgical Pain Control (Likert Scale) ........................ 76 
Appendix 4: Neurological Assessment ......................................................................................... 77 
Appendix 5: Degree of Sensory Nerve Block .............................................................................. 78 
Appendix 6: Degree of Motor Nerve Block ................................................................................. 80 
Appendix 7: Discharge Readiness ................................................................................................ 81 
Appendix 8: Clinical Laboratory Tests ......................................................................................... 82 
 
LIST OF TABLES 
Table 1:  Time and Events Schedule of Study Procedures (Screening Visit through 
PACU Discharge) ...................................................................................................................... 12 
Table 2: Time and Events Schedule of Study Procedures (6 hours through Day 29) ................... 14 


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Table 3: Time and Events Schedule of Study Procedures – Scheduled Pharmacokinetic 
Samples Blood Draws ................................................................................................................ 16 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
4.1. 
List of Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANOVA 
Analysis of variance 
AUC 
Area under the curve 
AUC0-tlast 
Area under the plasma concentration-versus-time curve from the time of 
administration to the time of the last quantifiable concentration 
AUC0-∞ 
Area under the plasma concentration-versus-time curve from the time of 
administration extrapolated to infinity 
BDR 
Blinded Data Review 
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 
IRB 
Institutional Review Board 
IV 
Intravenous 
MPADSS 
Modified Postanesthesia Discharge Scoring System 
NDA 
New Drug Application 
NRS 
Numeric rating scale 
NRS-R 
Numeric rating scale at rest 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OBAS 
Overall benefit of analgesia score 
OR 
Operating room 
PACU 
Post-anesthesia care unit 


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PCA 
Patient-controlled analgesia 
PK 
Pharmacokinetic 
PO 
Oral 
PRN 
As needed 
PT 
Preferred term 
PTAE 
Pretreatment adverse event 
q4h 
Every 4 hours 
q8h 
Every 8 hours 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
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 
TEAE 
Treatment-emergent adverse event 
TKA 
Total knee arthroplasty 
Tmax 
The time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States (of America) 
VAS 
Visual analog scale 
 
4.2. 
Definition of Terms 
Pharmacokinetic (PK) terms are defined in Section 12.4. 


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5. 
ETHICS 
5.1. 
Institutional Review Board/Independent Ethics Committee 
Prior to 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.  For study sites with IECs that comply with ICH GCP, but not US FDA 21 CFR 
Part 56, a waiver request will be submitted to FDA.  If granted, then FDA’s letter documenting 
the waiver will be provided to the Investigator to be maintained with the signed Investigator 
statement (Form FDA 1572) in the Investigator's study binder.  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, the Directive 2001/20/EC of the European 
Parliament and of the Council of 04 April 2001 and amendments, the Commission Directive 
2005/28/EC of 08 April 2005 and amendments, and the ICH GCP.  Study documents will be 
maintained in accordance with applicable regulations. 
 
5.3. 
Subject Information and Consent 
Before a subject undergoes any study-specific screening procedures, the Investigator or designee 
will thoroughly explain to the subject the purpose of the study, the associated procedures, and 
any expected effects and potential adverse reactions.  A copy of the IRB-approved ICF will be 
provided to the subject, who will be given sufficient time and opportunity to inquire about the 
details of the study and decide whether or not to participate. The subject, and the study staff with 
whom he or she discusses the ICF, will sign and date the ICF.  A photocopy of the signed ICF 
will be given to the subject. 
The Investigator will explain to the subject that he or she is completely free to decline entry into 
the study and may withdraw from the study at any time, for any reason, without risking his or her 
medical care.  Similarly, the Investigator and/or Pacira Pharmaceuticals, Inc. (Pacira) 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 
2013). 


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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 provide a prolonged period of decreased pain and decreased 
opioid use with a single dose administration without the use of indwelling catheters.  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 analgesic treatment include wound infiltration and nerve 
block with local anesthetic agents usually combined with the systemic administration of 
analgesics (multimodal therapy).  Multimodal therapy usually includes opioid medications, non- 
steroidal anti-inflammatory drugs (NSAIDs), and/or acetaminophen provided through a variety 
of routes including intravenous (IV), transdermal patch, and oral (PO) administration. Opioids 
are widely used and considered some of the most powerful analgesics; however, they also have 
considerable drawbacks including time and resources required for monitoring opioid-related side 
effects.  A reduction in the use of postoperative opioids is desirable to decrease the incidence and 
severity of opioid-induced adverse effects, such as respiratory depression, nausea, vomiting, 
constipation, somnolence, pruritus, and urinary retention. 
Total shoulder arthroplasty and rotator cuff repair are frequently performed surgical procedures 
that cause postsurgical pain of considerable intensity and duration. Standard analgesic 
medications used to provide analgesic relief after surgery include a multimodal approach, often 
with conventional PO and parenteral analgesia (including NSAIDs, acetaminophen, and 
narcotics); interscalene analgesia or intra-articular analgesia with or without continuous infusion; 
or suprascapular nerve block combined with local anesthetic wound infiltration (Beecroft 2008). 
Therefore, total shoulder arthroplasty and rotator cuff repair were selected as an appropriate pain 
model(s) for investigating a sustained-release formulation of bupivacaine, which has the 
potential to overcome the limitation reported in previous studies with regard to the duration of 
the analgesic effect obtained with commercially-available products. 
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 


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that all healthcare facilities practice adequate pain management and monitor opioid-related 
adverse events (AEs) (Apfelbaum 2003). 
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.  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.  Because of this, EXPAREL has been noted in wound infiltration studies to 
have a bimodal curve (Apseloff 2013), with an initial peak at approximately 0-2 hours and a 
second peak at approximately 24-48 hours (Hu 2013). 
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 
7.4.1. 
Wound Infiltration New Drug Application (NDA) 
During the original clinical development program (wound infiltration), Pacira conducted 
21 clinical studies and one observational follow-up study (SKY0402-C-318) to investigate 
EXPAREL (formerly known as SKY0402™).  Across these studies, a total of 1307 human 


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subjects received EXPAREL at doses ranging from 10-750 mg (or 9-665 mg free base) and by 
various routes: local administration into the surgical wound, subcutaneous, perineural, and 
epidural.  The investigational drug product has been well tolerated and the reported AEs 
occurred at a similar rate as the corresponding bupivacaine HCl controls in the active comparator 
studies. 
In doses up to 665 mg of EXPAREL, no signal of any of the central nervous system or 
cardiovascular system AEs observed with high doses of bupivacaine HCl solution have been 
observed. Two thorough QTc studies have been conducted; EXPAREL did not cause significant 
QTc prolongation even at the highest dose evaluated. 
Across all studies, the types of treatment-emergent AEs (TEAEs) reported and the incidence 
rates generally were similar between the EXPAREL All Doses group (all doses combined) and 
the bupivacaine HCl group.  The incidence rate for each of the three most common TEAEs 
(nausea, constipation, and vomiting) was lower in the EXPAREL All Doses group than in the 
bupivacaine HCl group. 
EXPAREL was demonstrated to produce statistically significant and clinically meaningful 
analgesia in two pivotal placebo-controlled Phase 3 studies (SKY0402-C-317 and SKY0402- 
C-316) involving both orthopedic and soft tissue procedures over 36 and 72 hours, respectively. 
In addition to meeting their primary endpoints (area under the curve [AUC] of the numeric rating 
scale [NRS] at rest [NRS-R] pain intensity scores through 72 hours [Study SKY0402-C-316] and 
through 24 hours [Study SKY0402-C-317]), key secondary endpoints also were met, 
demonstrating prolonged analgesia and reduction of opioid use by various measures (percentage 
of subjects who received no supplementary opioid medication; total amount of postoperative 
consumption of opioid medication; and time to first use of opioid medication). The robust nature 
of the efficacy results in both pivotal studies SKY0402-C-316 and SKY0402-C-317 was 
demonstrated across subgroups of subjects with various prognostic features and across 
demographic subgroups. 
An analysis was performed to compare the incidence of opioid-related AEs between the 
EXPAREL and bupivacaine HCl groups in all bupivacaine-controlled, parallel-group wound 
infiltration studies (SIMPLE TKA 311, SKY0402-C-208, SIMPLE Hemorrhoidectomy 312, 
SKY0402-C-209, SKY0402-C-207, SKY0402-C-201, and SIMPLE Breast Augmentation 315). 
There was a statistically significantly lower incidence of opioid-related AEs in the EXPAREL 
≤300 mg group compared to the bupivacaine HCl group through 72 hours postdose. This was 
consistent with the statistically significantly lower total postoperative consumption of opioids 
in the EXPAREL ≤300 mg group through 72 hours postdose. Fewer subjects in the EXPAREL 
≤300 mg group had at least one opioid-related AE compared to the bupivacaine HCl group 
(25.6% versus 45.6%; p<0.0001).  The total opioid medication administered (adjusted geometric 
mean) through 72 hours postdose was statistically significantly lower in the EXPAREL ≤300 mg 
group (7.94 mg) compared to the bupivacaine HCl group (15.84 mg); p<0.0001. The EXPAREL 
>300 mg group did not show a statistically significant advantage favoring EXPAREL; the mean 
(standard deviation [SD]) of the average number of opioid-related AEs per subject was 
0.58 (0.522), and the total opioid medication administered (adjusted geometric mean) through 
72 hours postdose was 22.82 mg in the EXPAREL >300 mg group. 
Please see the EXPAREL Full Prescribing Information for safety information regarding the use 
of EXPAREL for the treatment of postsurgical pain in the setting of wound infiltration. 


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7.4.2. 
Nerve Block Supplemental NDA 
A total of 335 human subjects received EXPAREL as a nerve block over six clinical studies 
(SKY0402-002, SKY0402-C-111, SKY0402-C-203, SKY0402-C-211, 402-C-322, and 402-C- 
323) utilizing three different surgical models (femoral nerve block, intercostal nerve block, and 
ankle nerve block).  Doses administered ranged from 2 mg to 310 mg.  The data from three of 
these studies (SKY0402-002, SKY0402-C-203, and SKY0402-C-211) were included in the 
wound infiltration NDA as well as the nerve block supplemental NDA. As of May 2015, these 
are the only six studies Pacira has conducted in the setting of nerve block in human subjects. 
Phase 3 Nerve Block Studies 
Study 402-C-322 was a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo- 
controlled study to investigate the efficacy and safety of EXPAREL (total of 266 mg in 20 mL) 
divided into three equal doses in three syringes of approximately 88 mg in 6.6 mL volume per 
nerve and administered to each of three nerve segments (index nerve, nerve above, and nerve 
below) compared with saline placebo nerve block.  The primary objective was to evaluate the 
efficacy of intercostal nerve block using EXPAREL compared with placebo in subjects 
undergoing posterolateral thoracotomy. 
Intercostal nerve block with EXPAREL was well tolerated in subjects undergoing posterolateral 
thoracotomy.  However, the study did not meet its primary efficacy endpoint: there was no 
statistically significant difference in the mean AUC of the NRS-R pain intensity scores through 
72 hours between subjects in the EXPAREL group and in the placebo group although a treatment 
effect was evident through 12 to 24 hours based upon a post hoc analysis. 
Fifty-six subjects (59.6%) in the EXPAREL group and 46 subjects (50.5%) in the placebo group 
experienced one or more TEAEs.  Most of the TEAEs were mild or moderate in severity. 
Three subjects (3.2%) in the EXPAREL group and no subjects in the placebo group experienced 
a TEAE that were assessed by the Investigator as related to study drug.  Twelve subjects (12.8%) 
in the EXPAREL group and 9 subjects (9.9%) in the placebo group experienced one or more 
treatment-emergent serious AEs (SAEs).  Two of these subjects in the EXPAREL group and four 
of these subjects in the placebo group died.  None of the SAEs or deaths was assessed by the 
Investigator as related to study drug. Two subjects (2.1%) in the EXPAREL group and seven 
subjects (7.4%) in the placebo group were withdrawn from the study due to an AE. 
Study 402-C-323 was a Phase 2/3, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled, dose-ranging study in subjects undergoing primary unilateral total knee 
arthroplasty (TKA) under general or spinal anesthesia. The primary objectives of Part 1 were to 
(1) evaluate three dose levels of EXPAREL versus placebo with respect to the magnitude and 
duration of the analgesic effect achieved following single dose injection femoral nerve block 
with EXPAREL, and (2) select a single therapeutic dose of EXPAREL from the three dose levels 
to be tested in Part 2. 
The primary objective of Part 2 was to compare the magnitude and duration of the analgesic 
effect of single injection femoral nerve block of a single dose level of EXPAREL (selected from 
Part 1) with placebo (preservative-free normal saline for injection). 
Femoral nerve block with EXPAREL at 67 mg, 133 mg, and 266 mg was well tolerated in 
subjects undergoing TKA.  There were no discernible safety differences across the treatment 


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groups.  There was a dose response in EXPAREL-treated subjects. A dose of 266 mg was 
selected for Part 2. 
Part 2 of the study met its primary efficacy endpoint: the difference in the AUC of the NRS-R 
pain intensity scores through 72 hours between the EXPAREL group and the placebo group was 
statistically significant.  Additionally, the difference in the total postsurgical opioid consumption 
(mg) through 72 hours between the EXPAREL 266 mg group and the placebo group was 
statistically significant indicating lower opioid consumption in the EXPAREL group. 
In Part 1, there were no discernible safety differences across the treatment groups.  In Part 2, 
the incidences of TEAEs and treatment-emergent SAEs were similar between the EXPAREL 
266 mg group and the placebo group.  There were no deaths or withdrawals due to an AE during 
the study. 
During Part 2 of the study, three subjects experienced a fall; each subject was in the EXPAREL 
266 mg group. Each of the three subjects was able to complete the 20-meter walk test at 
24 hours, 72 hours, and on Day 30.  The rate of inpatient falls in study 402-C-323, 1.8%, was 
very similar to the overall incidence of inpatient falls in TKA patients (between 1% and 2%). 
The 20-meter walk test was used to determine whether there was any significant degree of motor 
blockade with use of EXPAREL.  The percentage of subjects who were able to complete the 
walk test at 24 hours and 72 hours did not differ significantly across the EXPAREL and placebo 
groups in Part 1.  In Part 2, the percentage of subjects who were able to complete the walk test 
was comparable between EXPAREL 266 mg and placebo groups at 24 hours (53.0% vs. 58.5%, 
respectively) and 72 hours (83.1 vs. 92.6%, respectively).  This suggested a lack of significant 
motor blockade with EXPAREL. This is confirmed by physician satisfaction with return of 
sensory/motor function. 
Pooled Nerve Block Safety Data 
In the All Studies pool, 335 subjects received EXPAREL (All Doses), 33 subjects received 
bupivacaine HCl, and 207 subjects received placebo. 
Overall, 184/335 subjects (54.9%) in the EXPAREL All Doses group, 15/35 subjects (45.5%) in 
the bupivacaine HCl group, and 99/207 subjects (47.8%) in the placebo group experienced at 
least one TEAE in a preferred term (PT) that had an incidence of ≥2%. The incidence and types 
of TEAEs (PTs) were similar between the EXPAREL All Doses group and the placebo group. 
In the EXPAREL All Doses group, the TEAEs reported with an incidence ≥2% were anemia 
(5.1%), bradycardia (2.1%), sinus tachycardia (2.1%), constipation (13.4%), feeling cold (3.3%), 
local swelling (2.1%), pyrexia (20.3%), procedural hypotension (5.1%), body temperature 
increased (2.4%), headache (4.5%), hypoesthesia (7.8%), paresthesia (2.1%), urinary retention 
(4.2%), and pruritus (12.2%). 
In the EXPAREL 266 mg group, the TEAEs reported with an incidence ≥2% were anemia 
(5.7%), sinus tachycardia (2.4%), constipation (18.1%), feeling cold (4.8%), local swelling 
(2.9%), pyrexia (24.3%), procedural hypotension (6.2%), body temperature increased (3.8%), 
mobility decreased (2.9%), headache (3.3%), hypoesthesia (2.4%), urinary retention (5.7%), 
and pruritus (16.7%). 
In the bupivacaine HCl group (N=33 subjects), the TEAEs reported with an incidence ≥2% were 
abdominal pain (3.0%), diarrhea (6.1%), flatulence (3.0%), chills (3.0%), injection site 


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discomfort (3.0%), injection site erythema (9.1%), pyrexia (6.1%), drug hypersensitivity (3.0%), 
procedural hypotension (3.0%), back pain (6.1%), joint swelling (3.0%), headache (6.1%), 
hypoesthesia (24.2%), paresthesia (12.1%), nasal congestion (3.0%), and oropharyngeal pain 
(3.0%). 
In the placebo group, the TEAEs reported with an incidence ≥2% were anemia (3.9%), 
constipation (16.9%), feeling cold (3.9%), local swelling (2.4%), pyrexia (18.8%), procedural 
hypotension (2.9%), mobility decreased (2.4%), headache (3.4%), urinary retention (2.9%), and 
pruritus (15.9%). 
There were 17 TEAEs (anemia, bradycardia, sinus tachycardia, constipation, diarrhea, feeling 
cold, injection site erythema, pyrexia, postoperative wound infection, procedural hypotension, 
back pain, cluster headache, hypoesthesia, paresthesia, urinary retention, and pruritus) that 
occurred at an incidence of ≥5% in the EXPAREL 266 mg group where the incidence was 
greater in the EXPAREL group than in the placebo group. 
Please refer to the Investigator’s Brochure for additional information regarding the completed 
studies. 
 
7.5. 
Postmarketing 
As of June 2016, more than 2 million patients have received EXPAREL in the postmarketing 
setting. 


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8. 
OBJECTIVES 
8.1. 
Primary Objectives 
The primary objective of this study is to evaluate the magnitude and duration of the analgesic 
effect achieved following single-dose injection brachial plexus block with EXPAREL in subjects 
undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair. 
 
8.2. 
Secondary Objectives 
The secondary objectives of this study are to assess the efficacy, safety, and PK profiles of 
EXPAREL, as well as the onset and duration of sensory and motor function blockade, following 
administration for analgesia in subjects undergoing primary unilateral total shoulder arthroplasty 
or rotator cuff repair. 


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9. 
STUDY DESIGN AND PLAN 
9.1. 
Study Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in 
approximately 120 adult subjects undergoing primary unilateral total shoulder arthroplasty or 
rotator cuff repair with general anesthesia. 
Subjects will be screened within 30 days prior to study drug administration. During the 
screening visit, which must take place at least 1 day prior to surgery, subjects will be assessed for 
past or present neurologic, cardiac, and general medical conditions that in the opinion of the 
Investigator would preclude them from study participation. After the ICF is signed, the patient’s 
eligibility for participating in the study will be confirmed and demographic and baseline 
characteristics will be recorded.  A medical history, surgical history, neurological assessment, 
sensory and motor function assessments, physical examination, 12-lead electrocardiogram 
(ECG), vital sign measurements, urine drug screen, blood alcohol test, clinical laboratory tests 
(hematology, chemistry, and urinalysis), and urine pregnancy test for women of childbearing 
potential will be conducted. 
On Day 0, eligible subjects will be randomized in a 1:1 ratio to receive a single dose of 
EXPAREL 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total 
volume of 20 mL or placebo 20 mL.  Subjects may receive acetaminophen/paracetamol 1000 mg 
PO or IV every 8 hours (q8h) (maximum total daily dose of 3000 mg) prior to surgery. 
Study drug (EXPAREL or placebo) will be administered in a blinded manner via an ultrasound 
guided single-dose brachial plexus block at least 1 hour prior to surgery.  A confirmatory photo 
of the ultrasound nerve block needle placement will be taken. The type of brachial plexus block 
(i.e., interscalene or supraclavicular) will be documented. The use of opioids (other than 
ultrashort-acting opioids [i.e., fentanyl, sufentanil, or remifentanil]), acetaminophen/paracetamol, 
ketorolac, or other NSAIDs, and local anesthetics other than the study drug will not be permitted 
intraoperatively, except for emergency use to treat an AE. 
Subjects will be required to remain at the hospital facility through 72 hours. 
Postsurgical Rescue Medication 
Subjects should only receive rescue medication upon request for pain control, as needed. 
Postsurgical rescue medication will consist of PO immediate-release oxycodone (initiating at 5- 
10 mg every 4 hours [q4h] or as needed [PRN]).  If a subject cannot tolerate PO medication, 
IV morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) may be administered q4h or PRN. 
Patient-controlled analgesia (PCA) is not permitted. Postsurgically, all subjects will receive 
acetaminophen/paracetamol up to 1000 mg PO or IV q8h unless contraindicated. The total daily 
dose of acetaminophen/paracetamol should not exceed 3000 mg. 
No other analgesic agents, including NSAIDs, are permitted through 72 hours. After 72 hours, 
the analgesic regimen may be adjusted for each subject individually as deemed appropriate by 
the physician responsible for the postsurgical care. 


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Postsurgical Assessments 
Postsurgical assessments will include pain intensity scores using a 10-cm visual analog scale 
(VAS; see Appendix 1); total postsurgical opioid consumption; overall benefit of analgesia score 
(OBAS) questionnaire (see Appendix 2); subject satisfaction with overall analgesia using a 
5-point Likert scale (see Appendix 3); neurological assessment (see Appendix 4); sensory 
function assessment (as measured by cold, pinprick, and light touch testing; see Appendix 5); 
degree of motor nerve block (biceps, wrist, and thumb movement; see Appendix 6); discharge 
readiness (see Appendix 7); unscheduled phone calls or office visits related to pain; 12-lead 
ECGs; vital sign measurements; and clinical laboratory tests (hematology, chemistry, and 
urinalysis; see Appendix 8). At timepoints when multiple assessments coincide, the pain 
intensity assessment will be conducted first and the blood draw for PK analysis will be 
conducted second, as applicable. 
Adverse events will be recorded from the time the ICF is signed through postsurgical Day 29. 
If a cardiac or neurological AE of special interest (AESI), fall or SAE occurs during the study, an 
unscheduled PK blood sample must be collected.  In addition, a 12-lead ECG, vital signs, and 
any appropriate clinical laboratory tests must be conducted.  If conducted, the ECG must be read 
within 2 hours. Cardiac AESIs include chest pain (angina, myocardial infarction), abnormal/ 
irregular heart rate (bradycardia, tachycardia, extrasystoles), and shortness of breath requiring 
intervention.  Neurologic AESIs include altered mental status/altered sensorium, rigidity, 
dysarthria, seizure, tremors, metallic taste, tinnitus, perioral numbness, visual disturbance, severe 
or worsening dizziness, and any dizziness beyond 72 hours postdose.  Additionally, the 
following events are of special interest if they persist or occur beyond 72-hours postdose: 
hyperesthesia, muscular twitching, and tingling/paresthesia. 
Follow-up visits will be scheduled for all subjects on postsurgical Days 5 and 10. A follow-up 
phone call will be made on postsurgical Day 29 to all subjects who received study drug to assess 
for AEs. 
Pharmacokinetic Assessment 
A population PK analysis will be utilized to limit the number of blood draws. A total of 7 PK 
samples will be collected from each subject for this study. All subjects will have PK samples 
taken at baseline and upon arrival at the PACU. An additional 5 blood samples will be collected 
at the assigned time windows, spanning from 12 hours postdose to hospital discharge. There are 
two PK collection sequences for this study and a subject can only be randomized to one 
sequence. The PK schedule sequence will be indicated for each subject at the time of 
randomization and will also be noted on the randomization confirmation. 
Subjects in Sequence 
1 will have samples taken at 12, 24, 40, 52, and 72 hours.  Subjects in Sequence 2 will have 
samples taken at 24, 36, 48, and 60 hours, and at hospital discharge. 
Blood samples for PK analysis may be drawn using a properly maintained indwelling cannula 
(PICC line) at the discretion of the Investigator.  Blood samples will be collected from all 
subjects to maintain the treatment double-blind.  Blood samples from the subjects randomized to 
placebo will be analyzed through the 24-hour timepoint. 


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Interim PK Analysis 
A blinded interim PK analysis was completed after 13 subjects completed the assessments 
through postsurgical Day 10. All of the plasma samples from the subjects who received 
EXPAREL were analyzed and the plasma samples from the subjects randomized to placebo were 
analyzed through the 24-hour timepoint. Enrollment continued while the interim PK data were 
analyzed.  The goal of this blinded analysis was to determine the appropriateness of the PK 
timepoints selected and make recommendations to keep, remove, or revise them in order to fully 
characterize the PK profile. 
The results of this analysis showed a median Tmax of 48 hours for the 133 mg EXPAREL group 
and a median Tmax of 60 hours for the 266 mg EXPAREL group. These data informed the 
changes to the PK collection schedule contained in this protocol amendment. 
In addition, the safety assessment timepoints, including the neurological exam, vital signs, and 
ECG were adjusted based on the initial interim PK data; a confirmatory blinded PK interim 
analysis will be conducted once 30 subjects have completed the assessments through postsurgical 
Day 10. 
Duration of the Study and Subject Participation 
Participation will begin at the signing of the ICF.  No more than 30 days should pass between 
signing of the ICF and the administration of EXPAREL. The time from study drug 
administration through the end of participation is 30 ± 3 days.  Therefore, subjects may 
participate in the study for up to 63 days. 
Study Stopping Rules 
If Pacira, the investigator, or officials from regulatory authorities discover conditions during the 
study that indicate that the study or study site should be terminated, this action may be taken 
after Pacira has consulted with appropriate regulatory authorities and notified the Investigator(s). 
Blinded Data Review (BDR) of the subject data will be conducted by an independent Safety 
Monitor Committee after the first 30 subjects have completed Day 29 and subsequently after 
every 30 subjects have completed Day 29. The independent Safety Monitors will communicate 
their review findings to the Pacira Medical Management and Biostatistics team and records will 
be maintained. 
The outcome of the BDR process may trigger the Safety Stopping Rules based on the incidence 
rate of serious or severe AE based on the following rules: 
• Incidence rate of severe or serious AESIs as defined by the protocol including cardiac 
AESIs and neurologic AESIs exceeding 5% and in at least 5 subjects 
• Incidence rate of severe dizziness exceeding 10% and in at least 5 subjects 
• Incidence rate of severe or SAEs regardless of relationship to study drug exceeding 20% 
and in at least 10 subjects 
The study will be halted and an unblinded review of the data and a relative risk data analysis will 
occur if the study stopping rule is triggered. If the relative risk is greater than 2, the next step will 
be one of the following actions: 
• Permanently stop the study 


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• Revise eligibility criteria to exclude subjects who appear to be at higher risk for a 
particular AE. 
In addition to the study stopping rules described above, any death will be thoroughly reviewed 
and appropriate action taken 
 
9.2. 
Discussion of Study Design 
EXPAREL is approved for infiltration into a surgical site. This Phase 3, multicenter, 
randomized, double-blind, placebo-controlled study is designed to evaluate the efficacy, safety, 
and PK of brachial plexus block with EXPAREL for postsurgical analgesia in subjects 
undergoing total shoulder arthroplasty or rotator cuff repair. The double-blind study design is 
intended to avoid potential bias resulting from subject or Investigator knowledge of the assigned 
treatment. 
In the femoral nerve block study 402-C-323, following a blinded review of the initial plasma 
samples from 13 subjects who received the 266 mg dose of EXPAREL, it was apparent that in 
some subjects the last plasma sample collected contained the highest bupivacaine concentration, 
and that it could not be definitively determined whether their Tmax occurred prior to 72 hours, 
at 72 hours, or later.  Therefore, in the current study, the PK sampling period was extended 
through postsurgical Day 10 with more frequent PK blood draws scheduled between 60-84 hours 
for the first 13 subjects.  An interim assessment of the PK data from these subjects was then 
conducted and the protocol amended to revise the PK and safety assessment timepoints.  A 
confirmatory blinded PK interim analysis will be conducted once 30 subjects have completed the 
assessments through postsurgical Day 10. 
EXPAREL was developed in nerve block as an analgesic and not an anesthetic.  It does not 
produce a dense, consistent sensory blockade as would be required for anesthesia; this is 
reflected in the current package insert.  There is no expectation of a complete or sustained block. 
As there is no single universally clinically accepted validated outcomes instrument for motor 
testing, several motor tests of the muscles impacted by the nerve block will be undertaken. All 
subjects are required to have a Lovett score of 5 (normal) to be enrolled in the study. Onset of 
loss of motor function is the first timepoint after baseline at which the Lovett scale decreases to 
below a 3 in at least one of the motor function assessments (biceps, wrist, and thumb movement). 
Onset of return of motor function is the first timepoint after study drug administration where any 
of the motor function assessments increases to return to a 3 or above on the Lovett scale. The 
motor function assessment will be conducted at baseline (on Day 0 prior to the nerve block); 
approximately every 15 minutes before the subject goes to the operating room (OR); prior to 
discharge from the PACU; and at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours. 
Similarly, there is no universally clinically accepted validated outcomes instrument for sensory 
testing. Prior experience with EXPAREL (study 402-C-203) utilized warm threshold, cool 
threshold, and vibratory sensation as well as pinprick testing.  In the current study, the subject’s 
sensitivity to cold, pinprick, and light touch in the distal part of innervated dermatomes 
(musculocutaneous, median, ulnar, radial, and axillary) will be assessed with their eyes closed at 
baseline (on Day 0 prior to the nerve block); approximately every 15 minutes before the subject 
goes to the OR; prior to discharge from the PACU; and at 6, 9, 12, 18, 24, 36, 48, 60, and 72 
hours. 


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If a subject has a motor or sensory deficit at 72 hours, they will be further evaluated on 
postsurgical Day 5.  If on postsurgical Day 5 there continues to be a motor or sensory deficit, the 
deficit will be recorded as an AE.  The motor or sensory function will be further assessed on 
postsurgical Day 10.  If the a sensory deficit persists, or the Lovett Score is less than 5 on 
postsurgical Day 5, a physician must evaluate the subject to rule out other etiologies for 
persistent sensory and motor deficits, and the subject is to return for unscheduled visit(s) at the 
Investigator's discretion through postsurgical Day 29 or until the motor or sensory function has 
returned to baseline, whichever occurs first. 
All subjects will receive an opioid analgesic(s) as needed to control breakthrough postsurgical 
pain.  In addition, all subjects will receive acetaminophen/paracetamol up to 1000 mg PO or IV 
q8h unless contraindicated.  The total daily dose of acetaminophen/paracetamol should not 
exceed 3000 mg. 
If a cardiac or neurological AESI, fall, or SAE occurs during the study, an unscheduled PK blood 
sample should be collected.  In addition, a 12-lead ECG, vital signs, and any appropriate clinical 
laboratory tests should be conducted.  Cardiac AESIs include chest pain (angina, myocardial 
infarction), abnormal/irregular heart rate (bradycardia, tachycardia, extrasystoles), and shortness 
of breath requiring intervention. Neurologic AESIs include altered mental status/altered 
sensorium, rigidity, dysarthria, seizure, tremors, metallic taste, tinnitus, perioral numbness, visual 
disturbance, severe or worsening dizziness, and dizziness beyond 72 hours postdose. 
Additionally, the following events are of special interest if they persist or occur beyond 72-hours 
postdose: hyperesthesia, muscular twitching, and tingling/paresthesia. 


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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, at least 18 years of age at screening. 
2. Scheduled to undergo primary unilateral total shoulder arthroplasty or rotator cuff repair. 
3. Subjects scheduled for rotator cuff repair must have a magnetic resonance imaging (MRI) 
with a reading confirming a tear of at least 1 cm. 
4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3. 
5. Female subject must be surgically sterile; or at least 2 years postmenopausal; or have a 
monogamous partner who is surgically sterile; or practicing double-barrier contraception; or 
practicing abstinence (must agree to use double-barrier contraception in the event of sexual 
activity); or using an insertable, injectable, transdermal, or combination oral contraceptive 
approved by the FDA for greater than 2 months prior to screening and commit to the use of 
an acceptable form of birth control for the duration of the study and for 30 days after 
completion of the study. 
6. Able to demonstrate normal motor function (by obtaining a 5 on the Lovett Scale when 
exhibiting biceps, wrist, and thumb movement) and sensory function (by exhibiting 
sensitivity to cold, pinprick, and light touch) in the location where sensory function will be 
measured throughout the study: 2 cm superior to the coracoid process on the skin overlying 
the acromioclavicular joint. 
7. 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. Currently pregnant, nursing, or planning to become pregnant during the study or within 
1 month after study drug administration. 
2. Planned concurrent surgical procedure. 
3. Concurrent painful physical condition that may require analgesic treatment (such as an 
NSAID or opioid) in the postsurgical period for pain that is not strictly related to the shoulder 
surgery and which may confound the postsurgical assessments (e.g., significant pain from 
other joints, chronic neuropathic pain). 
4. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics. 
5. Smoking history of greater than 25 pack-years. 
6. Contraindication to any of the following: bupivacaine, oxycodone, morphine, or 
hydromorphine. 


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7. Use of any of the following medications within the times specified before surgery: long- 
acting opioid medications or NSAIDs (except for low-dose aspirin used for cardioprotection) 
within 3 days, or any opioid medication within 24 hours. 
8. 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. 
9. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study. 
10. Use of dexmedetomidine HCl (Precedex®) within 3 days of study drug administration. 
11. History of impaired kidney function, emphysema or other chronic respiratory disease, 
rheumatoid arthritis, coagulopathy, or loss of sensation in extremities. 
12. Impaired kidney function (e.g., serum creatinine level >2 mg/dL [176.8 µmol/L] or blood 
urea nitrogen level >50 mg/dL [17.9 mmol/L]) or impaired liver function (e.g., serum 
aspartate aminotransferase [AST] level >3 times the upper limit of normal (ULN) or serum 
alanine aminotransferase [ALT] level >3 times the ULN. 
13. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study 
assessments. 
14. Any chronic neuromuscular deficit effecting the peripheral nerves or muscles of the surgical 
extremity. 
15. Any chronic condition or disease that would compromise neurological or vascular 
assessments. 
16. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous 
cell carcinoma of the skin or localized carcinoma in situ of the cervix. 
17. Suspected or known history of drug or alcohol abuse within the previous year. 
18. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2. 
19. Previous participation in an EXPAREL study. 
20. 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. 


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10.3.1. 
Withdrawal Secondary to Adverse Events 
If a subject experiences an AE that renders him or her incapable of continuing with the  
remaining study assessments, then he or 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 or 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), sensory function, motor function, and any changes in the subject's health status 
will be recorded. 
After termination from the study, the subject may be followed for safety including monitoring of 
AEs through postsurgical Day 29. 


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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 expanded in volume with 10 mL 
of normal saline to achieve a total volume of 20 mL, or placebo 20 mL according to the 
randomization schedule.  Study drug administration will be performed in a blinded manner (see 
Section 11.5.1). 
Postsurgical Rescue Medication 
Subjects should only receive rescue medication upon request for pain control, as needed. 
Postsurgical rescue medication will consist of PO immediate-release oxycodone (initiating at 5- 
10 mg q4h or PRN).  If a subject cannot tolerate PO medication, IV morphine (2.5-5 mg) or 
hydromorphone (0.5-1 mg) may be administered q4h or PRN. PCA is not permitted. 
Postsurgically, all subjects will receive acetaminophen/paracetamol up to 1000 mg PO or IV q8h 
unless contraindicated.  The total daily dose of acetaminophen/paracetamol should not exceed 
3000 mg.  No other analgesic agents, including NSAIDs, are permitted through 72 hours. After 
72 hours, the analgesic regimen may be adjusted for each subject individually as deemed 
appropriate by the physician responsible for the postsurgical care.  All analgesic use must be 
recorded through postsurgical Day 29. 
 
11.1.1. 
Administration Technique 
Study drug (EXPAREL or placebo) will be administered under ultrasound guidance by the 
anesthesiologist into the brachial plexus as described below. A confirmatory photo of the 
ultrasound nerve block needle placement will be taken. 
The 10-13 MHz transducer is initially placed over the external jugular vein to visualize the 
brachial plexus, approximately 3 cm above the clavicle. Alternatively, the anesthesiologist may 
start at the supraclavicular fossa and scan cephalad.  Once the brachial plexus roots/trunks are 
clearly visualized with an ultrasound probe (an ideal view would include C5, C6, and C7 
between the anterior scalene muscle and the middle scalene muscle), a blunt tip block needle will 
be advanced in an "in plane" approach from posterior to anterior towards the superior portion of 
the brachial plexus at the level of a standard interscalene block (ideally within the interscalene 
space, inside the sheath – i.e., within the interscalene groove, and adjacent to the brachial plexus 
via in plane ultrasound guidance in order to visualize the entire needle). Once the needle is 
clearly seen approximated by the neural bundle, an injection of study drug will be deposited so 
as to surround the middle to superior portion of the plexus.  If the study drug does not 
immediately spread as desired, the needle will be repositioned during the procedure to ensure 
proper administration of study drug around the middle to superior portion of the plexus. Final 
probe, needle path, endpoints for needle target, and type of block needle are all at the discretion 
of the anesthesia team. 


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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. 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 for injection.  Subjects in the placebo group will receive 
20 mL of normal saline. 
 
11.2.3. 
Description of Diluents 
Normal saline for injection will be added to the 133 mg (10 mL) dose of EXPAREL to achieve a 
total volume of 20 mL. 
 
11.3. 
Method of Assigning Subjects to Treatment 
11.3.1. 
Randomization Scheme 
Approximately 120 subjects (50 subjects randomized to EXPAREL 133 mg, 50 subjects 
randomized to placebo, and any subjects enrolled under the original protocol and randomized to 
EXPAREL 266 mg) are planned for enrollment.  Subjects will be randomized in a 1:1 ratio to 
receive a single-dose injection brachial plexus block with EXPAREL 133 mg or placebo. 
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 unblinded 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. 


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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. 
 
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. EXPAREL 266 mg, the FDA-approved marketed dose, 
was chosen for the nerve block.  In an effort to ensure that the minimal effective dose is chosen, 
the study initially examined two doses levels of EXPAREL (133 mg and 266 mg), each 
compared to placebo.  After completion of the first PK interim analysis conducted after 13 
subjects completed Day 10, a single dose of 133 mg was selected for the remainder of the 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 and administer the study drug. Staff members conducting 
study-specific, postsurgical assessments and the subjects will remain blinded to the assigned 
treatment throughout the study.  If a subject experiences an SAE, Pacira will not automatically 
unblind the subject’s treatment, unless it is necessary to manage treatment of the SAE. 
Expedited SAEs will be unblinded by Pacira for regulatory reporting purposes. 
At each site, only the designated unblinded pharmacist will receive unblinded randomization 
assignments and be responsible for preparing study drug. 
Assignment of blinded and unblinded responsibilities regarding the preparation of study drug 
should take into account that EXPAREL must be administered within 4 hours of opening 
the vial. 
The individuals preparing and administering 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. 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 (see                 
Pharmacy Manual for additional details). 
No crossover will be permitted between the blinded and unblinded study site personnel during 
the study period. The assignment of site monitors will also be segregated.  Blinded monitors will 
review case report forms (CRFs), clinic charts, and all other study-related documents that do not 
disclose the allocation of study treatment.  Care should be taken in recording and review of OR 


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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 within the interactive response technology (IRT) system used for 
randomization.  The reason for unblinding will be documented. Any accidental unblinding 
events (i.e., through mishaps in the OR 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 
All medications taken within 30 days prior to study drug administration through 72 hours after 
study drug administration or until the subject is withdrawn from the study, whichever is sooner, 
will be recorded on the CRF.  All analgesic use must be recorded through postsurgical Day 29. 
Additionally, any medications administered in association with an AE will be recorded through 
postsurgical Day 29. 
 
11.6.1. 
Before Study Drug Administration 
Permitted Prior Medications and Therapy 
• Low-dose aspirin for cardioprotection. 
• Acetaminophen/paracetamol up to 1000 mg PO or IV q8h (maximum total daily dose of 
3000 mg) is permitted. 
• 1-2 mg of midazolam (Versed) pre-op 
Restricted Prior Medications and Therapy 
• Systemic glucocorticosteroids are prohibited within 1 month of enrollment in this study. 
• 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. 


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• Long-acting opioid medications and NSAIDs (except for low-dose aspirin used for 
cardioprotection) are not permitted within 3 days of study drug administration. 
• Dexmedetomidine HCl (Precedex) use is not permitted within 3 days of study drug 
administration. 
• No opioid medications are permitted within 24 hours of study drug administration. 
• Use of an investigational product within 30 days or 5 elimination half-lives of such 
investigational drug, whichever is longer, prior to study drug administration, or planned 
administration of another investigational product or procedure during the subject’s 
participation in this study is not permitted. 
 
11.6.2. 
During Surgery 
Permitted 
• Ultra-short acting opioids (i.e., fentanyl, sufentanil, or remifentanil) will be permitted 
during surgery. 
• Single-dose administration of ondansetron or metoclopramide may be used intra- 
operatively for nausea/vomiting prevention.  If not available or contraindicated, a single 
dose of dexamethasone 10 mg IV may be administered. 
Restricted 
• No drugs are to be admixed with study drug (e.g., epinephrine, dexamethasone, 
clonidine). 
• Lidocaine and other local anesthetics will not be permitted to be locally administered 
during surgery because they are known to interact with EXPAREL resulting in the 
displacement of bupivacaine and elevated plasma levels. 
• The use of long-acting opioids (e.g., morphine, hydromorphone HCl), acetaminophen/ 
paracetamol, ketorolac, or other NSAIDs will not be permitted intraoperatively except for 
emergency use to treat an AE. 
 
11.6.3. 
After Surgery 
Permitted 
• The permitted rescue medication is oxycodone (initiating at 5-10 mg q4h or PRN).  If a 
subject cannot tolerate PO medication, IV morphine (2.5-5 mg) or hydromorphone 
(0.5-1 mg) may be administered q4h or PRN. 
Post surgically, all subjects will receive the following scheduled medications until hospital 
discharge: 
• Cyclobenzaprine (eg, Flexeril®) 10 mg PO x1 dose (PRN at surgeon discretion) 
• Acetaminophen/paracetamol up to 1000 mg PO or IV q8h unless contraindicated. The 
total daily dose of acetaminophen/paracetamol should not exceed 3000 mg. 


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Restricted 
• No other analgesics, including fentanyl, are permitted within 72 hours after study drug 
administration. 
• PCA is not permitted. 
• Dexmedetomidine HCl (Precedex) use is prohibited. 
• Anesthetics in the "caine" family, which may interfere with the bupivacaine PK profile, 
are prohibited through postsurgical Day 10. 
For study purposes, it is important to standardize pain management modalities during the first 
72 hours following study drug administration. Therefore, the study staff must adhere closely to 
the treatment options and requirements noted in the protocol. After 72 hours, the analgesic 
regimen may be adjusted for each subject individually, as deemed appropriate by the physician 
responsible for the postsurgical care. 
All postsurgical analgesics administered must be documented through postsurgical Day 29. 
 
11.7. 
Treatment Compliance 
Not applicable, since study drug (EXPAREL or placebo) will be administered preoperatively by 
the study staff. 
 
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 assessed at the times specified after the beginning 
of the brachial plexus block with study drug: 
• 
Pain intensity scores using the VAS at predose (on Day 0 prior to the nerve block and 
prior to any premedication); upon arrival at the PACU, every 15 minutes while in the 
PACU, and prior to PACU discharge; at 6, 12, 24, 36, 48, 60, and 72 hours; and 
immediately prior to each administration of rescue pain medication through 72 hours (see 
Appendix 1). 
• 
Date, time of administration, and amount of all opioid rescue medication taken through 
72 hours. 
• 
The OBAS questionnaire at 24 and 72 hours, and on postsurgical Day 10 (see 
Appendix 2). 
• 
Subject satisfaction with overall analgesia (using a 5-point Likert scale) at 24 and 
72 hours, and on postsurgical Day 10 (see Appendix 3). 
• 
Discharge readiness at 12, 24, 36, 48, 60, and 72 hours or when the subject is considered 
to be discharge ready, whichever occurs first (see Appendix 7). 
• 
Unscheduled phone calls or office visits related to pain after discharge through 
postsurgical Day 10. 
 
12.2. 
Efficacy Endpoints 
The efficacy endpoints listed below will be assessed based on the efficacy measurements 
conducted at the times specified after the beginning of the brachial plexus block with study drug. 
Primary Endpoint: 
The primary endpoint is the AUC of the VAS pain intensity scores through 48 hours. 
Secondary Endpoints: 
The following secondary endpoints will be analyzed in the following order: 
1. Total postsurgical opioid consumption (in IV morphine equivalents) through 48 hours. 
2. Percentage of opioid-free subjects through 48 hours. 
3. Time to first opioid rescue through 48 hours. 
Tertiary Endpoints: 
• 
The AUC of the VAS pain intensity scores through 12, 24, and 72 hours. 
• 
The AUC of the VAS pain intensity scores from 24-48 hours and 48-72 hours. 
• 
VAS pain intensity scores at each assessed timepoint. 


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• 
Proportion of subjects who are pain free (defined as a VAS pain intensity score of ≤1.5 
without prior rescue medication use) at each assessed timepoint. 
• 
Sum of the pain intensity scores (SPIS) through 24, 48, and 72 hours. 
• 
SPIS from 24-48 and 48-72 hours. 
• 
Total opioid consumption in IV morphine equivalents through 24 and 72 hours. 
• 
Total opioid consumption in IV morphine equivalents from 24-48 hours and 48-72 hours. 
• 
Percentage of opioid-free subjects through 24 and 72 hours. 
• 
The OBAS total score at 24 and 72 hours, and postsurgical Day 10. 
• 
Subject satisfaction with overall analgesia (using a 5-point Likert scale) at 24 and 
72 hours, and on postsurgical Day 10. 
• 
Proportion of subjects meeting MPADSS criteria for discharge readiness at 12, 24, 36, 
48, 60, and 72 hours. 
• 
Number of unscheduled phone calls or office visits related to pain after discharge through 
postsurgical Day 10. 
 
12.3. 
Pharmacokinetic Analysis 
A population PK analysis will be utilized to limit the number of blood draws. A total of 7 PK 
samples will be collected from each subject for this study. All subjects will have PK samples 
taken at baseline and upon arrival at the PACU. An additional 5 blood samples will be collected 
at the assigned time windows, spanning from 12 hours postdose to just prior to discharge. There 
are two PK collection sequences for this study and a subject can only be randomized to one 
sequence.  The PK schedule sequence will be indicated for each subject at the time of 
randomization and will also be noted on the randomization confirmation. Subjects in Sequence 1 
will have samples taken at 12, 24, 40, 52, and 72 hours. Subjects in Sequence 2 will have 
samples taken at 24, 36, 48, and 60 hours, and at hospital discharge. 
Blood samples for PK analysis may be drawn using a properly maintained indwelling cannula 
(PICC line) at the discretion of the Investigator.  Blood samples will be collected from all 
subjects to maintain the treatment double-blind.  Blood samples from the subjects randomized to 
placebo will be analyzed through the 24-hour timepoint. 
 
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-versus-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-versus-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: AUC0-∞ = Ctlast/ λz. 


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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-versus- 
time curve. 
t1/2el 
The apparent terminal elimination half-life calculated as 0.693/λz. 
12.5. 
Safety Assessments 
The following safety assessments will be conducted at the times specified after the beginning of 
the brachial plexus block with study drug: 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis) at baseline (on Day 0 
prior to the nerve block) and on postsurgical Day 10. 
• 
Vital signs (resting heart rate and blood pressure) at baseline (on Day 0 prior to the nerve 
block); every 5 minutes during performance of the block up to 30 minutes; and every 15 
minutes until entering the OR; at PACU arrival; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, 
and 72 hours; and on postsurgical Days 5 and 10. 
• 
12-lead ECG recordings at baseline (on Day 0 prior to the nerve block); upon arrival at 
the PACU; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; and on postsurgical 
Days 5 and 10. Note: ECGs must be read within 2 hours. 
• 
Neurological assessment at baseline (on Day 0 prior to the nerve block); upon arrival at 
the PACU; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; and on postsurgical 
Days 5 and 10 (see Appendix 4). 
• 
Sensory function assessment (as measured by cold, pinprick, and light touch testing) at 
baseline (on Day 0 prior to the nerve block); at approximately 15, 30, and 45 minutes 
after the nerve block; prior to discharge from the PACU; at 6, 9, 12, 18, 24, 36, 48, 60, 
and 72 hours (see Appendix 5). If sensory deficit is present at 72 hours, the subject will 
be assessed on postsurgical Day 5. If on postsurgical Day 5 there is a sensory deficit, the 
sensory deficit will be recorded as an AE and the physician will assess the subject for 
other etiologies that may explain the persistent sensory deficit.  If there continues to be a 
sensory function deficit on Day 5, the sensory function will be further assessed on 
postsurgical Day 10.  If the sensory deficit persists on postsurgical Day 10, the subject is 
to return for unscheduled visit(s) at the Investigator's discretion through postsurgical Day 
29 or until the sensory function has returned to baseline, whichever occurs first. 
• 
Motor nerve function assessment (biceps, wrist, and thumb movement) at baseline (on 
Day 0 prior to the nerve block); at approximately 15, 30, and 45 minutes after the nerve 
block; prior to discharge from the PACU; at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours 
(see Appendix 6). If motor function deficit (Lovett score below 5) is present at 72 
hours, the subject will be assessed again on postsurgical Day 5. If on postsurgical Day 5 
there is a motor deficit, ie, the subject’s Lovett score has not returned to 5, the motor 
deficit will be recorded as an AE and the physician will assess the subject for other 


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etiologies that may explain the persistent motor deficit.  If there continues to be a motor 
function deficit on Day 5, the motor assessment will be further assessed on postsurgical 
Day 10.  If the motor deficit persists on postsurgical Day 10, the subject is to return for 
unscheduled visit(s) at the Investigator's discretion through postsurgical Day 29 or until 
the motor function has returned to a Lovett score of 5, whichever occurs first. 
• Adverse events from the time the ICF is signed through postsurgical Day 29. 
 
12.6. 
Safety Endpoints 
The following safety endpoints will be assessed based on the safety measurements conducted at 
the specified timepoints: 
• 
Change from baseline in clinical laboratory data at each assessed timepoint. 
• 
Change from baseline in vital sign data (resting heart rate and blood pressure) at each 
assessed timepoint. 
• 
Change from baseline in ECG data at each assessed timepoint. 
• 
Summary of neurological assessments (proportion of subjects who are oriented, and 
proportion of subjects who have any of the neurologic events). 
• 
Cold sensation at each assessed timepoint. 
• 
Pinprick sensation at each assessed timepoint. 
• 
Light touch sensation at each assessed timepoint. 
• 
Change from baseline in motor function (biceps, wrist, and thumb movement) at each 
assessed timepoint. 
• 
Incidence of TEAEs and SAEs through postsurgical Day 29. 
 
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. Measurements were further refined in this study based on 
previous nerve block experience with EXPAREL including the Phase 2/3 femoral nerve block 
study 402-C-323 in TKA and feedback from the FDA. 


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13. 
STUDY PROCEDURES 
A time and events schedule for all study procedures is provided in Table 1, Table 2, and Table 3. 
 
13.1. 
Instructions for Conducting Procedures and Measures 
All safety, efficacy, and PK assessments conducted after baseline will be timed from the 
beginning of the brachial plexus block with study drug. 
At timepoints when multiple assessments coincide, the pain intensity assessment will be 
conducted first and the blood draw for PK analysis will be conducted second, as applicable. 
Day 0 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. 
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 Assessment 
Pain intensity will be assessed using a 10-cm VAS (Carlsson 1983, McCormack 1988, and 
Scott 1976) at baseline (on Day 0 prior to the nerve block and prior to any premedication); upon 
arrival at the PACU; every 15 minutes while in the PACU, and prior to PACU discharge; at 6, 
12, 24, 36, 48, 60, and 72 hours; and immediately prior to each administration of rescue pain 
medication through 72 hours (see Appendix 1). 
 
13.1.2. 
Overall Benefit of Analgesia Score Questionnaire 
The OBAS questionnaire will be completed at 24 and 72 hours, and on postsurgical Day 10 
(see Appendix 2). 
 
13.1.3. 
Subject Satisfaction with Postsurgical Pain Control 
The subject’s satisfaction with postsurgical pain control will be assessed using the Likert Scale 
at 24 and 72 hours, and on postsurgical Day 10 (see Appendix 3). 
 
13.1.4. 
Neurological Assessment 
A neurological assessment will be conducted at screening; baseline (on Day 0 prior to the nerve 
block); upon arrival at the PACU; at 6, 9, 12, 24, 36, 40, 44. 48, 52, 56, 60, and 72 hours; and on 
postsurgical Days 5 and 10. The examination 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; vision problems; hearing 
problems; or muscle twitching (see Appendix 4). If the subject answers "yes" to any of these 
questions, the event should be recorded as an AE and additional safety procedures should be 
conducted (see Section 13.1.11). 


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13.1.5. 
Sensory Function Assessment 
Sensory function (as measured by cold, pinprick, and light touch testing) will be assessed at 
screening; baseline (on Day 0 prior to the nerve block); approximately every 15 minutes before 
the subject goes to the OR; prior to discharge from the PACU; at 6, 9, 12, 18, 24, 36, 48, 60, and 
72 hours (see Appendix 5).  If sensory deficit is present at 72 hours, the subject will be assessed 
on day 5. If on postsurgical Day 5 there is a sensory deficit, the sensory deficit will be recorded 
as an AE and the physician will assess the subject for other etiologies that may explain the 
persistent sensory deficit.  If there continues to be a sensory function deficit on Day 5, the sensory 
function will be further assessed on postsurgical Day 10.  If the sensory deficit persists on 
postsurgical Day 10, the subject is to return for unscheduled visit(s) at the Investigator's 
discretion through postsurgical Day 29 or until the sensory function has returned to baseline, 
whichever occurs first. 
The assessors will be deemed to be qualified if the following three conditions are met: 
1. They are a licensed medical professionals (physician, nurse, physical therapist, etc), 
2. They have prior experience completing the assessment being conducted or have similar 
and applicable experience, 
3. They have participated  and completed the 327 protocol specific training on the study 
assessment through either one of the following: 
a. Participation at the Investigator Meeting 
OR 
b. Completed the Pacira Pharmaceuticals ComplianceWire Training (the study 
specific Learning Management System) including review of the slide deck and 
training videos. 
 
13.1.6. 
Motor Nerve Block Assessment 
The motor nerve block assessment (i.e., biceps, wrist, and thumb movement) (Marashi 2015) will 
be assessed at screening; baseline (on Day 0 prior to the nerve block); approximately every 
15 minutes before the subject goes to the OR; prior to discharge from the PACU; at 6, 9, 12, 18, 
24, 36, 48, 60, and 72 hours (see Appendix 6).  If motor function deficit (Lovett score below 5) is 
present at 72 hours, the subject will be assessed again on day 5. If on postsurgical Day 5 there is 
a motor deficit, ie, the subject’s Lovett score has not returned to 5, the motor deficit will be 
recorded as an AE and the physician will assess the subject for other etiologies that may explain 
the persistent motor deficit.  If there continues to be a motor function deficit on Day 5, the motor 
assessment will be further assessed on postsurgical Day 10.  If the motor deficit persists on 
postsurgical Day 10, the subject is to return for unscheduled visit(s) at the Investigator's 
discretion through postsurgical Day 29 or until the motor function has returned to a Lovett score 
of 5, whichever occurs first. 
The assessors will be deemed to be qualified if the following three conditions are met: 
1. They are licensed medical professionals (physician, nurse, physical therapist, etc.), 


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2. They have prior experience completing the assessment being conducted or have similar 
and applicable experience, 
3. They have participated  and completed the 327 protocol specific training on the study 
assessment through either one of the following: 
a. Participation at the Investigator Meeting 
OR 
b. Completed the Pacira Pharmaceuticals ComplianceWire Training (the study 
specific Learning Management System) including review of the slide deck and 
training videos. 
 
13.1.7. 
Clinical Laboratory Tests 
A urine drug screen and blood alcohol test will be conducted at screening, and a urine drug 
screen and alcohol breath test will be conducted at baseline (on Day 0 prior to the nerve block). 
The scheduled clinical laboratory tests (hematology, chemistry, and urinalysis) will be conducted 
at screening; baseline (on Day 0 prior to the nerve block); and on postsurgical Day 10. Clinical 
laboratory tests, as appropriate, may also be conducted if a subject experiences an AESI 
(i.e., cardiac AE or neurological AE), fall, or an SAE (see Section 13.1.11). 
 
13.1.8. 
Vital Signs 
The scheduled vital signs (heart rate and blood pressure) will be measured after the subject has 
rested in a supine position for at least 5 minutes at screening; baseline (on Day 0 prior to the 
nerve block); every 5 minutes during the performance of the nerve block and up to 30 minutes 
after completion of the block and then every 15 minutes until entering the OR; upon arrival at the 
PACU; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; and on postsurgical Days 5 and 
10. Vital signs will also be measured if a subject experiences a cardiac or neurological AESI, 
fall, or an SAE (see Section 13.1.11). The subject will remain in a supine position during the 
assessment. 
 
13.1.9. 
Physical Examination 
A full physical examination will be conducted at screening. Superficial abnormalities that may 
interfere with participation in the study will be noted. A targeted physical examination will be 
conducted on postsurgical Day 10 and will include examination of the upper extremity including 
the site of the brachial plexus block and the shoulder itself. 
 
13.1.10. 
Electrocardiograms 
The scheduled 12-lead ECGs will be conducted after the subject has rested in a supine position 
for at least 5 minutes at screening; baseline (on Day 0 prior to the nerve block); upon arrival at 
the PACU; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; and on postsurgical Days 5 
and 10.  A 12-lead ECG will also be conducted if a subject experiences an AESI (i.e., cardiac AE 
or neurological AE), fall, or an SAE (see Section 13.1.11).  If conducted, the ECG must be read 
within 2 hours. 


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13.1.11. 
Adverse Events of Special Interest 
If a cardiac AE or neurological AESI, fall, or SAE occurs during the study, an unscheduled PK 
blood sample should be collected.  In addition, a 12-lead ECG, vital signs, and any appropriate 
clinical laboratory tests should be conducted.  If conducted, the ECG must be read within 2 
hours. 
Cardiac AESIs include: 
• 
Chest pain (angina, myocardial infarction) 
• 
Abnormal/irregular heart rate (bradycardia, tachycardia, extrasystoles) 
• 
Shortness of breath requiring intervention. 
Neurologic AESIs include: 
• 
Altered mental status/altered sensorium 
• 
Rigidity 
• 
Dysarthria 
• 
Seizure 
• 
Tremors 
• 
Metallic taste 
• 
Tinnitus 
• 
Perioral numbness 
• 
Visual disturbance 
• 
Severe or worsening dizziness 
• 
Dizziness beyond 72 hours postdose 
Additionally, the following events are of special interest if they persist or occur beyond 72-hours 
postdose: 
• 
Hyperesthesia 
• 
Muscular twitching 
• 
Tingling/paresthesia 
 
13.2. 
Screening Procedures 
• 
Explain study purpose and procedures. 
• 
Obtain signed ICF. 
• 
Assess eligibility. 
• 
Record relevant medical/surgical history, demographics, and baseline characteristics. 
• 
Conduct urine pregnancy test for women of childbearing potential. 
• 
Perform physical examination. 


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• 
Conduct urine drug screen and blood alcohol test. 
• 
Conduct clinical laboratory tests (hematology, chemistry, and urinalysis) (see 
Appendix 8). 
• 
Perform neurological assessment (see Appendix 4). 
• 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position. 
• 
Conduct 12-lead ECG after subject has rested in a supine position. ECG must be read 
within 2 hours. 
• 
Perform sensory function assessment (see Appendix 5). 
• 
Conduct motor function assessment (see Appendix 6). 
• 
Record concomitant medications. 
• 
Record AEs starting at signing of the ICF. 
 
13.3. 
Baseline Procedures (Day 0 - Prior to Study Drug Administration) 
• 
Confirm eligibility. 
• 
Update relevant medical and surgical history. 
• 
Conduct urine pregnancy test for women of childbearing potential. 
• 
Conduct urine drug screen and alcohol breath test. 
• 
Record baseline VAS pain intensity score prior to any premedication (see Appendix 1). 
• 
Collect baseline blood sample for PK analysis. 
• 
Perform neurological assessment (see Appendix 4). 
• 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position. 
• 
Conduct 12-lead ECG after subject has rested in a supine position. ECG must be read 
within 2 hours. 
• 
Perform sensory function assessment (see Appendix 5). 
• 
Conduct motor function assessment (see Appendix 6). 
• 
Conduct clinical laboratory tests (hematology, chemistry, and urinalysis; see 
Appendix 8). 
• 
Randomize subject and prepare study drug. 
• 
Record changes to concomitant medications since screening. 
• 
Record AEs and any treatment(s) for the events. 


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13.4. 
Baseline Procedures (Time 0) 
• 
Administer blinded study drug via brachial plexus block at least 1 hour prior to surgery. 
• 
Measure vital signs (resting heart rate and blood pressure) every 5 minutes during 
performance of the block 
• 
Record start and stop times of study drug administration. 
• 
Take confirmatory photo of the ultrasound nerve block needle placement. 
• 
Record type of brachial plexus block (i.e., interscalene or supraclavicular). 
• 
Record concomitant medications. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.5. 
Approximately 15, 30, and 45 Minutes After Beginning of Study 
Drug Administration 
• 
Perform sensory function assessment (see Appendix 5). 
• 
Conduct motor function assessment (see Appendix 6). 
• 
Measure vital signs (resting heart rate and blood pressure) every 15 minutes until entering 
the OR 
• 
Record concomitant medications. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.6. 
Intraoperative Procedures 
• 
Record intraoperative opioids administered and doses. 
• 
Record start and stop times of surgery. 
• 
Record concomitant medications. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.7. 
Upon Arrival at the Post-Anesthesia Care Unit 
• 
Record VAS pain intensity score (see Appendix 1) upon arrival at the PACU, and then 
every 15 minutes until PACU discharge. 
• 
Collect scheduled PK blood sample; record date and time. 
• 
Perform neurological assessment (see Appendix 4). 


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• 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position. 
• 
Conduct 12-lead ECG after subject has rested in a supine position. ECG must be read 
within 2 hours 
• 
Administer rescue medication upon request, as needed (see Section 11.1). 
• 
Record times and doses of all opioid and non-opioid rescue medication administered. 
• 
Record other concomitant medications. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.8. 
Prior to PACU Discharge 
• 
Record VAS pain intensity score (see Appendix 1) 
• 
Assess sensory function (see Appendix 5). 
• 
Assess motor function (see Appendix 6). 
• 
Record other concomitant medications. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.9. 
Postsurgical Assessments through Hour 72 
• 
Record VAS pain intensity score at 6, 12, 24, 36, 48, 60, and 72 hours; and immediately 
prior to each administration of rescue pain medication (see Appendix 1). 
• 
Collect scheduled blood samples for PK analysis per sequence schedule; record the date 
and time each sample is collected. 
o PK Sequence Schedule 1: Blood collected at 12 (±30 min) hrs, 24 (±1) hrs, 40 
(±1) hrs, 52 (±2) hrs, and 72 (±2) hrs. 
o PK Sequence Schedule 2: Blood collected at 24 (±1) hrs, 36 (±1) hrs, 48 (±1) 
hrs, and 60 (±2) hrs. 
• 
Perform neurological assessment at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours 
(see Appendix 4). 
• 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours. 
• 
Conduct 12-lead ECG after subject has rested in a supine position at 6, 9, 12, 24, 36, 40, 
44, 48, 52, 56, 60, and 72 hours. 
• 
Perform sensory function assessment at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours 
(see Appendix 5). 


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• 
Conduct motor function assessment at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours (see 
Appendix 6). 
• 
Complete OBAS questionnaire at 24 and 72 hours (see Appendix 2). 
• 
Obtain overall rating of subject satisfaction with postsurgical pain control using the 
Likert scale at 24 and 72 hours (see Appendix 3). 
• 
Administer rescue medication upon request, as needed (see Section 11.1). 
• 
Record date, time, and amount of all opioid and non-opioid rescue medication 
administered. 
• 
Record other concomitant medications. 
• 
Assess discharge readiness at 12, 24, 36, 48, 60, and 72 hours, or when subject is 
determined to be discharge ready, whichever occurs first (see Appendix 7). 
• 
Record date and time of discharge. 
• 
Document any unscheduled phone calls or office visits related to pain after discharge. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.10. 
Hospital Discharge 
• 
Collect blood samples for PK analysis for subjects in Sequence Schedule 2. 
• 
Record date and time of discharge. 
 
13.11. 
Postsurgical Day 5 Visit 
• 
Perform neurological assessment (see Appendix 4). 
• 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position. 
• 
Conduct 12-lead ECG after the subject has rested in a supine position. ECG must be read 
within 2 hours. 
• 
If sensory deficit was present at 72 hours, perform sensory function assessment 
(see Appendix 5).  If deficit persists, it should be recorded as an AE and the physician 
will assess the subject for other etiologies that may explain the persistent deficit. 
• 
If motor function deficit was present at 72 hours, perform motor function assessment 
(see Appendix 6).  If deficit persists, it should be recorded as an AE and the physician 
will assess the subject for other etiologies that may explain the persistent deficit. 
• 
Document any unscheduled phone calls or office visits related to pain after discharge. 
• 
Record concomitant medications including all analgesic medication administered. 
• 
Record AEs and any treatment(s) for the events. 


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• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.12. 
Postsurgical Day 10 Visit 
• 
Perform neurological assessment (see Appendix 4). 
• 
Measure vital signs (heart rate and blood pressure) after subject has rested in a supine 
position. 
• 
Conduct 12-lead ECG after the subject has rested in a supine position. ECG must be read 
within 2 hours. 
• 
Conduct targeted physical examination. 
• 
Complete OBAS questionnaire (see Appendix 2). 
• 
Obtain overall rating of subject satisfaction with postsurgical pain control using the 
Likert scale (see Appendix 3). 
• 
If on postsurgical Day 5 there was a sensory deficit, reassess sensory function 
(see Appendix 5). 
• 
If on postsurgical Day 5 there was a motor deficit, reassess motor function 
(see Appendix 6). 
• 
Conduct clinical laboratory tests (hematology, chemistry, and urinalysis; 
see Appendix 8). 
• 
Document any unscheduled phone calls or office visits related to pain after discharge. 
• 
Record concomitant medications including all analgesic medication administered. 
• 
Record AEs and any treatment(s) for the events. 
• 
Refer to Section 13.1.11 for additional procedures in the event a cardiac AE, neurological 
AE, fall, or SAE occurs. 
 
13.13. 
Unscheduled Visit(s) 
• 
If a sensory or motor function deficit persists on postsurgical Day 10, the subject is to 
return for unscheduled visit(s) at the Investigator's discretion through postsurgical Day 29 
or until the sensory or motor function has returned to baseline, (see Appendix 5 and 
Appendix 6, respectively) whichever occurs first. 
• 
Record concomitant medications including all analgesic medication administered. 
• 
Record AEs and any treatment(s) for the events. 
 
13.14. 
Postsurgical Day 29 Phone Call 
• 
Record concomitant medications including all analgesic medication administered. 
• 
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 FDA CFR Part 312 and the 
ICH GCP, AEs and SAEs are defined in Section 14.1.1 and Section 14.2.1, respectively. 
The concepts of AEs and SAEs represent regulatory instruments used to evaluate and monitor 
the safety of clinical study subjects.  Therefore, these terms only apply in light of their regulatory 
definition.  The term serious, in a regulatory sense, does not necessarily mean severe. The SAE 
concept is used primarily to identify, during the conduct of the study, those SAEs that may 
require expedited reporting to regulatory authorities. 
 
14.1. 
Adverse Events 
14.1.1. 
Definitions 
Definition of Adverse Event: Any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.  An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment about 
causality.  An AE can arise from any use of the drug (e.g., off-label use in combination with 
another drug) and from any route of administration, formulation, or dose, including an overdose. 
An AE can be any unfavorable and unintended change in a body structure or body function. 
Adverse events include any clinically significant deterioration of a subject’s medical status. 
The AE may involve any organ or system and can be represented by the new onset or 
deterioration of a disease, a syndrome, a symptom, a physical sign, as well as by findings and 
results of instrumental examinations and laboratory tests.  Any medically relevant and untoward 
change after the subject signs the ICF, including frequency or pattern changes for a fluctuating 
condition (e.g., migraine) is considered an AE. 
An AE that occurs after the 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.  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 
postsurgical Day 29 must be recorded regardless of whether or not they are considered related to 
study drug.  Whenever feasible, AE terms must be documented as medical diagnoses (highest 


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possible level of integration); otherwise, the AEs must be reported separately as individual signs 
or symptoms.  Only one AE per line should be recorded in the AE CRF; for example, an AE of 
nausea and vomiting would be listed as two separate events: the event of nausea and the event of 
vomiting.  If a diagnosis is established after symptoms are recorded on the AE CRF, 
the diagnosis must be recorded and the symptoms collapsed (removed; i.e., lined through and 
initialed).  Whenever possible, abnormal laboratory results must be reported as their clinical 
corollary (e.g., low potassium should be recorded as hypokalemia). 
A continuous AE with varying grades of severity must be recorded as one AE. The highest 
grade of severity experienced by that subject during the course of the continuous AE must be 
recorded. 
Any condition noted before the subject signs the ICF will be listed as Medical History and is 
considered a pre-existing condition.  If a pre-existing condition changes (i.e., becomes more 
severe or more frequent) at any time after the ICF is signed, or after study drug administration, 
it is considered an AE.  Note: A change in treatment for a pre-existing condition (e.g., new high 
blood pressure medication), does not necessarily indicate an AE. 
Information recorded on the AE CRF will include the AE term, the date and time of onset, 
severity, seriousness, relationship to study drug, action taken with subject due to AE, and the 
outcome of the AE, including the date and time of resolution, if applicable. 
 
14.1.3. 
Severity of Adverse Events 
The severity of an AE must be categorized using the following guidelines: 
Mild: 
An AE that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate: 
An AE that is discomforting and interferes with normal everyday 
activities. 
Severe: 
An AE that prevents normal everyday activities. 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); however, the event itself, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
 
14.1.4. 
Relationship of Adverse Events to Study Drug 
The Investigator must assess the relationship of the AE to study drug after careful medical 
consideration on a case-by-case basis.  General guidelines are provided below. 
Unrelated: 
A causal relationship between the study drug and the AE can be 
easily ruled out (e.g., based on the temporal sequence, absence of a 
reasonable pathophysiological mechanism, or direct evidence of 
actual cause). 


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Unlikely: 
A clinical event with a temporal relationship to study drug 
administration which makes a causal relationship improbable and in 
which other drugs, chemicals, or underlying disease provide a 
plausible explanation; 
Possible: 
A clinical event with a reasonable time sequence to administration 
of the study drug but which could also be explained by a concurrent 
disease or other drugs or chemicals; 
Probable: 
A clinical event with a reasonable time sequence to administration 
of the study drug unlikely to be attributed to a concurrent disease or 
other drugs or chemicals and which follows a clinically reasonable 
response on withdrawal (dechallenge); 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. 


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• 
Non-pharmaceutical therapy.  (The specific therapy used must be recorded in the 
CRF.) 
• 
Discontinued from study. 
• 
Other.  (The specific action taken must be recorded.) 
 
14.2. 
Serious Adverse Events 
14.2.1. 
Definition of a Serious Adverse Event 
Definition of a SAE: An AE is considered “serious” if, in the view of either the Investigator or 
Pacira, it results in any of the following outcomes: 
• 
Death1. 
• 
A life-threatening AE2. 
• 
Inpatient hospitalization or prolongation of existing hospitalization3. 
• 
A persistent or significant incapacity4. 
• 
Congenital anomaly/birth 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 must make every effort to obtain and document the cause of death for all subjects 
who die during the study.  If, despite all efforts, the cause of death remains unknown, the AE 
must be documented as an “unspecified fatal event.” 
2Life-threatening: An AE is considered life-threatening if, in the view of either the Investigator 
or Pacira, its occurrence places the subject at immediate risk of death. It does not include an AE 
that had it occurred in a more severe form might have caused death. 
3Hospitalization: It should be noted that hospitalization, in and of itself, does not represent an 
SAE.  It is the AE leading to the subject’s hospitalization that becomes “serious” when it 
requires inpatient care.  Consequently, an SAE must not be reported in case of preplanned 
hospitalizations for a pre-existing condition that did not worsen during the study.  However, 
any medical condition that delays a subject’s discharge from the hospital (i.e., prolonged 
hospitalization) or requires the subject to be readmitted must be reported as an SAE. 
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. 


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14.2.2. 
Reporting Serious Adverse Events 
Any SAE or death that occurs at any time after the subject signs the ICF through postsurgical 
Day 29, 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 
(973-201-0649).  In addition, the Investigator or designee is encouraged to contact the Medical 
Monitor to discuss the case, as needed. 
Investigators should not wait to receive additional information to fully document the event before 
notifying Pacira Drug Safety or designee of the SAE.  The fax or email report must be     
followed by a full written summary using the SAE Form detailing relevant aspects of the SAE in 
question.  Where applicable, information from relevant hospital records and autopsy reports must 
be obtained and all 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 postsurgical Day 29, these must also be 
reported to Pacira Drug Safety or designee provided the SAE is considered related to EXPAREL. 
The site would then provide a completed SAE form within 1 business day and the event would 
be followed until resolution, or until adequate stabilization is met. 


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15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be developed for this study. 
 
15.1. 
Study Hypothesis 
The primary null hypothesis is: 
H0: The mean of the AUC of the VAS pain intensity scores through 48 hours is not different 
between the EXPAREL and placebo groups. 
The alternative hypothesis is: 
HA: The mean AUC of the VAS 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 
The sample size was calculated based on efficacy as measured by the AUC of the NRS-R pain 
intensity scores through 72 hours from a previously conducted nerve block study. Assuming a 
2-sided 0.05 alpha and a common SD of 170 and controlling alpha for the two efficacy 
comparisons, a sample size of 50 subjects per treatment group should have at least 80% power to 
detect a 100-unit treatment difference. 
 
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. 
 
15.5. 
Handling Subject Dropouts and Discontinuations 
For the calculation of the AUC of VAS 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. 


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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 VAS pain intensity scores through 
48 hours. 
For the AUC of the VAS pain intensity scores through 48 hours, EXPAREL will be compared to 
placebo using analysis of variance (ANOVA) with treatment and site as main effects. A two- 
sided test will be performed comparing EXPAREL to placebo, at the two-sided 5% significance 
level. Based on the model, the difference between treatment groups will be estimated along with 
the 2-sided 95% confidence intervals (CIs). 
Handling of Subjects Requiring Rescue Medication 
For AUC of the VAS pain intensity scores, prior to analysis the windowed Worst-Observation- 
Carried-Forward (wWOCF) imputation method will be applied. For subjects who take rescue 
pain medication, their pain intensity scores recorded within the window of controlled type of 
rescue medication will be replaced by the ‘worst’ observation.  All pain scores within that 
window 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 pain intensity scores in the window that are higher than the worst 
value prior to rescue pain medication will not be overwritten.  If no pain intensity score is 
available prior to the first rescue pain medication, the worst observation from all available 
measurements will be used instead. 
 
15.6.3.2 
Secondary Efficacy Measures 
See significance testing in Section 15.7 for an explanation of the statistical approach for 
secondary efficacy measures. 
Total postsurgical opioid consumption through 48 hours will be converted to IV morphine 
equivalents and analyzed using the same ANOVA model as the primary endpoint. 
Percentage of opioid-free subjects through 48 hours will be analyzed using a Cochran-Mantel- 
Haenszel (CMH) test stratified by site. 
Time to first opioid rescue through 48 hours will be analyzed by the Kaplan-Meier method and 
the Gehan-Wilcoxon test. 


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15.6.3.2 
Tertiary Efficacy Measures 
Statistical testing will not be performed on any of the tertiary endpoints. 
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. 
Summary statistics for each measure will be shown at each timepoint by treatment group. 
Categorical Measures of Efficacy 
For categorizing subjects as pain-free, the VAS pain intensity score must be ≤1.5 without prior 
rescue medication use at the assessed timepoint. 
The proportion of subjects in each category will be calculated and summarized at each timepoint 
by treatment group. 
Time to Event Measures 
The time from start of study drug administration to event will be summarized with Kaplan-Meier 
estimates. 
 
15.6.4. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters will be estimated using a population PK approach. 
 
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 PTs 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 
PT. 
 
15.6.5.2. 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. 
 
15.6.5.3. Clinical Laboratory Data 
Descriptive statistics for each laboratory test for baseline, each timepoint, and change from 
baseline at each timepoint will be summarized for each treatment group. 


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15.6.5.4. 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. 
 
15.6.5.5. Neurological Assessment 
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. 
 
15.7. 
Significance Testing 
EXPAREL will be compared with placebo using ANOVA with treatment and site as the main 
effects for the primary efficacy endpoint of AUC of the VAS pain intensity scores through 
48 hours.  A hierarchical procedure will be used to provide control of the type 1 error across the 
four key null hypotheses, i.e., for the null hypotheses corresponding to the primary treatment 
group comparison (EXPAREL 133 mg treatment group versus placebo) in combination with 
each of the three secondary endpoints of greatest interest. Efficacy endpoints may be analyzed 
using ANOVA, chi-square tests, and Gehan-Wilcoxon tests, as appropriate. 
 
15.8. 
Interim Pharmacokinetic Analysis 
A blinded interim PK analysis was completed after 13 subjects completed the assessments 
through postsurgical Day 10.  All of the plasma samples from the subjects who received 
EXPAREL were analyzed, including the samples from subjects who had discontinued from the 
study or who had missing samples. Enrollment continued while the interim PK data were 
analyzed.  The goal of this unblinded analysis was to determine the appropriateness of the PK 
timepoints selected and make recommendations to keep, remove, or revise them in order to fully 
characterize the PK profile. 
The results of this analysis showed a median Tmax of 48 hours for the 133 mg EXPAREL group 
and a median Tmax of 60 hours for the 266 mg EXPAREL group. These data informed the 
changes to the PK collection schedule contained in this protocol amendment. 
In addition, the safety assessment timepoints, including the neurological exam, vital signs, and 
ECG were adjusted based on the initial interim PK data; a confirmatory blinded PK interim 
analysis will be conducted once 30 subjects have completed the assessments through postsurgical 
Day 10. 
 
15.8.1. 
Sample Size Reestimation Interim Analysis 
An interim analysis will be performed after 66 subjects have completed the assessments through 
Day 5.  The objective of the interim analysis is to verify the assumptions for the study sample 
size.  The verification of sample size assumptions will be based on the “quick and simple” 
procedure described by Kieser (2000) to estimate the pooled sample variance; all other 
assumptions used for the original sample size estimate will remain constant. No adjustment to 
the study significance level will be made to complete this interim analysis (Keiser 
2000). The interim analysis and verification of the sample size will be performed by a blinded 
biostatistician not involved in the conduct of the study. The statistician performing the interim 
analysis will communicate any change in sample size resulting from the interim analysis; all 


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other interim analyses and results will be embargoed until after database lock. Results from the 
interim assessment of sample size will be included as an appendix in the clinical study report. 
Pacira will be informed after completion of the assessment of the study sample size that either (a) 
the sample size will remain the same, no adjustments are to be made, or (b) the sample size will 
be increased to the determined study sample size up to a maximum of 200. Note that the only 
adjustment to the sample size allowed by this interim assessment is an increase.  The study 
sample size will not be reduced, and no comparative evaluation of efficacy to evaluate either 
superiority or futility will be completed as part of this interim assessment. 


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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. 
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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. 
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Apseloff G, Onel E, Patou G.  Time to onset of analgesia following local infiltration of liposome 
bupivacaine in healthy volunteers: a randomized, single-blind, sequential cohort, crossover 
study.  Int J Clin Pharmacol Ther.  2013;51:367−373. 
Beecroft CL, Coventry DM.  Anaesthesia for shoulder surgery. Continuing Education in 
Anaesthesia, Critical Care & Pain.  2008;8(6):193−198. 
Bigley GK. “Sensation,” Chapter 67 in Walker HK, Hall WD, Hurst JW (eds). Clinical methods: 
The history, physical and laboratory examinations, 3rd edition, Butterworths 1990. 
Bretz, F., Maurer, W., Brannath, W., and Posch M., A graphical approach to sequentially rejective 
multiple test procedures, Statistics in Medicine, 2009;28: 586-604. 
Bretz F, Posch M, Glimm E, et al. Graphical approaches for multiple comparison procedures 
using weighted Bonferroni, Simes, or parametric tests. Biom J. 2011;53(6): 894–913. 
Carlsson AM.  Assessment of Chronic Pain.  I.  Aspects of the Reliability and Validity of the 
Visual Analogue Scale.  Pain.  1983;16:87−101. 
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. 
Chung F.  Discharge criteria – A new trend. Can J Anesth. 1995;42:1056−1058. 
Chung F, Chan VW, Ong D. A post-anesthetic discharge scoring system for home readiness 
after ambulatory surgery.  J Clin Anesth.  1995;7(6):500−506. 
EXPAREL Full Prescribing Information, December 2015.  
EXPAREL Investigator’s Brochure, Edition 17.1, 08 December 2015. 
Florence JM, Pandya S, King WM, et al.  Intrarater reliability of manual muscle test (Medical 
Research Council scale) grades in Duchenne’s muscular dystrophy. Phys Ther. 
1992;72(2):115−122. 
Hu D, Onel E, Singla N, et al.  Pharmacokinetic profile of liposome bupivacaine injection 
following a single administration at the surgical site.  Clin Drug Investig.  2013;33:109−115. 


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Kieser M, Friede T. Blinded sample size reestimation in multiarmed clinical trials. Drug Inf J. 
2000;34:455–460. 
Lehmann N, Joshi GP, Dirkmann D, et al.  Development and longitudinal validation of the 
overall benefit of analgesia score: a simple multi-dimensional quality assessment instrument. 
Br J Anasth.  2010;105(4):511−518.  Epub 2010 Aug 6. 
Liu X, Zhao X, Lou J, et al.  Parecoxib added to ropivacaine prolongs duration of axillary 
brachial plexus blockade and relieves postoperative pain. Clin Orthop Relat Res. 
2013;471(2):562−568. 
Marashi SM, Sharifnia HR, Azimaraghi O, et al.  Naloxone added to bupivacaine or 
bupivacaine–fentanyl prolongs motor and sensory block during supraclavicular brachial plexus 
blockade: A randomized clinical trial.  Acta Anaesthesiol Scand.  2015;59(7):921−927. 
McCormack HM, DJ Horne, Sheather S. Clinical applications of visual analogue scales: 
A critical review. Psychol Med. 1988;18(4):1007−1019. 
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. 
Paternostro-Sluga T, Grim-Stieger M, Posch M, et al.  Reliability and validity of the Medical 
Research Council (MRC) scale and a modified scale for testing muscle strength in patients with 
radial palsy.  J Rehabil Med.  2008;40(8):665−671. 
Scott J, Huskinsson EC. Graphic representation of pain.  Pain.  1976;2(2):175−184. 
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. 


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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 
Pacira and/or the investigational product(s).  Consequently, I agree to disclose all 
such significant financial information to Pacira and to update this information 
promptly if any relevant changes occur during the course of the study through 1 year 
following completion of the study.  I also agree that any information regarding my 
significant financial interest related to Pacira and/or the investigational product(s) 
will be disclosed to the regulatory authorities by Pacira. 
 
 
Signature of Investigator 
Date 


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18. 
APPENDICES 


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Appendix 1:  Subject’s Reported Pain Intensity 
Subjects will be evaluated for pain using a 10-cm VAS at baseline (on Day 0 prior to the nerve 
block and prior to any premedication); upon arrival at the PACU, every 15 minutes while in the 
PACU, and prior to PACU discharge; at 6, 12, 24, 36, 48, 60, and 72 hours; and immediately 
prior to each administration of rescue pain medication through 72 hours. 
Subjects will be asked, "How much pain are you experiencing right now?  Please place a vertical 
mark on the line below to indicate the level of pain you are experiencing right now." 
 
 
 
 
(For reference only; not for clinical use.) 


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Appendix 2: 
Overall Benefit of Analgesia Score (OBAS) Questionnaire 
The OBAS questionnaire will be completed at 24 and 72 hours, and on postsurgical Day 10 
(Lehmann 2010). 
 
 
1.   Please rate your current pain at rest on a scale between 
0 = minimal pain and 4 = maximum imaginable pain 
2.   Please grade any distress and bother from vomiting in the past 24 h 
(0 = not at all to 4 = very much) 
3.   Please grade any distress and bother from itching in the past 24 h 
(0 = not at all to 4 = very much) 
4.   Please grade any distress and bother from sweating in the past 24 h 
(0 = not at all to 4 = very much) 
5.   Please grade any distress and bother from freezing in the past 24 h 
(0 = not at all to 4 = very much) 
6.   Please grade any distress and bother from dizziness in the past 24 h 
(0 = not at all to 4 = very much) 
7.  How satisfied are you with your pain treatment during the past 24 h 
(0 = not at all to 4 = very much) 


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Appendix 3: 
Subject Satisfaction with Postsurgical Pain Control (Likert Scale) 
The subject’s satisfaction with postsurgical pain control will be assessed at 24 and 72 hours, 
and on postsurgical 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 4: 
Neurological Assessment 
The neurological assessment will be conducted at screening; baseline (on Day 0 prior to the 
nerve block); upon arrival at the PACU; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; 
and on postsurgical Days 5 and 10. 
 
 
The examination will include the subject's orientation. 
• Is the subject oriented? 
  Yes 
∆ No ∆ Not Assessable 
 
If the subject is not oriented, the event should be recorded as an AE. 
 
 
Additionally, the subject will be asked the following questions: 
 
• Since your last assessment have you had numbness of the lips, the tongue, or around the 
mouth?   Yes 
∆ No 
 
• Since your last assessment have you had a metallic taste in your mouth? 
  Yes 
∆ No 
 
• Since your last assessment, have you had problems with your hearing not related to the 
use of a hearing aid? 
∆ Yes 
∆ No 
 
• Since your last assessment, have you had problems with your vision not related to the use 
of eye glasses? 
∆ Yes 
∆ No 
 
• Since your last assessment, have your muscles been twitching? 
  Yes 
∆ No 
 
If the subject answers “yes” to any of these questions, the event should be recorded as an AE and 
additional safety procedures should be conducted (see Section 13.1.11). 


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Appendix 5: 
Sensory Function Assessment (Cold, Pinprick, and Light Touch Tests) 
For the sensory function assessment, the subject’s sensitivity to cold, pinprick, and light touch in 
the distal part of innervated dermatomes (musculocutaneous, median, ulnar, radial, and axillary; 
see diagrams below) will be assessed with their eyes closed at screening, baseline (on Day 0 
prior to the nerve block); at approximately 15, 30, and 45 minutes prior to the OR; prior to 
discharge from the PACU; at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours.  If sensory deficit is 
present at 72 hours, the subject will be assessed on day 5. If on postsurgical Day 5 there is a 
sensory deficit, the sensory deficit will be recorded as an AE and the physician will assess the 
subject for other etiologies that may explain the persistent sensory deficit. If there continues to be 
a sensory function deficit on Day 5, the sensory function will be further assessed on postsurgical 
Day 10.  If the sensory deficit persists on postsurgical Day 10, the subject is to return for 
unscheduled visit(s) at the Investigator's discretion through postsurgical Day 29 or until the 
sensory function has returned to baseline, whichever occurs first. 
The cold, pinprick, and light touch tests will be conducted, starting with the cold test, followed 
randomly by the pinprick and light touch tests interspaced with blunt touch.  Subjects will be 
given four choices for reporting their perception of the stimulus: “sharp,” “blunt,” “cold, “or 
“light touch.” The test may be repeated in case of ambiguous or inconsistent responses until the 
examiner is satisfied with the accuracy of the assessment. Only cold, pinprick, and light touch 
sensitivity will be assessed and recorded for study purposes. Blunt touch stimulation serves as a 
way to gauge the subject response and reduce the chance that the subject may guess the correct 
answer. 
Cold sensitivity will be tested by gently applying ice (Sakura 1998) to contact the skin spot in the 
distal part of dermatome for 3 seconds.  For the pinprick assessment, a disposable sharp-bevel 
needle will be used to prick the skin spot in the distal part of the dermatome using the point and 
guard in a random fashion. The subject should reply "sharp" or "dull" with eyes closed. Care is 
to be taken to prevent penetration of the dermis, and the sharp object used should be discarded 
after the test. Blunt touch with a cotton swab (e.g., Q-tip) will be conducted the same way. 
Testing for light touch will be done using a wisp of cotton pulled from a cotton ball. The 
assessments will be conducted single-blinded (i.e., the nature of the stimulus will be concealed 
from the subject) and the result will be defined as presence/absence of cold, pinprick, and light 
touch sensation. 
Instructions 
1. To prepare subjects for the cold, pinprick, and light touch tests, they should be placed in a 
comfortable position with their eyes closed. 
2. Before starting the assessments, all subjects should be well trained in all aspects of the 
testing.  It is critical that each subject knows precisely what to expect during the testing. 
3. Interactions between study subjects and Investigators should be limited to those 
necessary for collecting data. Joking and small talk should be discouraged because they 
may compromise data consistency. 
4. Keep the instructions clear, simple, and consistent.  Emphasize that pain is subjective, 
and there are no right or wrong answers.  It is most important to be consistent. 


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Appendix 6: 
Motor Function Assessment 
The degree of motor nerve block will be assessed at screening; baseline (on Day 0 prior to the 
nerve block); at approximately 15, 30, and 45 minutes prior to the OR; prior to discharge from 
the PACU; at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours .  If motor function deficit (Lovett score 
below 5) is present at 72 hours, the subject will be assessed again on Day 5. If on postsurgical 
Day 5 there is a motor deficit, ie, the subject’s Lovett score has not returned to 5, the motor 
deficit will be recorded as an AE and the physician will assess the subject for other etiologies 
that may explain the persistent motor deficit.  If there continues to be a motor function deficit on 
Day 5, the motor assessment will be further assessed on postsurgical Day 10.  If the motor deficit 
persists on postsurgical Day 10, the subject is to return for unscheduled visit(s) at the 
Investigator's discretion through postsurgical Day 29 or until the motor function has returned to a 
Lovett score of 5, whichever occurs first. 
The motor block will be evaluated by performing thumb abduction (radial nerve), thumb 
adduction (ulnar nerve), thumb opposition (median nerve), and elbow flexion in seated position 
(musculocutaneous nerve). 
Onset of loss of motor function is the first timepoint after baseline at which the Lovett scale 
(Florence 1992, Paternostro-Sluga 2008) decreases to below a 3 in at least one of the motor 
function assessments (biceps, wrist, and thumb movement).  Return of motor function is the first 
timepoint after loss of motor function where any of the motor function assessments return to a 
3 or above on the Lovett scale (Liu 2013). 
 
 
Lovett Scale for grading muscle strength and function level 
 
Functional Level 
Lovett Scale 
Grade 
Percentage of Normal 
No evidence of contractility 
Zero (Z) 
0 
0 
Evidence of slight contractility 
Trace (T) 
1 
10 
Complete range of motion without gravity 
Poor (P) 
2 
25 
Complete range of motion with gravity 
Fair (F) 
3 
50 
Complete range of motion against gravity 
with some resistance 
Good (G) 
4 
75 
Complete range of motion against gravity 
with full resistance 
Normal (N) 
5 
100 


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Appendix 7: 
Discharge Readiness 
The subject’s discharge readiness will be assessed at 12, 24, 36, 48, 60, and 72 hours until the 
subject is determined to be discharge ready, whichever occurs first, using the MPADSS shown 
below (Chung 1995a; Chung 1995b). This discharge readiness assessment will be used for data 
collection only and is not intended to interfere with the surgical center’s policy for determining 
when the subject should be discharged from the site. Only subjects who achieve a score of 9 or 
higher are considered ready for discharge. Discontinue assessing discharge readiness once a 
score of 9 or higher is reached. 
 
Modified Postanesthesia Discharge Scoring System (MPADSS) 
 
Parameter 
Score 
Vital Signs 
≤20% of preoperative value 
2 
20%-40% of preoperative value 
1 
>40% of preoperative value 
0 
Ambulation 
Steady gait/no dizziness 
2 
With assistance 
1 
None/dizziness 
0 
Nausea and Vomiting 
Minimal 
2 
Moderate 
1 
Severe 
0 
Pain 
Minimal 
2 
Moderate 
1 
Severe 
0 
Surgical Bleeding 
Minimal 
2 
Moderate 
1 
Severe 
0 


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Appendix 8: 
Clinical Laboratory Tests 
The scheduled clinical laboratory tests (hematology, chemistry, and urinalysis) will be conducted 
at screening; baseline (on Day 0 prior to the nerve block); and on postsurgical Day 10. 
 
Additionally, appropriate clinical laboratory tests should be conducted if a subject experiences an 
AESI (i.e., cardiac AE or neurological AE), fall, or an SAE (see Section 13.1.11). 
 
General Chemistry Analysis 
General Hematology (CBC with 
Differential) Components 
Urinalysis 
Albumin 
White blood cells 
Color 
Alkaline phosphatase 
Red blood cells 
Appearance 
Alanine transaminase (ALT) 
Hemoglobin 
Specific gravity 
Amylase 
Hematocrit 
pH 
Aspartate transaminase (AST) 
Mean corpuscular volume 
Protein 
Bilirubin, direct 
Mean corpuscular hemoglobin 
Glucose 
Bilirubin, total 
Mean corpuscular hemoglobin concentration 
Ketones 
Blood urea nitrogen 
Red cell distribution width 
Bilirubin 
Calcium 
Platelets 
Blood 
Carbon dioxide (bicarbonate) 
Mean platelet volume 
Urobilinogen 
Chloride 
Absolute/percent neutrophil count 
Nitrite 
Cholesterol 
Absolute/percent lymphocyte count 
Leukocyte esterase 
Creatine kinase (CK), total 
(or creatine phosphokinase [CPK]) 
Absolute/percent monocyte count 
Creatinine, serum 
Absolute/percent eosinophil count 
Gamma-glutamyl transpeptidase 
(GGT) 
Absolute/percent basophil count 
Glucose 
Iron 
Iron binding capacity 
(UIBC/TIBC) 
Lactate dehydrogenase (LDH) 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Transferrin 
Triglycerides 
Uric acid 
 

SAP_000.pdf: 
 
Document No. <  > 
 
 
CONFIDENTIAL 
i of i 
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STATISTICAL ANALYSIS PLAN 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of Brachial Plexus Block with EXPAREL for 
Postsurgical Analgesia in Subjects Undergoing Total Shoulder Arthroplasty or Rotator 
Cuff Repair 
 
 
 
 
Protocol No.: 402-C-327 
IND No.: 69,198  
Study Phase: 3 
Study Drug: EXPAREL (bupivacaine liposome injectable 
suspension) 
Date/Version: 26 June 2017/ Version 1.0  
Prepared by: Richard Willey, M.S. 
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 
 
Document No. <  > 
 
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2. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE 
2 
2. 
TABLE OF CONTENTS 
3 
3. 
LIST OF ABBREVIATIONS 
5 
4. 
INTRODUCTION 
6 
5. 
STUDY OBJECTIVES 
7 
5.1. 
Primary Objective 
7 
5.2. 
Secondary Objectives 
7 
6. 
STUDY OVERVIEW 
8 
7. 
DEFINITIONS 
10 
8. 
ANALYSIS SETS 
13 
9. 
STATISTICAL METHODS OF ANALYSIS 
14 
9.1. 
General Principles 
14 
9.1.1. 
Handling Missing Values 
16 
9.1.1.1. 
Area under the VAS-Time Curve 
16 
9.1.1.2. 
Exposure, Surgery, and Rescue Medication Date or Time 
17 
9.1.1.3. 
Rescue Pain Medication 
17 
9.1.1.4. 
Adverse Event or Concomitant Medications Dates or Times 
17 
9.1.1.5. 
Adverse Event Severity or Relationship to Study Drug 
18 
9.1.1.6. 
Time to Event 
18 
9.1.2. 
Multiplicity Adjustments 
18 
9.1.3. 
By-Center Analyses 
18 
9.2. 
Subject Disposition 
18 
9.3. 
Description of Demographics and Baseline Characteristics 
19 
9.3.1. 
Demographics 
19 
9.3.2. 
Baseline Characteristics 
20 
9.4. 
Surgery Characteristics 
20 
9.5. 
Intraoperative, Prior, and Concomitant Medications 
20 
9.6. 
Measurements of Treatment Compliance 
21 
9.7. 
Efficacy Analysis 
21 
9.7.1. 
Efficacy Endpoints 
21 
9.7.1.1. 
Primary Efficacy 
21 
9.7.1.2. 
Secondary Efficacy 
21 
9.7.1.3. 
Tertiary Efficacy 
22 
9.7.1.4. 
Area under the Curve 
22 


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9.7.1.5. 
Opioid Consumption 
22 
9.7.1.6. 
Time to First Opioid Rescue Medication Use 
23 
9.7.1.7. 
Pain-free 
23 
9.7.1.8. 
Overall Benefit of Analgesia Score (OBAS) 
23 
9.7.2. 
Methods of Analysis 
23 
9.7.2.1. 
Primary Efficacy Analysis 
24 
9.7.2.2. 
Secondary Efficacy Analyses 
24 
9.7.2.3. 
Tertiary Efficacy Analyses 
25 
9.8. 
Safety Analyses 
28 
9.8.1. 
Vital Signs 
28 
9.8.2. 
Electrocardiograms 
28 
9.8.3. 
Neurological Assessments 
29 
9.8.4. 
Sensation Tests 
29 
9.8.5. 
Degree of motor nerve block Assessments 
30 
9.8.6. 
Adverse Events 
30 
9.8.7. 
Laboratory Parameters 
32 
9.9. 
Pharmacokinetic Analysis 
32 
9.10. 
Interim Analysis 
33 
9.10.1. 
Pharmacokinetic Review 
33 
9.10.2. 
Sample Size Review 
33 
9.11. 
Significance Testing 
34 
10. 
SAMPLE SIZE CALCULATIONS 
35 
11. 
REFERENCES 
36 
12. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
37 
13. 
MULTIPLE IMPUTATION EXAMPLE PROGRAM CODE 
38 
14. 
TABLE OF CONTENTS FOR TABLE MOCK-UPS 
40 
15. 
TABLE OF CONTENTS FOR LISTING MOCK-UPS 
127 
16. 
TABLE OF CONTENTS FOR FIGURE MOCK-UPS 
162 


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3. 
LIST OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ATC 
Anatomical therapeutic class 
AUC 
Area under the curve 
BLOQ 
Below the limit of quantification 
BMI 
Body mass index 
bpm 
Beats per minute 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CSR 
Clinical study report 
d 
Day 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FNB 
Femoral nerve block 
hr, h 
hour 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IV 
Intravenous 
LOCF 
Last observation carried forward 
LS 
Least square 
MedDRA 
Medical dictionary for regulatory affairs 
MPADSS 
Modified Postanesthesia Discharge Scoring System 
min 
minutes 
MED mg 
Morphine equivalent dose in mg 
n 
Number of subjects 
OBAS 
Overall benefit of analgesia 
OR 
Operating room 
PACU 
Postanesthesia care unit 
PCA 
Patient-controlled analgesia 
PK 
Pharmacokinetics 
PO 
Oral 
ROW 
Rest of world 
RCR 
Rotator cuff repair 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SPI 
Sum of pain intensity scores 
TEAE 
Treatment-emergent adverse event 
TLF 
Table, listings and figures 
TSA 
Total shoulder arthroplasty 
VAS 
Visual analog scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
wWOCF 
Windowed worst observation carried forward 
 


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4. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting of 
the clinical study 402-C-327 titled “A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of Brachial Plexus 
Block with EXPAREL for Postsurgical Analgesia in Subjects Undergoing Total Shoulder 
Arthroplasty or Rotator Cuff Repair”. This study is intended to evaluate the magnitude and 
duration of the analgesic effect of a single-dose injection brachial plexus block with EXPAREL 
in subjects undergoing primary unilateral total shoulder arthroplasty (TSA) or rotator cuff repair 
(RCR). 
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 reports (CSRs), 
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 were reviewed in preparation of this SAP: 
 
Amendment 1 of Protocol 402-C-327 issued on 15Feb2016. 
 
Amendment 2 of Protocol 402-C-327 issued on 17Nov2016. 
 
Original Protocol 402-C-327 issued on24Nov2015. 
 
CRF version 1.0 issued on 04Dec2015.  
 
ICH Guidance on Statistical Principles for Clinical Trials (E9). 
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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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective  
The primary objective of this study is to evaluate the magnitude and duration of the analgesic 
effect achieved following single-dose injection brachial plexus block with EXPAREL in subjects 
undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair. 
5.2. 
Secondary Objectives 
The secondary objectives of this study are to assess the efficacy, safety, and pharmacokinetic 
(PK) profiles of EXPAREL, as well as the onset and duration of sensory and motor function 
blockade, following administration for analgesia in subjects undergoing primary unilateral total 
shoulder arthroplasty or rotator cuff repair. 


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Statistical Analysis Plan 
 
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6. 
STUDY OVERVIEW 
This is a Phase 3, double-blind, placebo-controlled, randomized study.  Subjects will be 
monitored for 5 days after surgery and followed for 30 days after surgery.  Subjects will be 
randomized (1:1) to receive a 20mL injection of EXPAREL 133mg (10mL of EXPAREL 
266mg/20mL expanded with 10mL of normal saline) via an ultrasound guided single-injection 
brachial plexus, interscalene or supraclavicular, nerve block at least 1 hour before surgery. 
Major changes impacting the statistical analysis plan between Protocol Amendment 1 and 
Protocol Amendment 2 are as follows (for a complete record of the changes, see Protocol 
Amendment 2):  
 
Under Protocol Amendment 1, subjects were randomized to (1:1:1) to receive 
EXPAREL 133mg, EXPAREL 266mg or placebo.  Under Protocol Amendment 2 the 
EXPAREL 266mg dose was removed from the randomization scheme and efficacy 
endpoints for the study.  
 
Under Protocol Amendment 1, 300 subjects were planned to be randomized into the 
study.  Under Protocol Amendment 2, approximately 120 subjects were planned to be 
randomized into the study in order to achieve 50 subjects on EXPAREL 133mg and 
50 subjects on placebo. 
 
Under Protocol Amendment 1, the VAS was not scheduled to be measured every 15 
minutes while in the PACU and prior to PACU discharge as it is in Protocol 
Amendment 2.  
 
Under Protocol Amendment 1,  subjects had their PK assessments scheduled under 
the same sampling schedule, where under Protocol Amendment 2, a population PK 
sampling scheme was implemented. 
 
Under Amendment 2, assessments at 84, 96, 108, and 120 hours were removed.  
 
The Study Stopping Rules were modified.   
 
Under Amendment 2, postsurgically, all subjects will receive 
acetaminophen/paracetamol up to 1000 mg PO or IV every 8 hours (q8h) unless 
contraindicated.  The total daily dose of acetaminophen/paracetamol should not 
exceed 3000 mg. 
Subjects will be allowed rescue medication upon request to control their pain.  Rescue 
medication will be oral (PO) immediate release oxycodone.  If subject cannot tolerate PO 
medication, intravenous (IV) morphine or hydromorphone may be used as rescue medication. 
 
Pain will be assessed using a 10 cm visual analog scale (VAS).  Pain will be assessed at multiple 
timepoints during the study. 
Plasma bupivacaine concentrations will be determined at multiple timepoints during the study.   
Other postsurgical assessments include: 
 Postsurgical opioid consumption;  


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 Overall benefit of analgesia score (OBAS);  
 Subject satisfaction with overall analgesia using a 5-point Likert scale;  
 Subject’s discharge readiness as assessed by Modified Postanesthesia Discharge Scoring 
System (MPADSS);  
 Unscheduled phone calls or office visits related to pain;   
 Clinical laboratories;  
 Vital sign measurements; 
 ECGs; 
 Neurological assessment;  
 Sensory function assessment at 2 locations as measured by: 
o Cold, 
o Pinprick, 
o Light touch; 
 Degree of motor nerve block (Lovett scale) assessments : 
o Thumb, 
 Abduction (radial nerve), 
 Adduction (ulnar nerve), 
 Opposition (median nerve), 
o Elbow flexion (musculocutaneous nerve);  
 Adverse events; 
 Concomitant medications. 
 
 


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7. 
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.  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.   
This Study Day definition differs from the protocol defined Study Day.  By this definition Day 1 
is the day of the operation while the protocol defines this as Day 0.  The definition assigning the 
operation to Day 1 aligns with the CDISC implementation guidance and FDA expectations. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those with onset between the start date and 
time 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 start of study drug administration. 
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) 
0-12 
[0 to 13] 
0-24 
[0 to 25] 
0-48 
[0 to 50] 
0-72 
[0 to 76] 
0-96 
[0 to 100] 
0-Day 5 
[0 to 144] 
0-Day 10 
[0 to 264] 
24-48 
[23 to 50] 
48-72 
[ 46 to 76] 
72-96 
[68 to 100] 
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 
and with highest value 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.  In addition, if there are two 
measurements for a given assessment at the exact same time, the measurement with the highest 
value should be used. 


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Baseline 
Baseline is defined as the last available measurement or assessment prior to start of study 
treatment. 
Sensation Loss 
Sensation loss is when the subject reports absence of sensation for the sensory test (cold, 
pinprick or light touch) at each location (dermatome) [shoulder (axillary), forearm 
(musculocutaneous), middle finger (median), fifth finger (ulnar) and thumb (radial)]. Subjects may 
experience loss of sensation multiple times and at different times in different locations.  A 
subject must have a return of sensation in the same sensory test in the same location before 
another loss of sensation can occur. 
Time to Sensation Loss 
Time to first loss of sensation is the first timepoint after baseline at which one of the three 
sensations (cold, pinprick and light touch) is absent at any of the test locations (dermatomes).  If 
sensation is not lost, time to sensation loss will be censored at the last available sensory 
assessment available for that subject.  Subjects who experience multiple losses of sensation will 
have multiple times to sensation loss but the time to first sensation loss will be used for analysis 
of time to first sensation loss.  
Return of Sensation 
Return of sensation is when a subject reports the presence of sensation after reporting a loss of 
sensation for the same sensory test (cold, pinprick and light touch) and location (dermatome).  
Subjects may experience returns of sensation multiple times.  A subject must experience multiple 
losses of sensation before multiple returns can be experienced.  Subjects who experience 
multiple returns of sensation will have multiple times to sensation return. 
Time to Return of Sensation 
Time to return of sensation is when all three sensations (cold, pinprick and light touch) are 
present after a subject experienced a loss of sensation in at least one of the sensory tests.  If 
sensation doesn’t return, it will be censored at the time of the last sensory assessment available 
for that subject.  Only subjects who experience a loss of sensation can experience a return of 
sensation. 
Duration of Sensory Loss 
Duration of sensory loss is defined as the time from sensation loss to the time of sensation return.  
Subjects who never lost sensation will not be included in any analysis of Duration of Sensory 
Loss.  If sensation doesn’t return, then duration will be censored and is defined as the time 
between sensation loss and last sensory assessment.  
Duration will be calculated for each loss-return cycle for those subjects with multiple cycles.  If 
after the last sensation loss there is no return of sensation, the duration of the last cycle will be 
censored and defined as the time between sensation loss for that cycle and last sensory 
assessment. 
Total duration is the sum of all durations for a subject. 
Onset of Motor Function Loss 


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Onset of loss motor function is the first timepoint after baseline where the Lovett score drops 
below a three for at least one of the motor function assessments. 
Return of Motor Function 
Return of motor function is defined as when the Lovett score returns to three or above for any 
motor function assessment.  
Time to Return of Motor Function 
Time to return of motor function is the time from first loss of motor function to return of motor 
function for the motor assessment.  If a subjects doesn’t have return of motor function, the time 
to return of motor function will be censored on the date and time of last motor function 
assessment.  For those subjects who never lose motor function, time to return will be missing; 
these subjects will not be included in any analysis of time to return.   
Loss-Return Cycle 
A loss-return cycle is the event where a subject has loss and return of sensory or motor function.  
Subjects may experience multiple cycles.  Cycles are defined separately for each sensory and 
motor function tests. 
Ready for Discharge 
Ready for discharge is defined as a total score of 9 or more on the MPADSS.  The total score is 
the sum of all scores.  If there are missing data then the total score will not be calculated. 
Sum of Pain Intensity Score (SPIS) 
Sum of pain intensity scores (SPIS) are calculated by summing the imputed VAS scores for the 
timeframes of interest.  Only scheduled VAS assessments under Protocol Amendment 1 will be 
used to derive SPIS.  
Region 
Region is defined as US and ROW where ROW is any site outside of the US. 


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8. 
ANALYSIS SETS 
The safety analysis set will include all subjects who receive study drug.  All analyses based on 
the safety set will be by actual treatment received. 
The efficacy analysis set will include all subjects in the safety analysis set who undergo the 
planned surgery.  All analyses based on the efficacy analysis set will be by randomized treatment 
regardless of treatment actually received. 
The per-protocol efficacy analysis set will include all subjects in the efficacy analysis set and do 
not have any important protocol deviations.  Important protocol deviations may include, but are 
not limited to, the following: 
1) Planned concurrent surgical procedure; 
2) 50% or more of the rescue medications are missing a VAS assessment (baseline through 48 hours +/- 
2 hours) within 30 minutes prior to rescue medication use and at least 4 rescue medication doses are 
missing the associated VAS assessments within 30minutes prior to rescue medication use.; 
3) Missing two or more scheduled VAS assessments between start study drug administration as the 
baseline  VAS assessment and the 48 hour VAS assessment; 
4) Subject did not receive the study treatment to which he/she was randomized (determined after 
database lock and unblinding). 
All analyses for the per-protocol analysis set will be by randomized treatment. 
 


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9. 
STATISTICAL METHODS OF ANALYSIS 
9.1. 
General Principles 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs).  All 
analyses and tabulations will be performed using SAS Version 9.1 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). 
Unless otherwise noted, tabulations of categorical data will present only those categories 
appearing in the data. 
On all figures, the comparator treatment will be represented in black with solid lines and filled 
squares; EXPAREL will be represented in red with solid lines and dots.   
For tables presenting summaries of VAS scores, if more than one VAS score is presented for a 
specific 
timeframe/timepoint 
of 
interest, 
the 
highest 
score 
within 
that 
specific 
timeframe/timepoint should be used. 
Plots of the VAS scores will show both observed and imputed scores.  A change in color and line 
type will differentiate the imputed VAS scores.  Imputed values will be represented by blue and 
green symbols and dashed lines for the comparator and EXPAREL respectively.  VAS scores 
obtained immediately prior to rescue will be indicated by a change in symbol.  For the 
comparator the symbol should be a triangle, for EXPAREL the symbol is a star.  The following 
table shows the SAS symbol statements: 
Treatment 
VAS 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 VAS 
score group indicator variables. 
Sites with fewer than 5 subjects per treatment arm will be pooled with other sites for analysis.  
US sites will be pooled with other small US sites based on the US Census Bureau geographic 
regions (see Table 1) and European sites will be pooled with other small European sites based on 
country.  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 meets the pooling criteria, the site will be pooled with other small sites 
within the region.  If 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.   


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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 
South Atlantic 
Delaware, District of Columbia, Florida, Georgia, Maryland, North Carolina, 
South Carolina, Virginia, West Virginia 
West South Central 
Arkansas, Louisiana, Oklahoma, Texas 
West 
Mountain 
Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, Wyoming 
Pacific 
Alaska, California, Hawaii, Oregon, Washington 
 
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 opioid medication window will be replaced.  For this study the prescribed opioid rescue 
medication is oxycodone; however morphine or hydromorphone may be used.  The durations of 
effect for various opioids are listed in Table 2. 
Table 2: Opioid Windows 
Medication 
Route 
Window Used to Impute VAS 
Oxycodone, Oxycocet, Percocet, 
acetaminophen-oxycodone, 
Oxycontin 
PO, IM, IV, SC 
6 hours 
Morphine 
IV, PO, SC 
4 hours 
Hydromorphone (Dilaudid), 
Hydromorphone hydrochloride 
IV 
2 hours 
Hydromorphone (Dilaudid) ), 
Hydromorphone hydrochloride 
PO, IM, SC 
4 hours 
Hydrocodone 
PO 
6 hours 
Fentanyl 
IV, PO, IM 
6 hours 
Vicodin, Norco, Lorcet, Lortab, 
hydrocodone-acetaminophen 
PO 
6 hours 
Codeine (Tylenol 3, 
acetaminophen-coedine, 
Paracetamol Forte, Tylenol 4) 
PO 
6 hours 
Ultram, Tramadol, Tramacol 
hydrochloride 
PO 
6 hours 
PO = oral; IV = intravenous; VAS = visual analog scale. 
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 post surgically with an indication such as ‘anesthesia maintenance’ will not be included 
for imputation purposes. 
 
 
 


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All non-efficacy tables will present EXPAREL 133 mg, EXPAREL 266 mg, All EXPAREL 
(combined doses), placebo, and all treatments as separate columns. 
Efficacy tables will present EXPAREL 133 mg and placebo as separate columns.  EXPAREL 
266 mg will not be presented in the efficacy tables and figures, but will be presented in the 
efficacy listings.    
If there are multiple VAS records with the same actual date/time for a given subject, then the record 
with the highest VAS score will be used for that actual date/time for all endpoint derivations, 
summaries, and analyses. 
    
9.1.1. Handling Missing Values 
9.1.1.1. 
Area under the VAS-Time Curve 
9.1.1.1.1. 
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 VAS 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 subjects who take a rescue medication, their VAS scores recorded within the window 
of controlled type of rescue medication (see Table 2) will be replaced by the ‘worst’ 
observation.  The non-rescue VAS score recorded right before taking a rescue medication 
(start of Rescue window) is considered as the ‘worst’ observation. This non-rescue worst 
VAS score shall be after the end of previous rescue window, where a rescue window ends 
once a subject is no longer considered under the effect of opioids (see Table 2 for 
individual rescue medication durations).  If there is no value available between the end of 
previous rescue window and the start of the current rescue window, then the first VAS 
score recorded on or right after the start of the current rescue window will be used for the 
imputation.   VAS scores recorded prior to the end of surgery will not be considered. 
b) After the wWOCF imputation, described in Step a, subject data still missing scheduled 
assessments with a non-monotone missing pattern (i.e., 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 within each surgery and 
treatment, which will be applied in the multiple imputation procedure for arbitrary 
missing patterns.  This MCMC method will simulate 10 datasets with only monotone 
missing data. In order to achieve the stationary distribution and to avoid dependency 
within samples generated by MCMC method, the number of iteration for the burn in 
period will be set to 2000 and the number of iterations between each sample will be set to 
1000 (i.e.,  NBITER=2000 and NITER=1000.) 
  


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c) The AUC and SPIS at various time intervals will be derived from the imputed VAS 
scores resulting from Step b.    
d) 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 c will be created based on Rubin and Schenker 
method (1986)7. 
SAS pseudo-code for multiple imputations is provided in Section 13. 
9.1.1.2. 
Exposure, Surgery, and Rescue Medication Date or Time 
It is expected that all necessary information on study drug exposure, surgery, and postsurgical 
rescue medication (dates and times) 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. 
9.1.1.3. 
Rescue Pain Medication 
For calculation of the total rescue pain medication usage (IV Morphine Equivalent) through a 
time point, if a subject is discontinued early (e.g., dies, withdraws consent, is withdrawn from the 
study, or is lost to follow-up) before the end of the time interval (e.g., 24 hours after study drug 
administration), his or her total rescue pain medication usage through the time interval will be a 
projected amount.  For example, if a subject discontinues early at 6 hours after surgery, the 
projected amounts through 24 hours will be actual amount + average amount (actual amount/6 
hours) multiplied by the number of hours remaining in the time interval (18=24-6). 
9.1.1.4. 
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 used to impute the missing month and 
corresponding day. 
ii) 
Otherwise, ‘January’ will be assigned. 
 If the day is unknown, then: 
i) 
If the month and year match the month and year of the dose of study drug date, 
then the day of the dose of study drug date will be imputed. 
ii) 
Otherwise, ‘01’ will be assigned. 
 If the time is unknown, then: 
i) 
If the date (day, month, and year) matches the date of the administration of study 
drug, then the time of the dose of study drug time will be imputed. 


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ii) 
Otherwise, ’00:00’ will be assigned. 
For partial stop date/time: 
 If the year is unknown, then the date will be assigned 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’). 
9.1.1.5. 
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. 
9.1.1.6. 
Time to Event  
For calculating time to an event when only the hour is reported, the minutes will be set to zero. 
9.1.2. Multiplicity Adjustments 
For the efficacy analyses, EXPAREL 133 mg will be compared to placebo at the 0.05 alpha level 
for the efficacy analysis set.  In order to maintain strong type I error control, a hierarchical 
gatekeeping structure will be utilized.  If a test fails to reject the null hypothesis at the 0.05 alpha 
level, then no additional hypothesis testing will be conducted.  The hierarchical gatekeeping 
order will be as follows: 
1) AUC of the VAS pain intensity scores through 48 hours [AUC(0-48)] 
2) Total postsurgical opioid consumption (mg) through 48 hours 
3) Percentage of opioid-free subjects through 48 hours 
4) Time to first rescue medication (opioid) dose through 48 hours 
Any analyses of tertiary efficacy endpoints are for sensitivity or exploratory purposes.  No 
multiplicity adjustments will be made for these endpoints. 
9.1.3. By-Center Analyses 
By-site summaries will present descriptive statistics only; no statistical analyses will be 
performed on individual sites.  By-site summaries will be presented for disposition, 
demographics, the primary efficacy endpoint, and the secondary efficacy endpoints.  By-site 
summaries will present both pooled and individual sites.  The pooled site should be presented 
first immediately followed by the sites within that pool. 
9.2. 
Subject Disposition 
Subject disposition summaries will include the number of subjects that were: 
 Screened, 
o Screen failure 


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o Enrolled 
 Randomized  
o Randomized not treated,  
o Randomized treated,  
 In the safety analysis set, 
 In the efficacy analysis set,  
 In the per-protocol analysis set,  
 Protocol 
o Enrolled under Amendment 2 
o Enrolled under Amendment 1 
o Enrolled under Original Protocol 
 Completed the study as planned, 
 Discontinued from the study, and 
 Reasons for discontinuation from the study. 
Percentages will be reported for the screen failures and enrolled using the number of subjects 
screened as the denominator; efficacy analysis set and per-protocol analysis set will use the 
number of subjects randomized, treated, and having surgery as denominator for percentages; all 
other percentages will use the number of subjects randomized and treated as denominator. 
The safety analysis set data and enrollment data will be presented as treated.  All other data will 
be presented as randomized.  
The disposition summary will present the data for each treatment group (EXPAREL 133 mg, 
EXPAREL 266 mg, placebo), EXPAREL treatments combined (All EXPAREL), and across 
treatment groups (Total).  This summary table will present overall sites and for each site 
separately. 
9.3. 
Description of Demographics and Baseline Characteristics  
9.3.1. Demographics  
The summary of demographic data will present: 
 Age (years) – descriptive statistics 
 Sex – n (%) 
 Ethnicity – n (%) 
 Race – n (%) 
 Country – n (%) 
 Dominant hand – n (%) 
Age is calculated from the date the subject signed the informed consent form (ICF) and birth.  It 
is presented as the number of years between, rounding down to the nearest integer year.  For 
partial birthdates, impute the first of the month for missing day and January for missing month to 
calculate age.  It is presumed that birth year is known. 
The demographic summary will present the data for each treatment group (EXPAREL 133 mg, 
EXPAREL 266 mg, placebo), EXPAREL treatments combined (All EXPAREL), and across 
treatment groups (Total).  Summaries will be provided for all (safety, efficacy, and per-protocol) 
analysis sets.  This summary will present overall sites and for each site separately. 


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9.3.2. Baseline Characteristics 
The summary of baseline characteristic data will present: 
 American Society of Anesthesiologists (ASA) Classification – n (%) 
 Baseline VAS scores 
 Baseline neurological assessments 
 Baseline ECG interpretation 
 Baseline degree of motor nerve block assessments  
o Thumb abduction 
o Thumb adduction 
o Thumb opposition 
o Elbow flexion 
 Height (cm) 
 Weight (kg) 
 Body Mass Index (BMI) (kg/m2) 
 Baseline vital signs 
o Heart rate (bpm) 
o Systolic blood pressure (mmHg) 
o Diastolic blood pressure (mmHg) 
The formula for BMI is       , 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. 
Baseline characteristics summaries will present the data for each treatment group (EXPAREL 
133 mg, EXPAREL 266 mg, All EXPAREL doses, placebo) and across treatment groups (Total).  
Summaries will be provided for all (safety, efficacy, and per-protocol) analysis sets.  This 
summary table will show summaries across all sites and for each site separately.  
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be provided for VAS 
scores, degree of motor blockade, height, weight, BMI and vital signs.  The number and percent 
of subjects will be tabulated for the various categories of sensory assessments, neurological 
assessments and ECG interpretation. 
9.4. 
Surgery Characteristics 
Surgery characteristics include surgery type (TSA or RCR), and if TSA then the type of TSA 
(conventional or reverse), nerve block type (interscalene or supraclavicular), duration of surgery, 
and total incision length.  Duration of surgery is calculated as the difference between the end of 
surgery and start of surgery times and reported in hours.  Descriptive statistics will be provided 
for the duration of surgery and total incision length by treatment group and across all treatment 
groups. Surgery, TSA type, and nerve block type will be tabulated by treatment group and across 
all treatment groups. 
9.5. 
Intraoperative, Prior, and Concomitant Medications 


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Intraoperative, 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 4) classification term and standard medication name. 
Intraoperative medications are defined as medications given as part of the surgical procedure. 
These may include anesthesia, opioids or other medications with start and stop dates on the day 
of surgery and start and stop times overlapping with the surgery start and stop times. 
Prior medications are defined as medications with a stop date and time prior to the start of study 
drug administration.   
Concomitant medications are defined as medications taken after the start of study drug 
administration (i.e., started prior to the start of study drug administration and continued after or 
started after the start of study drug administration). 
Intraoperative, 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 standard 
medication name for the safety analysis set.  Subjects may have more than one medication per 
ATC category and standard medication 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 standard medication name to verbatim term will be 
presented. 
9.6. 
Measurements of Treatment Compliance 
Study treatment is administered by a party other than the subject, therefore compliance is 
assured.   
9.7. 
Efficacy Analysis 
For Primary and Secondary Efficacy Analyses, descriptive statistics that are appropriate for the 
efficacy variable will also be shown by site but no statistical analyses will be performed within a 
site.  The primary and secondary efficacy analyses will be performed on the efficacy and 
per-protocol analysis sets.  Tertiary efficacy analyses will be performed on the efficacy analysis 
set only. 
9.7.1. Efficacy Endpoints 
9.7.1.1. 
Primary Efficacy 
The primary endpoint is AUC of the VAS pain intensity scores through 48 hours [AUC(0-48)]. 
9.7.1.2. 
Secondary Efficacy 
The following secondary endpoints will be analyzed as described in Section 9.1.2: 
 Total postsurgical opioid consumption (in IV morphine equivalents per mg) through 48 
hours. 
 Percentage of opioid-free subjects through 48 hours. 
 Time to first rescue medication (opioid) dose through 48 hours. 


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9.7.1.3. 
Tertiary Efficacy 
 
The AUC of the VAS pain intensity scores through 12, 24, and 72 hours.  
 
The AUC of VAS pain intensity scores from 24-48 and 48-72 hours.  
 
VAS pain intensity scores at each assessed timepoint. 
 
Proportion of subjects who are pain free (VAS score of ≤ 1.5) at each assessed timepoint. 
 
SPIS through 24, 48, and 72hours. 
 
SPIS from 24-48 and 48-72 hours. 
 
Total opioid consumption in IV morphine equivalents through 24 and 72 hours.  
 
Total opioid consumption in IV morphine equivalents from 24-48 and 48-72 hours. 
 
Percentage of subjects who are opioid-free through 24 and 72 hours. 
 
Overall benefit of analgesia scale (OBAS) total score at 24 and 72 hours and Day 10. 
 
Subject satisfaction with overall analgesia (using a 5-point Likert scale) at 24 and 72 
hours, and Day 10. 
 
Proportion of subjects ready for discharge at 12, 24, 36, 48, 60, and 72 hours 
 
Number of unscheduled phone calls or office visits related to pain after discharge through 
Day 10. 
9.7.1.4. 
Area under the Curve 
Area under the pain-time curve is derived using the trapezoidal rule (see formula below) on the 
pain scores adjusted for rescue medication use using the imputed values (see Section 9.1.1.1).  
AUC will start with the first pain assessment obtained after surgery and use all following pain 
assessments including those collected prior to rescue medication and unscheduled.  Actual 
assessment times will be used in deriving AUC. 
     ∑ 
 
   
                         
Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery.  Note that i starts at 3 since 
t1 is not used in AUC calculation (prior to surgery) and t2 is arrival at PACU.  
9.7.1.5. 
Opioid Consumption 
Opioids will be converted to IV morphine equivalent dose (MED mg) using the appropriate 
conversion factor from Table 3 for all summaries.  Total opioid dose is the IV morphine 
equivalent 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 summaries and changed 
to the lesser of 0.1 or half of the smallest total amount observed in the study, whichever is 
smaller, prior to being transformed with the natural logarithm for analysis. 
 
Table 3: IV Morphine Equivalents 
Medication 
Unit 
Route 
Conversion (Multiplication) 
Factor 


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Oxycodone, Oxycocet, Percocet, acetaminophen-
oxycodone, Oxycontin 
mg 
PO, 
IV,IM,SC 
2 
Morphine 
mg 
IV,IM,SC 
1 
Morphine 
mg 
PO 
0.33 
Hydromorphone (Dilaudid), Hydromorphone 
hydrochloride 
mg 
IV,IM 
7.7 
Hydromorphone (Dilaudid), Hydromorphone 
hydrochloride 
mg 
PO 
1.3 
Hydromorphone (Dilaudid), Hydromorphone 
hydrochloride 
mg 
SC 
4 
Fentanyl 
mg 
IV,PO,IM 
100 
Vicodin, Norco, Lorcet, Lortab, hydrocodone-
acetaminophen 
mg 
PO 
2 
Codeine (Tylenol 3, acetaminophen-coedine, 
Paracetamol Forte, Tylenol 4) 
mg 
PO 
0.05 
Ultram, Tramadol, Tramacol hydrochloride 
mg 
PO, IM 
0.08 
PO = oral; IV = intravenous; VAS = visual analog scale. 
If other rescue medications are given then the conversion to IV Morphine Equivalent will be determined post-
hoc.  If a combination opioid product is given then the IV Morphine Equivalent will be determined by the opioid 
part of the medication.  Opioids given post surgically with an indication such as ‘anesthesia maintenance’ will not be 
included. 
 
9.7.1.6. 
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. 
9.7.1.7. 
Pain-free 
Pain-free is defined as an observed VAS score less than or equal to 1.5 with no prior rescue 
medication and all prior VAS scores less than or equal to 1.5. 
9.7.1.8. 
Overall Benefit of Analgesia Score (OBAS) 
The OBAS is derived as follows: 
1. Add all of the scores of questions 1 to 6. 
2. To this number, add four. 
3. Subtract the score of question 7 from this number.  
If a response is missing to any question in the OBAS, the total score will not be calculated. 
9.7.2. Methods of Analysis 
For Primary and Secondary Efficacy Analyses, descriptive statistics that are appropriate for the 
efficacy variable will also be shown by site but no statistical analyses will be performed within a 
site.   


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9.7.2.1. 
Primary Efficacy Analysis 
The primary efficacy variable is the AUC of VAS scores through 48 hours [AUC(0-48)] using 
the multiple imputation method described in Section 9.1.1.1. 
Tests for the treatment effect of EXPAREL 133 mg 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(0-48) for EXPAREL 133 mg and the mean of AUC(0-48) 
for placebo, respectively. A two-sided test will be performed at 5% level of significance 
comparing EXPAREL 133 mg to placebo. The treatment effect of EXPAREL 133 mg 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(0-48) in favor of EXPAREL 133 mg (mean for 
EXPAREL 133 mg less than the mean for placebo) is observed. 
For the primary efficacy variable of AUC(0-48), EXPAREL 133 mg will be compared to 
placebo using analysis of variance (ANOVA) with age, weight, and height as covariates. Based 
on the model, the least squares (LS) mean and the standard error (SE) of the LS mean, will be 
reported for each treatment group.   The LS treatment difference for the active minus placebo, 
95% CI for the active minus placebo treatment difference, and p-value will be reported as well as 
for each active treatment. 
Descriptive statistics of the primary efficacy variable will also be shown by site but no statistical 
analyses will be performed within a site. 
 
 
9.7.2.2. 
Secondary Efficacy Analyses 
9.7.2.2.1. 
Postsurgical Opioid Consumption 
Postsurgical narcotic consumption (MED mg) will be summarized (n, Geometric Mean, 
coefficient of variation, minimum, and maximum) by treatment group for the total dose 
consumed over the 48 hours after the end of surgery.  The number and percentages of the types 
of opioids used will be presented by treatment group, subjects will be counted only once for each 
opioid used.  This summary table will show summaries across all sites and for each site 
separately. 
Prior to analysis, the natural logarithm transformation will be applied to the total amount. When 
total amount of opioids (IV Morphine Equivalent) used is 0, the result will be changed to 0.1 or 
half of the smallest total amount observed in the study, whichever is smaller, prior to being 
transformed with the natural logarithm. To test for significant differences between EXPAREL 
133 mg and placebo, the same ANOVA model used in the primary efficacy analysis will be used. 
The LS means, LS mean difference between the two treatment groups, 95% CI for the LS mean 
difference between EXPAREL and placebo, and p-value will be reported.  The LS means, LS 
mean differences and 95% CI will be back transformed for presentation (note the LS mean 
difference becomes the ratio when back-transformed) along with the descriptive statistics 
(untransformed) by treatment. 
9.7.2.2.2. 
Opioid-free 


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Percentage of opioid-free subjects through 48 hours will be analyzed using a Cochran-Mantel-
Haenszel (CMH) test.  The p-value from the CMH analysis and mean treatment difference and 
95% CI about the mean difference using the Newcombe8 method (SAS pseudo-code below) will 
be presented. The tabulation of opioid-free subjects will be presented across all sites and 
surgeries separately.  No inferential statistics will be calculated for individual sites. 
The number and percentage of subjects opioid-free will also be tabulated by timepoint.   
Pseudo-code for Newcombe method: 
PROC FREQ; 
TABLE TREATMENT*RESPONSE / RISKDIFF(CL=NEWCOMBE COMMON); 
RUN; 
9.7.2.2.3. 
Time to First Opioid Rescue Medication 
Time to first opioid rescue medication will be computed in hours as the date and time of the first 
opioid rescue medication minus the date and time of the end of surgery. If a subject is not 
administered an opioid rescue medication, the time to first administration will be censored at 48 
hours after surgery or at the time of last follow-up, whichever is earliest. Time of last follow-up 
will be defined as the latter of (1) the last pain assessment, (2) the start time of the last 
concomitant medication, or (3) the start time of the last AE.  
Time to first opioid rescue will be analyzed by the Kaplan-Meier method and the log-rank test. 
The n (%) of subjects administered an opioid as well as the n (%) of censored observations will 
be presented for each treatment group. In addition, Kaplan-Meier estimates in terms of the 
median and its 95% CI, and the 25th and 75th percentiles will be presented for each treatment. 
Log-rank tests will be used to compare EXPAREL to placebo. 
9.7.2.3. 
Tertiary Efficacy Analyses 
P-values computed for the tertiary endpoints are for descriptive purposes only and are not 
adjusted for multiple comparisons. 
9.7.2.3.1. 
Visual analog scale (VAS) AUC 
Summary statistics will be presented by treatment for VAS AUC(0-12), VAS AUC(0-24), VAS 
AUC(0-72), AUC(24-48), and AUC(48-72).  For each of these variables, EXPAREL 133 mg 
will be compared to placebo using analysis of variance (ANOVA) with age, weight, and height 
as covariates. Based on the model, the LS mean and SE of the LS mean will be reported for each 
treatment. The LS treatment difference for the active minus placebo, 95% CI for the active minus 
placebo treatment difference, and p-value will be reported as well as for the active treatment. 
9.7.2.3.2. 
Visual analog scale (VAS) 
Summary statistics will be presented by treatment for VAS at each assessment timepoint.  This 
summary will be based on the observed VAS values. 
9.7.2.3.3. 
Proportion of Pain-Free Subjects 
The proportion of pain-free subjects will be tabulated by treatment.  The number and proportion 
of subjects who are pain-free and not pain-free (or VAS score is missing) will be presented at 
assessment timepoint. For the proportion of pain-free subjects, EXPAREL 133 mg will be 


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compared to placebo using a Cochran-Mantel-Haenszel (CMH) test.  The p-value from the CMH 
analysis and mean treatment difference and 95% CI about the mean difference derived using the 
Newcombe9 method.  
9.7.2.3.4. 
Sum of Pain Intensity Scores (SPIS) 
Summary statistics will be presented by treatment for SPIS(0-12), SPIS(0-24), SPIS(0-48), 
SPIS(0-72), SPIS(24-48), and SPIS(48-72). For each of these variables, EXPAREL 133 mg will 
be compared to placebo using analysis of variance (ANOVA) with age, weight, and height as 
covariates. Based on the model, the LS mean and SE of the LS mean will be reported for each 
treatment. The LS treatment difference for the active minus placebo, 95% CI for the active minus 
placebo treatment difference, and p-value will be reported as well as for each active treatment.  
9.7.2.3.5. 
Total Opioid Consumption through 24 and 72 hours 
Total opioid consumption through 24 and 72 hours will be summarized and analyzed by 
treatment group.  These summaries and analyses will be calculated similar to the postsurgical 
opioid consumption through the 48 hour secondary endpoint (see Section 9.7.1.2).  
9.7.2.3.6. 
Total Opioid Consumption during Specific Time Intervals 
Total opioid consumption from 24-48 and 48-72 hours will be summarized and analyzed by 
treatment group.  These summaries and analyses will be calculated similar to the postsurgical 
opioid consumption through the 48 hour secondary endpoint (see Section 9.7.1.2).  
9.7.2.3.7. 
Percentage of Opioid-free Subjects through 24 and 72 hours  
The percentage of opioid-free subjects will be tabulated and analyzed by treatment.  These 
summaries and analyses of the percentage of opioid-free subjects at 24  and 72 hours will be 
calculated similar to the percentage of opioid-free subjects at 48 hours secondary endpoint (see 
Section 9.7.2.2.2). 
9.7.2.3.8. 
Overall Benefit of Analgesia (OBAS) 
The OBAS total score will be summarized by treatment and individual question responses 
tabulated at following timepoints: 24 and 72 hours and postsurgical Day 10.  For the OBAS total 
score, EXPAREL 133 mg will be compared to placebo using a Kruskal-Wallis test at 24 and 72 
hours and postsurgical Day 10. 
9.7.2.3.9. 
Subject Satisfaction with Overall Analgesia 
Subject satisfaction with overall analgesia (obtained using a 5-point Likert scale) will be 
summarized and individual responses tabulated by treatment for each of the following 
assessment timepoints: 24 and 72 hours and postsurgical Day 10.  The numeric value of the 
response will be presented using descriptive statistics.  For each value of the scale the number 
and percentage of subjects selecting that value will also be presented. For the subject satisfaction 
with overall analgesia, EXPAREL 133 mg will be compared to placebo using a Kruskal-Wallis 
test for each of the following assessment timepoints: 24 and 72 hours and postsurgical Day 10. 
9.7.2.3.10. 
Discharge Readiness 
Time to discharge ready will be computed in hours as the date and time of subjects first meeting 
the discharge readiness criteria and time of the end of surgery.  Discharge ready criteria will be 
met when the MPADSS criterion is met (total score of 9 or more) for discharge readiness or the 


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subject is discharged, whichever occurs first.  If a subject has not met the discharge ready criteria 
prior to or at a given timepoint (12, 24, 36, 48, 60, and 72 hours), then the time to discharge 
ready will be censored at the time of their last MPADSS assessment in the study or the specific 
assessment timepoint (12, 24, 36, 48, 60, and 72 hours), whichever occurs sooner. 
Time to discharge ready will be analyzed by the Kaplan-Meier method for each of the following 
assessment timepoints: 12, 24, 36, 48, 60, and 72 hours.  The n (%) of subjects who are discharge 
ready as well as the n (%) of censored observations will be presented for each treatment group. 
In addition, Kaplan-Meier estimates in terms of the median and its 95% CI, and the 25th and 
75th percentiles will be presented for each treatment at 12, 24, 36, 48, 60, and 72 hours. Log-
rank tests will be used to compare EXPAREL 133 mg to placebo at 12, 24, 36, 48, 60, and 72 
hours.  
The number and percent of subjects meeting the discharge readiness criteria at 12, 24, 36, 48, 60, 
and 72 hours will be summarized.   
If a subject is discharge ready at an early timepoint, the subject will be considered discharge 
ready at all subsequent (future) timepoints.  If a subject has a discharge readiness total score of 
less than 9 or if the total score is missing, the subject will be considered not discharge ready, 
unless they were previously considered discharge ready. 
9.7.2.3.11. 
Number of Pain-Related Visits/Phone Calls after Discharge 
The number of pain-related unscheduled phone calls or office visits after discharge through 
postsurgical Day 10 will be summarized (n, mean, SD, median, minimum and maximum) by 
treatment group.  The number and 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.  For the number of pain-related unscheduled phone calls or office 
visits, EXPAREL 133 mg will be compared to placebo using a Kruskal-Wallis test.  
9.7.2.3.12. 
Region Analysis 
Summaries and tabulations looking at region will be performed for the following: 
 
Disposition 
 
Demographics 
 
Baseline Characteristics 
 
Intraoperative medicines 
 
VAS AUC(0-48)  
 
Total opioid consumption through 48 hours 
 
Percentage opioid-free through 48 hours  
 
Sensory loss and return 
 
Motor function loss and return 
 
Overall summary of adverse events 
 
Incidence of TEAEs 
 
Incidence of Serious TEAEs 
The populations for each the summary and tabulation as planned for the non-region tables will be 
repeated for the region tables.   
For analyses considering region, the age, weight, and height scovariates will be replaced with 
region, this will be performed for the following: 
 
VAS AUC(0-48)  


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 
Total opioid consumption through 48 hours 
 
Percentage opioid-free through 48 hours  
 
Sensation Loss and Return 
 
Motor Function Loss and Return   
Region summaries, tabulations, and analyses will be the final block within the 14.1, 14.2 and 
14.3 series of tables. 
9.8. 
Safety Analyses 
Safety assessments in this study consist of vital signs, 12-lead ECGs, neurological assessments, 
sensory and motor nerve block assessments, motor function assessments and AEs.  Vital signs, 
ECGs, neurological, nerve block assessments (sensory and motor) and motor function 
assessments will be serially collected (see Time and Events Schedule of Study Procedures). 
Adverse events will be collected from the time of informed consent through Day 30. 
P-values computed for the safety endpoints are for descriptive purposes only and are not adjusted 
for multiple comparisons. 
9.8.1. Vital Signs 
Vitals signs are resting heart rate (bpm), systolic blood pressure (mmHg), and diastolic blood 
pressure (mmHg).  Vital signs will be summarized by treatment group and the All EXPAREL 
group at each assessment timepoint.  The assessment timepoints for the vital signs are: at 
baseline (prior to the nerve block); every 5 minutes during performance of the block up to 30 
minutes; and every 15 minutes until entering the OR; at PACU arrival; at 6, 9, 12, 24, 36, 40, 44, 
48, 52, 56, 60, and 72 hours; and on postsurgical Days 5 and 10.  Summaries will present both 
actual and change-from-baseline results.  Baseline statistics will be presented at each assessment 
timepoint for those subjects reporting data at that timepoint. 
Vital signs will also be assessed for potentially clinically significant abnormal values (see Table 
4).  The number and percentage of subjects satisfying the potentially clinically significant 
abnormal criteria (critical value, critical change separately and then value and change 
concurrently) at any time during the study and at each assessment timepoint will be tabulated by 
treatment and overall treatments.   
Table 4: 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. 
9.8.2. Electrocardiograms 
Investigators will classify ECG tracings as ‘normal, ‘abnormal not clinically significant’ or 
‘abnormal clinically significant’.  The investigator classifications will be tabulated by treatment 
and overall treatments at any time during the study and each assessment timepoint.  The 
assessment timepoints for the ECGs are: at baseline (prior to the nerve block); upon arrival at the 
PACU; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; and on postsurgical Days 5 and 
10.   


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A shift table comparing the investigator classification of the ECG results at baseline to each 
timepoint will also be provided. 
9.8.3. Neurological Assessments 
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 any time after baseline and at each assessment timepoint.  The 
assessment timepoints for the neurological assessments are: at baseline (prior to the nerve block); 
upon arrival at the PACU; at 6, 9, 12, 24, 36, 40, 44, 48, 52, 56, 60, and 72 hours; and on 
postsurgical Days 5 and 10.  
9.8.4. Sensation Tests 
Sensations tests are assessed on the shoulder (axillary nerve), forearm (musculocutaneous nerve), 
middle finger (median nerve), fifth finger (ulnar nerve) and thumb (radial nerve).  The number and 
percentage of subjects will be tabulated for each response (present/absent) within each nerve and 
sensory test (cold, pinprick and light touch) by treatment group at each assessment timepoint.  
The assessment timepoints for the sensation tests are: at baseline (prior to the nerve block); at 
approximately 15, 30, and 45 minutes after the nerve block; prior to discharge from the PACU; 
at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours. 
The number and percentage of subjects will be tabulated for loss and return of sensation (see 
Section 7) across all locations and within each location and each sensory test (cold, pinprick and 
light touch) and combinations of sensory tests (ANY, CPL, CP, CL, and PL) by treatment group 
at each assessment timepoint.  Where the combinations of ANY, CPL, CP, CL and PL are 
defined as follows: 
 ANY = at least one sensation 
 CPL = all sensations (cold, pinprick and light touch) 
 CP = cold and pinprick 
 CL = cold and light touch 
 PL = pinprick and light touch 
A subject will be considered as having a loss of sensation if either of the locations has a loss of 
sensation; a return across locations is when both locations have return of sensation for the 
subject. 
The times to loss of and return of sensation (see Section 7, subsections loss of sensation and 
return of sensation) will be summarized by treatment using Kaplan-Meier estimates.  In addition, 
Kaplan-Meier estimates in terms of the median and its 95% CI (using log-log method), and the 
25th and 75th percentiles will be presented for each treatment. Log-rank tests will be used to 
compare EXPAREL 133 mg to placebo.  . 
Duration of sensation loss will be summarized across locations and within each location.  Total 
duration is defined as the sum of durations of each lost-return cycle for a subject.  If more than 
10% of the subjects in at least one treatment group experience multiple lost-return cycles, then 
duration will be summarized for total duration and within each cycle. 


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An additional table summarizing the number of cycles and tabulating the distribution number of 
cycles by treatment group will be presented within each location by treatment group. 
9.8.5. Degree of motor nerve block Assessments 
Degree of motor nerve block assessments includes thumb abduction (radial nerve), thumb 
adduction (ulnar nerve), thumb opposition (median nerve) and elbow flexion (musculocutaneous 
nerve) as assessed using the Lovett scale.  The actual and change from baseline values for each 
of these parameters will be summarized by treatment at each assessment timepoint.  At each 
assessment timepoint the baseline values will be summarized for those subjects who have data at 
that timepoint. 
The assessment timepoints for the degree of motor nerve block are: at baseline (prior to the nerve 
block);  
at approximately 15, 30, and 45 minutes after the nerve block; prior to discharge from the 
PACU; at 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours.  At each assessment timepoint, the number 
and percent of subjects with loss and return of motor function (see Section 7) will be summarized 
by treatment. 
For each active assessment the time to return to motor function will be analyzed by treatment in 
the same manner as time to first rescue medication (see Section 9.7.1.6).   
9.8.6. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).   
An AE will be considered TEAE if the onset date and time is between the start date and time of 
study treatment and Day 30.   
If an AE has a partial onset date and time the imputed start and stop dates and times will be used 
to determine treatment-emergence (e.g., stop date and time is before start date and time of study 
treatment). 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 number and percentage of subjects reporting the preferred term, thus the sort order of rows 
will remain the same for the relation or severity tables as the tables by preferred term. . 


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The following summaries will be presented for the AEs reported by the subjects: 
An overview of all TEAEs, serious TEAEs and TEAEs of Special Interest will present the 
number and percentage of subjects in the following categories: 
 Any TEAE 
o Maximum severity: Mild 
o Maximum severity: Moderate 
o Maximum severity: Severe 
 At least one related TEAE 
 At least one serious TEAE 
 Subjects discontinued due to a TEAE 
 Died on study 
Subjects will be counted once in each of the above categories except for maximum severity.  
Subjects will be counted only once at the highest severity reported.  For example, if a subject has 
a mild and severe headache and a moderate rash, the subject will be counted under maximum 
severity of severe only. 
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 treatment related TEAEs 
 TEAEs leading to study withdrawal 
 Study treatment related TEAEs leading to study withdrawal 
 All TEAEs by severity  
 All TEAEs by relationship to study treatment 
 All serious TEAEs 
 Study treatment related serious TEAEs 
 Serious TEAEs leading to study withdrawal 
 Study treatment related serious TEAEs leading to study withdrawal 
 Serious TEAEs resulting in death 
 Study treatment related serious TEAEs resulting in death 
 All TEAEs of special interest 
 Study treatment related TEAEs of special interest 
 TEAEs of special interest leading to study withdrawal 
 Study treatment related TEAEs of special interest leading to study withdrawal 
 TEAEs of special interest resulting in death 
Study treatment related TEAEs of special interest resulting in deathIf 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 investigator assessment of relationship to study 
treatment is either ‘possible’, ‘probable’ or ‘definite’.  
All AE summaries based on related AEs will be produced based on the investigator assessment 
of relatedness.  Below are the MedDRA terms for the adverse events of special interest: 


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A listing of the mapping of the system organ class and preferred terms to verbatim terms will be 
presented.  
9.8.7. Laboratory Parameters 
Clinical laboratory assessments (hematology, chemistry, and urinalysis) are collected at 
screening, baseline and Day 10. Laboratory results will be summarized by treatment group and 
the All EXPAREL group at each assessment timepoint.  Summaries will present both actual and 
change-from-baseline results.  Baseline statistics will be presented at each assessment timepoint 
for those subjects reporting data at that timepoint. 
Tabulations of the number and percentage of subjects with value below normal, normal or above 
normal will be provided by treatment group, All EXPAREL group and across all treatment 
groups at each timepoint. 
Shifts in laboratory results categorized as low (below the lower limit of the normal range), 
normal (within the normal range, limits inclusive) and above (above the upper limit of the 
normal range) will be presented in shift tables with baseline categories across the columns and 
Day 10 down the rows for EXPAREL 133 mg, EXPAREL 266 mg, All EXPAREL and placebo 
separately.  Each cell will present the number and percentage of subjects in that cell. Due to the 
width of these tables, only 2 treatments can be presented on a page.  For ease of comparing 
active treatments to placebo, placebo data will be presented on each page.  Thus the shift table 
will present all laboratory data for EXPAREL 133 mg and placebo then for EXPAREL 266 mg 
and placebo and finally for All EXPAREL and placebo. 
9.9. 
Pharmacokinetic Analysis 
 
 
MedDRA 18.1 Dictionary Terms 
Group 
Protocol term 
Term Level 
Term 
Cardiac 
Angina 
Preferred term 
Angina Pectoris 
Myocardial infarction 
Preferred term 
Myocardial Infarction 
Bradycardia 
Preferred term 
Bradycardia 
Tachycardia 
Preferred term 
Tachycardia 
Extrasystoles 
Preferred term 
Extrasystoles 
Shortness of breath requiring intervention 
Preferred term 
Dyspnoea 
Neurologic 
Altered mental status 
Preferred term 
Mental Status Changes 
Altered sensorium 
Preferred term 
Depressed level of consciousness 
Rigidity 
Preferred term 
Muscle Rigidity 
Dysarthria 
Preferred term 
Dysarthria 
Seizure 
Preferred term 
Seizure 
Tremors 
Preferred term 
Tremor 
Metallic taste 
Preferred term 
Dysgeusia 
Tinnitus 
Preferred term 
Tinnitus 
Perioral numbness 
Preferred term 
Hypoaesthesia Oral 
Visual disturbance 
Preferred term 
Visual Impairment 
Dizziness 
Preferred term 
Dizziness 
Hyperesthesia 
Preferred term 
Hyperaesthesia 
Muscular twitching* 
Preferred term 
Muscle Twitching 
Tingling* 
Preferred term 
Paraesthesia 
Paresthesia* 
Preferred term 
Paraesthesia 
Other 
Fall 
Preferred term 
Fall 
* if event persists beyond or occurs after 72 hours after start of study treatment dose. 


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The analysis of the PK endpoints will be described in a separate document.   
9.10. 
Interim Analysis 
9.10.1. Pharmacokinetic Review 
 An interim PK analysis was completed by QuantPharm LLC after 13 subjects completed the 
assessments through postsurgical Day 10. All of the plasma samples from the subjects who 
received EXPAREL were analyzed and the plasma samples from the subjects randomized to 
placebo were analyzed through the 24-hour timepoint. Enrollment continued while the interim 
PK data were analyzed.  The goal of this third-party analysis was to determine the 
appropriateness of the PK timepoints selected and make recommendations to Pacira 
Pharmaceuticals (while maintaining the blind within Pacira Pharmaceuticals) to keep, remove, or 
revise the PK sampling scheme in order to fully characterize the PK profile. 
QuantPharm LLC indicated that the results of this analysis showed a median Tmax of 48 hours for 
the 133 mg EXPAREL group and a median Tmax of 60 hours for the 266 mg EXPAREL group. 
Based on this information, QuantPharm LLC recommended changes to the PK collection 
schedule contained protocol amendment 2. 
In addition, the safety assessment timepoints, including the neurological exam, vital signs, and 
ECG were adjusted based on the initial interim PK data.  
A confirmatory interim PK analysis was conducted by QuantPharm LLC once 30 subjects had 
completed the assessments through postsurgical Day 10.  No changes to the conduct of the study 
were recommended by QuantPharm LLC based on the confirmatory interim PK analysis. 
9.10.2. Sample Size Review 
The Original Protocol 402-C-327 issued on 24Nov2015 and Amendment 1 of Protocol 402-C-
327 issued on 15Feb2016 randomized subjects (1:1:1) to one of three treatment-arms 
(EXPAREL 266 mg, EXPAREL 133 mg, or Placebo).  Subjects randomized under Amendment 
2 of Protocol 402-C-327 were randomized (1:1) to one of two treatment-arms (EXPAREL 133 
mg or Placebo).    
The sample size of 120 subjects from Amendment 2 of Protocol 402-C-327 section 15.3 was 
calculated based on the assumption that the observed efficacy through 72 hours in 402-C-323 
would be the same as the observed efficacy through 48 hours in 402-C-327.  In 402-C-323, a 
common standard deviation (SD) of 170 was observed and with a 100-unit treatment difference 
for pain intensity scores through 72 hours.     
At the two-sided alpha level of 0.05, 47 subjects per treatment group would have at least 80% 
power to detect a 100 unit difference between treatment groups for the AUC of pain intensity 
scores through 48 hours, if the assumption of a common standard deviation (SD) of 170 is 
correct.  Approximately 120 subjects were planned for enrollment into this study in order to have 
at least 94 evaluable subjects between the EXPAREL 133 mg and placebo treatment groups. 
Within Amendment 2 of Protocol 402-C-327 section 15.8.1, an interim analysis was planned 
after 66 subjects had completed the assessments through Day 5.  This goal of this blinded interim 
analysis was to assess the assumption of a common standard deviation (SD) of 170.  This was to 
be based on the “quick and simple” procedure described by the Kieser and Friede paper10.  The 
procedure was designed to assess a blinded sample with subjects randomized 1:1 to two 


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treatment-arms, however the blinded 402-C-327 data contained subjects from three different 
treatment-arms.  Based on this revelation, it was concluded that the procedure described by 
Kieser and Friede would yield an inaccurate estimate of the common standard deviation (SD). 
A blinded interim analysis was conducted after 66 subjects had completed their assessments 
through Day 5.  This analysis did not utilize the blinded 402-C-327 data or the procedure 
described by Kieser and Friede.  Instead, this blinded interim analysis focused on the original 
assumptions linking the 402-C-323 results to the 402-C-327 sample size calculation. 
Consideration had not been previously given to the differences in statistical analysis methods 
between 402-C-323 and 402-C-327.  There were three key differences identified in the blinded 
interim analysis, they were: 
 
In the ANOVA model, 402-C-323 used the baseline pain intensity score as the covariate 
while 402-C-327 considered age, weight, and height as covariates. 
 
The 402-C-323 pain intensity score AUC from 0-72 hours was assumed to be the same as 
the observed 402-C-327 pain intensity score AUC from 0-48 hours. 
 
The 402-C-323 study addressed missing pain intensity score data using a single 
imputation technique while 402-C-327 addresses missing pain intensity score data using a 
multiple imputation technique.  
When the 402-C-323 data was reanalyzed using the 402-C-327 statistical analysis methods, the 
common standard deviation (SD) was found to be approximately 97 and a 46.6-unit treatment 
difference in 0-48 hour AUC of Pain Intensity scores was identified.  The sample size re-
estimation was based on these updated assumptions for a common standard deviation (SD) and 
treatment difference..  
9.11. 
Significance Testing 
See section 9.1.2. 


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10. 
SAMPLE SIZE CALCULATIONS 
The sample size was calculated based on efficacy as measured by the AUC of Pain Intensity 
scores through 48 hours from a previously conducted nerve block study using the 402-C-327 
primary analysis methods.  Assuming a 2-sided 0.05 alpha and a common standard deviation 
(SD) of 97, a sample size of 69 subjects per treatment group should have approximately 80% 
power to detect a 46.6-unit treatment difference.  Approximately 156 subjects are planned for 
enrollment into this study in order to have at least 138 evaluable subjects between the EXPAREL 
133 mg and placebo treatment groups. 


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11. 
REFERENCES 
 
                                                     
1 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 
2 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. 
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 Newcombe RG, Interval Estimation for the Difference between Independent Proportions: Comparison of Eleven 
Methods.  Statist. Med. 17, 873-890 (1998). 
 
9M Keiser, T Friede.  Simple procedures for blinded sample size adjustment that do not affect the type I error rate.  
Statistics in Medicine.  2003;22:3571-3581. 


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12. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES  
 
Please see the Protocol for the full “Time and Events Schedule of Study Procedures”.  Note that 
the study days defined in the table and footnotes start with surgery as Day 0; however, the SAP 
definitions start with surgery as Day 1.  The SAP follows the CDISC convention to define study 
day.  Thus in the SAP preop Day 0 is Day 1, Day 7 is Day 8, Day 10 is Day 11 and Day 29 is 
Day 30. 


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13. 
MULTIPLE IMPUTATION EXAMPLE PROGRAM CODE 
 
** Note: INPUT_DATA is the dataset that contains the VAS data with the wWOCF imputation performed 
**; 
 
** Step 1 use Markov-Chain Monte-Carlo (MCMC) method **; 
** Note the value for the random seed is fixed to be 123 so that the results are reproducible 
**; 
proc mi data= INPUT_DATA seed=123 nimpute=10 out= OUTPUT_STEP1 minimum=0 maximum=10; 
        by TRT01P; 
        mcmc impute=monotone nbiter=2000 niter=1000; 
        var aval atptn; 
run; quit; 
 
*** Step 2 derive endpoint using appropriate techniques   from INPUT_DATA to create INPUT_DATA2 
 
**; 
 
*** Step 3 analyze imputations   
 
 
 
 
 
 
 
**;  
DATA &a;  
 
set INPUT_DATA2; 
 
if param = &select and efffl = 'Y' and trt01pn ne 2; 
run; quit; 
proc sort data=&a; by _IMPUTATION_; run; quit; 
 
PROC MIXED DATA= &a METHOD=TYPE3; 
 
by _IMPUTATION_; 
 
class TRT01P; 
 
model AVAL = TRT01P AGE WEIGHT HEIGHT; 
 
lsmeans TRT01P/ diff= CONTROL('Placebo')  CL ; 
 
ods output LSMeans  = &b; 
 
ods output diffs    = &c; 
run; quit;  
 
proc sort data= &b; by TRT01P; run; 
PROC MIANALYZE DATA=&b ALPHA=0.05 THETA0=0;  
 
by TRT01P; 
 
modeleffects ESTIMATE;  
 
stderr STDERR; 
 
ods output PARAMETERESTIMATES=&d; 
run; quit; 
 
** Step 4 build report    
 
 
 
 
 
 
 
**; 
 
 


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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 is not to appear on any 
TLF. 
Note headers and footers on mock-ups are reflective of the SAP document and are not intended 
to appear on the TLFs. 
Titles on the TLFs in the mock-ups are presented left-justified as a single line of text.  However, 
the presentation for final TFLs should be center-justified with the TLF number on one line and 
the remaining titles on multiple lines of text where the line breaks are delimited by hyphens (-) in 
the TLF mock-ups titles.  For example, for Table 14.2-1.1.1 the title in the mock-up appears as: 
Table 14.2-1.1.1: Analysis of AUC of VAS Pain Intensity Scores through 48 
hours – Efficacy Analysis Set – Multiple Imputation Results 
but should appear as follows on the final TLF: 
Table 14.2-1.1.1 
Analysis of AUC of VAS Pain Intensity Scores through 48 hours 
Efficacy Analysis Set 
Multiple Imputation Results 
The title format in the mock-ups is due to limitations of MSWord.  The mock-up format enables 
MSWord to generate a table of contents for the mock-ups. 
On all listings the treatments, in order of appearance, are: EXPAREL 133 mg, EXPAREL 266 
mg, PLACEBO and, if applicable, NOT RANDOMIZED.  Always insert a page break between 
treatments. 
Sort all listings within treatment by site, subject with further sorts dependent on listing. 
Table and listing shells follow. 
For categorical variables, if subjects are missing data for a certain category (example Race), a 
missing subcategory should be added under the respective category. 
 


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14. 
TABLE OF CONTENTS FOR TABLE MOCK-UPS 
TABLE 14.1-1: SUMMARY OF SUBJECT DISPOSITION – ALL SCREENED SUBJECTS 
46 
TABLE 14.1-2.1.1: SUMMARY OF SUBJECT DEMOGRAPHICS - SAFETY ANALYSIS SET 
48 
TABLE 14.1-2.1.2: SUBJECT DEMOGRAPHICS – EFFICACY ANALYSIS SET 
48 
TABLE 14.1-2.1.3: SUBJECT DEMOGRAPHICS – PER-PROTOCOL ANALYSIS SET 
48 
TABLE 14.1-2.2.1: SUMMARY OF SUBJECT BASELINE CHARACTERISTICS - SAFETY 
ANALYSIS SET 
49 
TABLE 14.1-2.2.2: SUBJECT BASELINE CHARACTERISTICS – EFFICACY ANALYSIS SET 
53 
TABLE 14.1-2.2.3: SUBJECT BASELINE CHARACTERISTICS – PER-PROTOCOL ANALYSIS SET53 
TABLE 14.1-3.1: SUMMARY OF SURGERY CHARACTERISTICS - SAFETY ANALYSIS SET 
54 
TABLE 14.1-3.2: SUMMARY OF SURGERY CHARACTERISTICS (HOURS) – EFFICACY 
ANALYSIS SET 
54 
TABLE 14.1-3.3: SUMMARY OF SURGERY CHARACTERISTICS (HOURS) – PER-PROTOCOL 
ANALYSIS SET 
54 
TABLE 14.1-4.1: TABULATION OF INCIDENCE OF INTRAOPERATIVE MEDICATIONS - 
SAFETY ANALYSIS SET 
55 
TABLE 14.1-4.2: TABULATION OF INCIDENCE OF INTRAOPERATIVE MEDICATIONS - 
EFFICACY ANALYSIS SET 
55 
TABLE 14.1-4.3: TABULATION OF INCIDENCE OF INTRAOPERATIVE MEDICATIONS – PER-
PROTOCOL ANALYSIS SET 
55 
TABLE 14.1-5.1: SUMMARY OF SUBJECT DISPOSITION – BY REGION – ALL SCREENED 
SUBJECTS 
56 
TABLE 14.1-5.2.1.1: SUMMARY OF SUBJECT DEMOGRAPHICS – BY REGION - SAFETY 
ANALYSIS SET TABLE 14.1-5.2.1.2: SUMMARY OF SUBJECT DEMOGRAPHICS – 
BY REGION – EFFICACY ANALYSIS SET 
56 
TABLE 14.1-5.2.1.3: SUMMARY OF SUBJECT DEMOGRAPHICS – BY REGION – 
PER-PROTOCOL ANALYSIS SET 
56 
TABLE 14.1-5.2.2.1: SUMMARY OF SUMMARY OF SUBJECT BASELINE CHARACTERISTICS – 
BY REGION - SAFETY ANALYSIS SET 
56 
TABLE 14.1-5.2.2.2: SUMMARY OF SUBJECT BASELINE CHARACTERISTICS – BY REGION – 
EFFICACY ANALYSIS SET 
56 
TABLE 14.1-5.2.2.3: SUMMARY OF SUBJECT BASELINE CHARACTERISTICS – BY REGION – 
PER-PROTOCOL ANALYSIS SET 
56 
TABLE 14.1-5.3.1: SUMMARY OF SURGERY CHARACTERISTICS – BY REGION - SAFETY 
ANALYSIS SET 
56 
TABLE 14.1-5.3.2: SUMMARY OF SURGERY CHARACTERISTICS – BY REGION – EFFICACY 
ANALYSIS SET 
56 
TABLE 14.1-5.3.3: SUMMARY OF SURGERY CHARACTERISTICS – BY REGION – 
PER-PROTOCOL ANALYSIS SET 
56 
TABLE 14.2-1.1.1: ANALYSIS OF AUC OF VAS PAIN INTENSITY SCORES THROUGH 48 HOURS 
– EFFICACY ANALYSIS SET - MULTIPLE IMPUTATION RESULTS 
57 


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TABLE 14.2-1.1.2: SUMMARY OF AUC OF VAS PAIN INTENSITY SCORES THROUGH 48 
HOURS BY SITE AND SURGERY – EFFICACY ANALYSIS SET - MULTIPLE 
IMPUTATION RESULTS 
58 
TABLE 14.2-1.2.1: ANALYSIS OF AUC OF VAS PAIN INTENSITY SCORES THROUGH 48 HOURS 
– PER-PROTOCOL ANALYSIS SET - MULTIPLE IMPUTATION RESULTS 
62 
TABLE 14.2-1.2.2: SUMMARY OF AUC OF VAS PAIN INTENSITY SCORES THROUGH 48 
HOURS BY SITE AND SURGERY – PER-PROTOCOL ANALYSIS SET - MULTIPLE 
IMPUTATION RESULTS 
62 
TABLE 14.2-2.1.1: ANALYSIS OF POSTSURGICAL TOTAL OPIOID CONSUMPTION (MED MG) 
THROUGH 48 HOURS – EFFICACY ANALYSIS SET 
63 
TABLE 14.2-2.1.2: SUMMARY OF TOTAL OPIOID CONSUMPTION (MED MG) THROUGH 48 
HOURS BY SITE AND SURGERY - EFFICACY ANALYSIS SET 
64 
TABLE 14.2-2.1.3: ANALYSIS OF TOTAL OPIOID CONSUMPTION (MED MG) BY TIME PERIOD 
- EFFICACY ANALYSIS SET 
66 
TABLE 14.2-2.1.4: SUMMARY OF THE NUMBER OF TIMES OPIOID (RESCUE) MEDICATION 
WAS USED BY SUBJECT - EFFICACY ANALYSIS SET 
68 
TABLE 14.2-2.2.1: ANALYSIS OF POSTSURGICAL TOTAL OPIOID CONSUMPTION (MED MG) 
THROUGH 48 HOURS – PER-PROTOCOL ANALYSIS SET 
69 
TABLE 14.2-2.2.2: SUMMARY OF TOTAL OPIOID CONSUMPTION (MED MG) THROUGH 48 
HOURS BY SITE AND SURGERY - PER-PROTOCOL ANALYSIS 
69 
TABLE 14.2-2.2.3: ANALYSIS OF TOTAL OPIOID CONSUMPTION (MED MG) BY TIME PERIOD 
- PER-PROTOCOL ANALYSIS SET 
69 
TABLE 14.2-2.2.4: SUMMARY OF THE NUMBER OF TIMES OPIOID (RESCUE) MEDICATION 
WAS USED BY SUBJECT - PER-PROTOCOL ANALYSIS SET 
69 
TABLE 14.2-3.1.1: ANALYSIS OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS - EFFICACY 
ANALYSIS SET 
70 
TABLE 14.2-3.1.2: SUMMARY OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS BY SITE AND 
SURGERY - EFFICACY ANALYSIS SET 
71 
TABLE 14.2-3.2.1: ANALYSIS OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS - 
PER-PROTOCOL ANALYSIS SET 
72 
TABLE 14.2-3.2.2: SUMMARY OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS BY SITE AND 
SURGERY - PER-PROTOCOL ANALYSIS SET 
72 
TABLE 14.2-4.1: ANALYSIS OF TIME TO FIRST RESCUE MEDICATION USE (HOURS) - 
EFFICACY ANALYSIS SET 
73 
TABLE 14.2-4.2: ANALYSIS OF TIME TO FIRST RESCUE MEDICATION USE (HOURS) – 
PER-PROTOCOL ANALYSIS SET 
73 
TABLE 14.2-5.1: ANALYSIS OF VAS AUC AT VARIOUS TIME INTERVALS - EFFICACY 
ANALYSIS SET 
75 
TABLE 14.2-5.2: SUMMARY OF VAS AT ASSESSMENT TIMEPOINTS - EFFICACY ANALYSIS 
SET 
77 
TABLE 14.2-5.3: ANALYSIS OF VAS SPIS AT VARIOUS TIME INTERVALS - EFFICACY 
ANALYSIS SET 
78 
TABLE 14.2-6: ANALYSIS OF PAIN-FREE SUBJECTS AT ASSESSMENT TIMEPOINTS - 
EFFICACY ANALYSIS SET 
79 


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TABLE 14.2-7: ANALYSIS OF OPIOID-FREE SUBJECTS THROUGH 24 AND 72 HOURS - 
EFFICACY ANALYSIS SET 
80 
TABLE 14.2-8: ANALYSIS OF OVERALL BENEFIT OF ANALGESIA TOTAL SCORE BY 
TIMEPOINT AND QUESTION - EFFICACY ANALYSIS SET 
81 
TABLE 14.2-9: ANALYSIS OF SATISFACTION WITH POSTSURGICAL PAIN CONTROL 
QUESTIONNAIRE SCORE BY TIMEPOINT - EFFICACY ANALYSIS SET 
83 
TABLE 14.2-10.1: ANALYSIS OF TIME TO DISCHARGE READY - EFFICACY ANALYSIS SET 
84 
TABLE 14.2-10.2: SUMMARY OF DISCHARGE READY AT ASSESSMENT - EFFICACY 
ANALYSIS SET 
85 
TABLE 14.2-11: ANALYSIS OF NUMBER OF UNSCHEDULED PHONE CALLS OR OFFICE 
VISITS RELATED TO PAIN - EFFICACY ANALYSIS SET 
87 
TABLE 14.2-12.1.1.1: REGION ANALYSIS OF AUC OF VAS PAIN INTENSITY SCORES 
THROUGH 48 HOURS – EFFICACY ANALYSIS SET - MULTIPLE IMPUTATION 
RESULTS 
88 
TABLE 14.2-12.2.1.1: REGION ANALYSIS OF POSTSURGICAL TOTAL OPIOID CONSUMPTION 
(MED MG) THROUGH 48 HOURS – EFFICACY ANALYSIS SET 
88 
TABLE 14.2-12.2.1.2: REGION SUMMARY OF TOTAL OPIOID CONSUMPTION (MED MG) 
THROUGH 48 HOURS BY REGION - EFFICACY ANALYSIS SET 
88 
TABLE 14.2-12.2.1.3: REGION SUMMARY OF TOTAL OPIOID CONSUMPTION (MED MG) BY 
TIME PERIOD - EFFICACY ANALYSIS SET 
88 
TABLE 14.2-12.2.1.4: REGION SUMMARY OF THE NUMBER OF TIMES OPIOID (RESCUE) 
MEDICATION WAS USED BY SUBJECT - EFFICACY ANALYSIS SET 
88 
TABLE 14.2-12.2.2.1: REGION ANALYSIS OF POSTSURGICAL TOTAL OPIOID CONSUMPTION 
(MED MG) THROUGH 48 HOURS – PER-PROTOCOL ANALYSIS SET 
88 
TABLE 14.2-12.2.2.2: REGION SUMMARY OF TOTAL OPIOID CONSUMPTION (MED MG) 
THROUGH 48 HOURS BY SITE - PER-PROTOCOL ANALYSIS SET 
89 
TABLE 14.2-12.2.2.3: REGION SUMMARY OF TOTAL OPIOID CONSUMPTION (MED MG) BY 
TIME PERIOD - PER-PROTOCOL ANALYSIS SET 
89 
TABLE 14.2-12.2.2.4: REGION SUMMARY OF THE NUMBER OF TIMES OPIOID (RESCUE) 
MEDICATION WAS USED BY SUBJECT - PER-PROTOCOL ANALYSIS SET 
89 
TABLE 14.2-12.3.1.1: REGION ANALYSIS OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS - 
EFFICACY ANALYSIS SET 
89 
TABLE 14.2-12.3.1.2: REGION SUMMARY OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS 
BY SITE - EFFICACY ANALYSIS SET 
89 
TABLE 14.2-12.3.2.1: REGION ANALYSIS OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS - 
PER-PROTOCOL ANALYSIS SET 
89 
TABLE 14.2-12.3.2.2: REGION SUMMARY OF OPIOID-FREE SUBJECTS THROUGH 48 HOURS 
BY SITE - PER-PROTOCOL ANALYSIS SET 
89 
TABLE 14.3-1.1.1: SUMMARY OF CLINICAL LABORATORY DATA BY TIMEPOINT – 
HEMATOLOGY - SAFETY ANALYSIS SET 
90 
TABLE 14.3-1.1.2: SUMMARY OF CLINICAL LABORATORY DATA BY TIMEPOINT – 
CHEMISTRY - SAFETY ANALYSIS SET 
91 
TABLE 14.3-1.1.3.1: SUMMARY OF CLINICAL LABORATORY DATA BY TIMEPOINT – 
URINALYSIS - SAFETY ANALYSIS SET 
91 


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TABLE 14.3-1.1.3.2: TABULATION OF CLINICAL LABORATORY DATA BY TIMEPOINT – 
URINALYSIS - SAFETY ANALYSIS SET 
92 
TABLE 14.3-1.2.1: TABULATION OF CLINICAL LABORATORY RANGE BY TIMEPOINT – 
HEMATOLOGY - SAFETY ANALYSIS SET 
93 
TABLE 14.3-1.2.2: TABULATION OF CLINICAL LABORATORY RANGE BY TIMEPOINT – 
CHEMISTRY - SAFETY ANALYSIS SET 
93 
TABLE 14.3-1.2.3: TABULATION OF CLINICAL LABORATORY RANGE BY TIMEPOINT – 
URINALYSIS - SAFETY ANALYSIS SET 
93 
TABLE 14.3-1.3.1: SHIFT TABLE FOR CLINICAL LABORATORY DATA BY TIMEPOINT – 
HEMATOLOGY - SAFETY ANALYSIS SET 
94 
TABLE 14.3-1.3.2: SHIFT TABLE FOR CLINICAL LABORATORY DATA BY TIMEPOINT – 
CHEMISTRY - SAFETY ANALYSIS SET 
94 
TABLE 14.3-1.3.3: SHIFT TABLE FOR CLINICAL LABORATORY DATA BY TIMEPOINT – 
URINALYSIS - SAFETY ANALYSIS SET 
94 
TABLE 14.3-2.1: SUMMARY OF VITAL SIGNS BY TIMEPOINT – SAFETY ANALYSIS SET 
95 
TABLE 14.3-2.2: SUMMARY OF POTENTIALLY CLINICALLY SIGNIFICANT ABNORMAL 
VITAL SIGNS – SAFETY ANALYSIS SET 
97 
TABLE 14.3-3.1: SUMMARY OF ELECTROCARDIOGRAM INTERPRETATION – INVESTIGATOR 
READ - SAFETY ANALYSIS SET 
100 
TABLE 14.3-3.2: SHIFT TABLE FOR ELECTROCARDIOGRAM INTERPRETATION – 
INVESTIGATOR READ - SAFETY ANALYSIS SET 
101 
TABLE 14.3-4: SUMMARY OF NEUROLOGICAL ASSESSMENTS BY TIMEPOINT- SAFETY 
ANALYSIS SET 
102 
TABLE 14.3-5.1: TABULATION OF SENSATION TESTS – SAFETY ANALYSIS SET 
103 
TABLE 14.3-5.2: SUMMARY OF SENSATION LOSS AND RETURN BY TIMEPOINT – SAFETY 
ANALYSIS SET 
104 
TABLE 14.3-5.3.1: ANALYSIS OF TIME TO FIRST SENSATION LOSS – SAFETY ANALYSIS SET106 
TABLE 14.3-5.4.1: ANALYSIS OF TIME TO FIRST SENSATION RETURN – SAFETY ANALYSIS 
SET 
108 
TABLE 14.3-5.5: SUMMARY OF DURATION (HRS) OF SENSATION LOSS – SAFETY ANALYSIS 
SET 
110 
TABLE 14.3-5.6: SUMMARY OF THE NUMBER OF SENSATION LOSS-RETURN CYCLES - 
SAFETY ANALYSIS SET 
111 
TABLE 14.3-6.1: SUMMARY OF MOTOR FUNCTION LOSS AND RETURN BY TIMEPOINT – 
SAFETY ANALYSIS SET 
112 
TABLE 14.3-6.2: ANALYSIS OF TIME TO ONSET OF MOTOR FUNCTION LOSS - EFFICACY 
ANALYSIS SET 
113 
TABLE 14.3-6.3: ANALYSIS OF TIME TO RETURN OF MOTOR FUNCTION - EFFICACY 
ANALYSIS SET 
114 
TABLE 14.3-6.4: SUMMARY OF MOTOR FUNCTION ASSESSMENTS BY TIMEPOINT – SAFETY 
ANALYSIS SET 
115 
TABLE 14.3-7.1.1: OVERVIEW OF TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) - 
SAFETY ANALYSIS SET 
117 


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TABLE 14.3-7.1.2: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) - SAFETY ANALYSIS SET 
118 
TABLE 14.3-7.1.3: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS (TEAES) - SAFETY ANALYSIS SET 
118 
TABLE 14.3-7.1.4: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) LEADING TO STUDY WITHDRAWAL - SAFETY ANALYSIS SET118 
TABLE 14.3-7.1.5: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS (TEAES) LEADING TO STUDY WITHDRAWAL - 
SAFETY ANALYSIS SET 
118 
TABLE 14.3-7.1.6: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) BY SEVERITY - SAFETY ANALYSIS SET 
119 
TABLE 14.3-7.1.7: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) BY RELATIONSHIP TO STUDY DRUG - SAFETY ANALYSIS SET120 
TABLE 14.3-7.2.1: OVERVIEW OF SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS 
(TEAES) - SAFETY ANALYSIS SET 
121 
TABLE 14.3-7.2.2: SUMMARY OF INCIDENCE OF SERIOUS TREATMENT-EMERGENT 
ADVERSE EVENTS (TEAES) - SAFETY ANALYSIS SET 
121 
TABLE 14.3-7.2.3: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED SERIOUS 
TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) - SAFETY ANALYSIS SET121 
TABLE 14.3-7.2.4: SUMMARY OF INCIDENCE OF SERIOUS TREATMENT-EMERGENT 
ADVERSE EVENTS (TEAES) LEADING TO STUDY WITHDRAWAL - SAFETY 
ANALYSIS SET 
121 
TABLE 14.3-7.2.5: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED SERIOUS 
TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) LEADING TO STUDY 
WITHDRAWAL - SAFETY ANALYSIS SET 
121 
TABLE 14.3-7.2.6: SUMMARY OF INCIDENCE OF SERIOUS TREATMENT-EMERGENT 
ADVERSE EVENTS (TEAES) RESULTING IN DEATH - SAFETY ANALYSIS SET 121 
TABLE 14.3-7.2.7: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED SERIOUS 
TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) RESULTING IN DEATH - 
SAFETY ANALYSIS SET 
121 
TABLE 14.3-7.3.1: OVERVIEW OF TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) OF 
SPECIAL INTEREST - SAFETY ANALYSIS SET 
121 
TABLE 14.3-7.3.2: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) OF SPECIAL INTEREST - SAFETY ANALYSIS SET 
121 
TABLE 14.3-7.3.3: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS (TEAES) OF SPECIAL INTEREST - SAFETY 
ANALYSIS SET 
121 
TABLE 14.3-7.3.4: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) OF SPECIAL INTEREST LEADING TO STUDY WITHDRAWAL - 
SAFETY ANALYSIS SET 
121 
TABLE 14.3-7.3.5: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS (TEAES) OF SPECIAL INTEREST LEADING TO 
STUDY WITHDRAWAL - SAFETY ANALYSIS SET 
122 
TABLE 14.3-7.3.6: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) OF SPECIAL INTEREST RESULTING IN DEATH - SAFETY 
ANALYSIS SET 
122 


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TABLE 14.3-7.3.7: SUMMARY OF INCIDENCE OF STUDY DRUG-RELATED TREATMENT-
EMERGENT ADVERSE EVENTS (TEAES) OF SPECIAL INTEREST RESULTING IN 
DEATH - SAFETY ANALYSIS SET 
122 
TABLE 14.3-8.1: INCIDENCE OF PRIOR MEDICATIONS – SAFETY ANALYSIS SET 
123 
TABLE 14.3-8.2: INCIDENCE OF CONCOMITANT MEDICATIONS – SAFETY ANALYSIS SET 123 
TABLE 14.3-9.1.1: REGION TABULATION OF SENSATION TESTS – SAFETY ANALYSIS SET 124 
TABLE 14.3-9.1.2: REGION SUMMARY OF SENSATION LOSS AND RETURN BY TIMEPOINT – 
SAFETY ANALYSIS SET 
124 
TABLE 14.3-9.1.3: REGION ANALYSIS OF TIME TO SENSATION LOSS – SAFETY ANALYSIS 
SET 
124 
TABLE 14.3-9.1.4: REGION ANALYSIS OF TIME TO SENSATION RETURN – SAFETY 
ANALYSIS SET 
124 
TABLE 14.3-9.1.5: REGION SUMMARY OF DURATION (HRS) OF SENSATION LOSS – SAFETY 
ANALYSIS SET 
124 
TABLE 14.3-9.2.1: REGION SUMMARY OF ACTIVE MOTOR FUNCTION LOSS AND RETURN 
BY TIMEPOINT – SAFETY ANALYSIS SET 
124 
TABLE 14.3-9.2.2: REGION ANALYSIS OF TIME TO ONSET OF MOTOR FUNCTION LOSS - 
EFFICACY ANALYSIS SET 
124 
TABLE 14.3-9.2.3: REGION ANALYSIS OF TIME TO RETURN OF MOTOR FUNCTION - 
EFFICACY ANALYSIS SET 
124 
USE MOCK-UP 14.3-6.4 FOR TABLE: 
124 
TABLE 14.3-9.2.4: REGION SUMMARY OF MOTOR FUNCTION ASSESSMENTS BY TIMEPOINT 
– SAFETY ANALYSIS SET 
124 
TABLE 14.3-9.3.1: REGION OVERVIEW OF TREATMENT-EMERGENT ADVERSE EVENTS 
(TEAES) - SAFETY ANALYSIS SET 
125 
TABLE 14.3-9.3.2: REGION SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT 
ADVERSE EVENTS (TEAES) - SAFETY ANALYSIS SET 
126 
TABLE 14.3-9.3.3: REGION SUMMARY OF INCIDENCE OF SERIOUS TREATMENT-EMERGENT 
ADVERSE EVENTS (TEAES) - SAFETY ANALYSIS SET 
126 


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Table 14.1-1: Summary of Subject Disposition – All Screened Subjects 
 
Site: Overall 
EXPAREL 
 
 
 
133 mg 
n (%) 
266 mg 
n (%) 
All EXPAREL 
n (%) 
Placebo 
n (%) 
Total 
n (%) 
Screened [1] 
 
 
 
 
xx 
   Screen Failure [1] 
 
 
 
 
xx (xx.x) 
   Enrolled [1] 
 
 
 
 
xx (xx.x) 
 
 
 
 
 
 
Randomized 
xx 
xx 
xx 
xx 
xx 
  Not Treated 
xx 
xx 
xx 
xx 
xx 
  Treated 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Safety Analysis Set [2]# 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Efficacy Analysis Set [3]@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Per-Protocol Analysis Set [4]@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Protocol 
 
 
 
 
 
  Enrolled under Amendment 2 [2]# 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Enrolled under Amendment 1 [2]# 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Enrolled under Original Protocol [2]# 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Completed Study@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Discontinued from Study@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Reasons for Discontinuation@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Death@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Adverse Event@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lack of Efficacy@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lost to Follow-up@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Withdrawal by Subject@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Other@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
# = as treated; 
@ = as randomized; 
[1] Signed the informed consent form; 
[2] Received study drug; 
[3] Received study drug and surgery; 
 
[4] All subjects in the efficacy analysis set who do not have any important protocol deviations;  
Percentages for screen failure and enrolled based on number screened; others on number randomized. 
Subjects randomized to EXPAREL but treated with placebo: list subjects; 
Subjects randomized to placebo but treated with EXPAREL: list subjects; 


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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 reasons for discontinuation only those reasons that appear in the data will appear on 
the table.  For individual sites the label should be the site number.  For the footnotes “Subjects 
randomized to … treated with...” if no subjects were mistreated, then omit footnote. 
 
 


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Protocol: 402-C-327 
Table 14.1-2.1.1: Summary of Subject Demographics - Safety Analysis Set 
 
Site: Overall 
 
EXPAREL 
 
 
 
Statistic 
133 mg 
[N=XX] 
266 mg 
[N=XX] 
All EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XX] 
Age (yrs) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
Sex 
 
 
 
 
 
 
  Female 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Male 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ethnicity 
 
 
 
 
 
 
  Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Race 
 
 
 
 
 
 
  American Indian/Alaska Native 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Black/African American 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Hawaiian/Pacific Islander 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Country 
 
 
 
 
 
 
  Belgium 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Denmark 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  USA 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Dominant Hand 
 
 
 
 
 
 
  Left 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Right 
n (%) 
xx (xx.x) 
xx (xx.x) 
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: First page will present overall sites; subsequent pages will present each site – one 
site per page. Only categories available in the data will appear on the table.  For individual sites the 
label should be the site number. If subjects are missing data for a category (example Race), a missing 
subcategory should be added under the respective category. Use this template also for table: 
 
Table 14.1-2.1.2: Subject Demographics – Efficacy Analysis Set  
Table 14.1-2.1.3: Subject Demographics – Per-protocol Analysis Set  
 


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Protocol: 402-C-327 
Table 14.1-2.2.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
 
Site: Overall 
 
EXPAREL 
 
 
 
Statistic 
133 mg  
[N=XX] 
266 mg 
[N=XX] 
All EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XX] 
 
 
 
 
 
 
 
Neurological Assessments 
 
 
 
 
 
 
   Subject oriented 
 
 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Numb lips, tongue, mouth 
 
 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Metallic taste 
 
 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Problems hearing 
 
 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Problems with vision 
 
 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Muscle twitch 
 
 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
ECG 
 
 
 
 
 
 
  Normal 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Abnormal, NCS 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Abnormal, CS 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
NCS = Not clinically significant 
CS = Clinically significant 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If subjects are missing data for a category (example Race), a missing subcategory should be added under the respective 
category. 
 


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Table 14.1-2.2.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
 
Site: Overall 
 
EXPAREL 
 
 
 
Statistic 
133 mg  
[N=XX] 
266 mg 
[N=XX] 
All EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XX] 
 
 
 
 
 
 
 
Motor Assessments 
 
 
 
 
 
 
  Thumb Abduction 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
  Thumb Adduction 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
  Thumb Opposition 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
  Elbow Flexion 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Protocol: 402-C-327 
Table 14.1-2.2.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
 
Site: Overall 
 
EXPAREL 
 
 
 
Statistic 
133 mg  
[N=XX] 
266 mg 
[N=XX] 
All EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XX] 
 
 
 
 
 
 
 
VAS Score (cm) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
ASA Classification 
 
 
 
 
 
 
  1 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  2 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  3 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  ≥ 4 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Height(cm) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Weight (kg) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name  
 
 


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Pacira Pharmaceuticals 
(Page 4 of 4) 
Protocol: 402-C-327 
Table 14.1-2.2.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
 
Site: Overall 
 
EXPAREL 
 
 
 
Statistic 
133 mg  
[N=XX] 
266 mg 
[N=XX] 
All EXPAREL 
[N=XX] 
Placebo 
[N=XX] 
Total 
[N=XX] 
 
 
 
 
 
 
 
Body Mass Index (kg/m2) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Heart Rate (bpm) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Systolic Blood Pressure (mmHg) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
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: 


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Table 14.1-2.2.2: Subject Baseline Characteristics – Efficacy Analysis Set  
Table 14.1-2.2.3: Subject Baseline Characteristics – Per-protocol Analysis Set  
 
 


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Table 14.1-3.1: Summary of Surgery Characteristics - Safety Analysis Set 
 
Site: Overall 
EXPAREL 
 
 
Characteristic 
Statistic 
133 mg  
[N=XX] 
266 mg 
[N=XX] 
All EXPAREL 
[N=XX] 
Placebo  
[N=XX] 
Total 
[N=XX] 
 
 
 
 
 
 
 
Surgery Type 
 
 
 
 
 
 
  Rotator Cuff Repair 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Total Shoulder Arthroplasty n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Conventional 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Reverse 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
Nerve Block Type 
 
 
 
 
 
 
  Interscalene 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Supraclavicular 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
Duration of Surgery (hours) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx 
xx 
xx 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Total Incision Length (cm) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
xx 
xx 
xx 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
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 tables: 
 
Table 14.1-3.2: Summary of Surgery Characteristics (hours) – Efficacy Analysis Set  
Table 14.1-3.3: Summary of Surgery Characteristics (hours) – Per-protocol Analysis Set 
 
Pacira Pharmaceuticals 
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Table 14.1-4.1: Tabulation of Incidence of Intraoperative Medications - Safety Analysis Set 
 
EXPAREL 
 
 
Anatomical Therapeutic Class (ATC) 
  Preferred Name 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 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) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
ATC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
ATC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PN2.1 
xx (xx.x) 
xx (xx.x) 
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) 
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 for Total column.  Subjects using the same intraoperative 
medication (PT) more than once or multiple medications within an ATC class are counted only once at each 
ATC summary level. 
Intraoperatives medications are those indicated as such by the investigator. 
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: 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 tables: 
 
Table 14.1-4.2: Tabulation of Incidence of Intraoperative Medications - Efficacy Analysis Set  
Table 14.1-4.3: Tabulation of Incidence of Intraoperative Medications – Per-Protocol Analysis Set  
 
 
 


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Note to programmer:  For the following region summaries, ‘Site:’ will be replaced with ‘Region:’.  Regions, 
in order of appearance, are US and ROW.  There will be no overall region summary presented on these tables. 
  
Use template 14.1-1 for table: 
 
Table 14.1-5.1: Summary of Subject Disposition – By Region – All Screened Subjects 
 
Use template 14.1-2.1.1 for tables: 
 
Table 14.1-5.2.1.1: Summary of Subject Demographics – By Region - Safety Analysis Set 
Table 14.1-5.2.1.2: Summary of Subject Demographics – By Region – Efficacy Analysis Set  
Table 14.1-5.2.1.3: Summary of Subject Demographics – By Region – Per-protocol Analysis Set  
 
Use template 14.1-2.2.1 for tables: 
 
Table 14.1-5.2.2.1: Summary of Summary of Subject Baseline Characteristics – By Region - Safety Analysis 
Set 
Table 14.1-5.2.2.2: Summary of Subject Baseline Characteristics – By Region – Efficacy Analysis Set  
Table 14.1-5.2.2.3: Summary of Subject Baseline Characteristics – By Region – Per-protocol Analysis Set  
 
Use template 14.1-3.1 for tables: 
 
Table 14.1-5.3.1: Summary of Surgery Characteristics – By Region - Safety Analysis Set 
Table 14.1-5.3.2: Summary of Surgery Characteristics – By Region – Efficacy Analysis Set  
Table 14.1-5.3.3: Summary of Surgery Characteristics – By Region – Per-protocol Analysis Set 
 
 
 


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Table 14.2-1.1.1: Analysis of AUC of VAS Pain Intensity Scores through 48 hours – Efficacy Analysis Set - 
Multiple Imputation Results 
 
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
N 
 
xx 
 
xx 
Mean 
 
xxx.x 
 
xxx.x 
SD 
 
xxx.xx 
 
xxx.xx 
Median 
 
xxx.x 
 
xxx.x 
Minimum 
 
xx 
 
xx 
Maximum 
 
xxx 
 
xxx 
 
 
 
LS Mean [1]  
 
xxx.x 
 
xxx.x 
Standard Error of LS Mean [1] 
 
xxx.xx 
 
xxx.xx 
LS Treatment Difference [1][2] 
 
xx.x 
 
Treatment Difference 95% Confidence Interval [1][2] 
(xx.x, xx.x) 
 
Treatment Difference p-value [1][2] 
 
0.xxx 
 
 
 
 
 
AUC = area under the curve calculated using the trapezoidal method; 
LS = least squares; 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain; 
[1] From an ANOVA with age, weight, and height as covariates.   
[2] Treatment difference is EXPAREL – placebo. 
 
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)..  
 
  
 
 
 
 
 
 
 
 
 


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Table 14.2-1.1.2: Summary of AUC of VAS Pain Intensity Scores through 48 hours by Site and Surgery – 
Efficacy Analysis Set - Multiple Imputation Results 
 
 
Site 
Surgery 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
XXX 
All 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
     
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
RCR 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
     
 
Maximum 
xx 
xx 
 
 
 
 
 
 
TSA-All 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
TSA-Conventional  n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
     
TSA-Reverse  
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 


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Site 
Surgery 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
RCR = Rotator Cuff Repair; TSA = Total Shoulder Arthoplasty; 
AUC = area under the curve calculated using the trapezoidal method; 
 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain; 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Present for each site by surgery (All, RCR, TSA-ALL, TSA-Conventional, TSA-Reverse).  
For pooled sites, present the pooled site first and then each site contributing to the pool immediately 
after.  Do not split a site’s/surgery statistics across pages.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Note to programmer: The raw SAS outputs from the procedures used to produce ALL 14.2-1.1.* series tables 
should be saved as a possible appendix to the clinical study report (CSR).  
 
 


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Note to programmer:  Use the mock-ups indicated to for following tables: 
Mock-up 14.2-1.1.1:  
Table 14.2-1.2.1: Analysis of AUC of VAS Pain Intensity Scores through 48 hours – Per-protocol Analysis Set 
- Multiple Imputation Results  
 
 
Mock-up 14.2-1.1.2:  
Table 14.2-1.2.2: Summary of AUC of VAS Pain Intensity Scores through 48 hours by Site and Surgery – 
Per-protocol Analysis Set - Multiple Imputation Results 
 
 
 


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Table 14.2-2.1.1: Analysis of Postsurgical Total Opioid Consumption (MED mg) through 48 hours – Efficacy 
Analysis Set  
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
N 
 
xx 
 
xx 
Geometric Mean 
 
xxx.x 
 
xxx.x 
%CV 
 
xxx.xx 
 
xxx.xx 
Minimum 
 
xx 
 
xx 
Maximum 
 
xxx 
 
xxx 
 
 
 
LS Mean [1]  
 
xxx.x 
 
xxx.x 
 Standard Error of LS Mean [1] 
 
xxx.xx 
 
xxx.xx 
LS Treatment Ratio [1][2] 
 
xx.x 
 
Treatment Ratio 95% Confidence Interval [1][2] 
(xx.x, xx.x) 
 
Treatment Ratio p-value [1][2] 
 
0.xxx 
 
 
 
 
 
[1] From an ANOVA with age, weight, and height as covariates on log-transformed total opioid consumption.   
    Subjects without any opioid use are set to 0.1 or half of the smallest total amount observed in the 
study, whichever is smaller, prior to being transformed with the natural logarithm. Results are back-
transformed. 
[2] Treatment ratio is EXPAREL / placebo. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Table 14.2-2.1.2: Summary of Total Opioid Consumption (MED mg) through 48 hours by Site and Surgery - 
Efficacy Analysis Set 
 
 
Site 
Surgery 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
XXX 
All 
n 
xx 
xx 
 
 
Geometric Mean 
xx.x 
xx.x 
 
 
%CV 
x.xx 
x.xx 
     
 
Minimum 
xx 
xx 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
RCR 
n 
xx 
xx 
 
 
Geometric Mean 
xx.x 
xx.x 
 
 
%CV 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
     
 
Maximum 
xx 
xx 
 
 
 
 
 
 
TSA-All 
n 
xx 
xx 
 
 
Geometric Mean 
xx.x 
xx.x 
 
 
%CV 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
TSA-Conventional  n 
xx 
xx 
 
 
Geometric Mean 
xx.x 
xx.x 
 
 
%CV 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
     
TSA-Reverse  
n 
xx 
xx 
 
 
Geometric Mean 
xx.x 
xx.x 
 
 
%CV 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Maximum 
xx 
xx 
RCR = Rotator Cuff Repair; TSA = Total Shoulder Arthoplasty; 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 


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Note to programmer: Present for each site by surgery (All, RCR, TSA-ALL, TSA-Conventional, TSA-Reverse).  
For pooled sites, present the pooled site first and then each site contributing to the pool immediately 
after.  Do not split a site’s/surgery statistics across pages.  
 
 


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Table 14.2-2.1.3: Analysis of Total Opioid Consumption (MED mg) by Time Period - Efficacy Analysis Set 
 
Time Period 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
0-24 hrs 
N 
xx 
xx 
 
Geometric Mean 
xxx.x 
xxx.x 
 
%CV 
xxx.xx 
xxx.xx 
 
Minimum 
xx 
xx 
 
Maximum 
xxx 
xxx 
 
 
 
 
 
LS Mean [1]  
xxx.x 
xxx.x 
 
 Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
 
LS Treatment Ratio [1][2] 
xx.x 
xx.x 
 
Treatment Ratio 95% Confidence Interval [1][2] 
(xx.x, xx.x) 
 
 
Treatment Ratio p-value [1][2] 
0.xxx 
 
     
 
 
 
0-72 hrs 
N 
xx 
xx 
 
Geometric Mean 
xxx.x 
xxx.x 
 
%CV 
xxx.xx 
xxx.xx 
 
Minimum 
xx 
xx 
 
Maximum 
xxx 
xxx 
 
 
 
 
 
LS Mean [1]  
xxx.x 
xxx.x 
     
 Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
 
LS Treatment Ratio [1][2] 
xx.x 
xx.x 
 
Treatment Ratio 95% Confidence Interval [1][2] 
(xx.x, xx.x) 
 
 
Treatment Ratio p-value [1][2] 
xxx.x 
 
 
 
 
 
 
 
 
 
[1] From an ANOVA with age, weight, and height as covariates on log-transformed total opioid consumption.   
    Subjects without any opioid use are set to 0.1 or half of the smallest total amount observed in the 
study, whichever is smaller, prior to being transformed with the natural logarithm. Results are back-
transformed.   
[2] Treatment ratio is EXPAREL / placebo. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 


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Note to programmer: Present overall sites and for each site. Time periods to appear on this table, in 
order, are 0-24, 0-72, 24-48 and 48-72.  Do not split a time period statistics across pages. 
 
 


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Table 14.2-2.1.4: Summary of the Number of Times Opioid (Rescue) Medication was used by Subject - Efficacy 
Analysis Set 
 
 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
Count Summary 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
SD 
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 overall sites and for each site. Distribution should present all counts up to 
the highest number of times for opioid rescue in the data (U) on each page. 
 
 


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Note to programmer:  Use the mock-ups indicated to for following tables: 
Mock-up 14.2.1.1: 
Table 14.2-2.2.1: Analysis of Postsurgical Total Opioid Consumption (MED mg) through 48 hours – 
Per-protocol Analysis Set  
Mock-up 14.2.1.2: 
Table 14.2-2.2.2: Summary of Total Opioid Consumption (MED mg) through 48 hours by Site and Surgery - 
Per-protocol Analysis  
Mock-up 14.2.1.3: 
Table 14.2-2.2.3: Analysis of Total Opioid Consumption (MED mg) by Time Period - Per-protocol Analysis Set  
Mock-up 14.2.1.4: 
Table 14.2-2.2.4: Summary of the Number of Times Opioid (Rescue) Medication was used by Subject - 
Per-protocol Analysis Set 
 
 
 
 


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Table 14.2-3.1.1: Analysis of Opioid-Free Subjects through 48 hours - Efficacy Analysis Set 
 
 
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
No Opioid Use 
n (%) 
xx (xx.x) 
xx (xx.x) 
Opioid Used 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Treatment Difference [1] 
xx.x 
 
 
95% CI for Difference [1] 
(xx.x, xx.x) 
 
 
p-value [2] 
0.xxxx 
 
 
 
 
 
[1] Treatment difference (EXPAREL – placebo) and 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. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


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Table 14.2-3.1.2: Summary of Opioid-Free Subjects through 48 hours by Site and Surgery - Efficacy Analysis 
Set 
 
Site 
Surgery 
Opioid Use 
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
 
 
XXX 
All 
No Opioid Use 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
Opioid Used 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
RCR 
No Opioid Use 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
Opioid Used 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
TSA-All 
No Opioid Use 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
Opioid Used 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
TSA-Conventional 
No Opioid Use 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
Opioid Used 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
TSA-Reverse 
No Opioid Use 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
Opioid Used 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
RCR = Rotator Cuff Repair; TSA = Total Shoulder Arthoplasty; 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Present for each site on a separate page.  For pooled sites, present the pooled site 
first and then each site contributing to the pool immediately after. 
 
 


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Note to programmer:  Use the mock-ups indicated to for following tables: 
Mock-up 14.2-3.1.1: 
Table 14.2-3.2.1: Analysis of Opioid-Free Subjects through 48 hours - Per-protocol Analysis Set  
Mock-up 14.2-3.1.2: 
Table 14.2-3.2.2: Summary of Opioid-Free Subjects through 48 hours by Site and Surgery - Per-protocol 
Analysis Set  
 
 
 
 
 


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Table 14.2-4.1: Analysis of Time to First Rescue Medication Use (hours) - Efficacy Analysis Set 
 
 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo 
[N=XX] 
 
 
 
 
Number of Subjects on 
 
 
 
  Rescue Medication (Opioid) 
n (%) 
xx (xx.x) 
xx (xx.x) 
  No Rescue Medication (censored) 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Time to First Rescue 
 
 
 
  Quartiles [1] 
 
 
 
    First (25% rescued) 
Estimate  
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
    Median (50% rescued) 
Estimate 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
    Third (75% rescued) 
Estimate 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
  Minimum 
Observed 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx 
 
 
 
 
  p-value [2] 
 
0.xxxx 
 
 
 
 
 
* indicates censored observation 
 
CI = confidence interval 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from Log-Rank test comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this mock-ups indicated to for following table: 
Table 14.2-4.2: Analysis of Time to First Rescue Medication Use (hours) – Per-protocol Analysis Set 
 
 


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Table 14.2-5.1: Analysis of VAS AUC at Various Time Intervals - Efficacy Analysis Set 
 
 
Parameter 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
AUC(0-24) 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
 
LS Mean [1]  
xxx.x 
xxx.x 
 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
 
LS Treatment Difference [1][2] 
xx.x 
 
 
Treatment Difference 95% Confidence Interval [1][2] 
(xx.x, xx.x) 
 
 
Treatment Difference p-value [1][2] 
0.xxx 
 
 
 
 
 
 
 
 
 
Etc. 
n 
xx 
xx 
     
Mean 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
 
LS Mean [1]  
xxx.x 
xxx.x 
 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
 
LS Treatment Difference [1][2] 
xx.x 
 
 
Treatment Difference 95% Confidence Interval [1][2] 
(xx.x, xx.x) 
 
 
Treatment Difference p-value [1][2] 
0.xxx 
 
 
 
 
 
AUC = area under the curve calculated using the trapezoidal method; 
LS = least squares; 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain; 
[1] From an ANOVA with age, weight, and height as covariates.   
[2] Treatment difference is EXPAREL – placebo. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 


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Note to programmer: VAS AUCs to be presented on this table are, in order, AUC(0-12), AUC(0-24), AUC(0-72), 
AUC(24-48), and AUC(48-72). Do not break an AUC’s statistics across pages.  
 
 


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Table 14.2-5.2: Summary of VAS at Assessment Timepoints - Efficacy Analysis Set 
 
 
Timepoint 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
Baseline 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
PACU 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
Etc. 
n 
xx 
xx 
     
Mean 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
PACU is Post Anesthesia Care Unit 
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, in order, Baseline, PACU, and 6, 12, 24, 36, 
48, 60, and 72 hours.   
 
 
 


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Note to programmer: Use the indicated mock-up for the following tables: 
 
Use mock-up 14.2-5.1: 
 
Table 14.2-5.3: Analysis of VAS SPIS at Various Time Intervals - Efficacy Analysis Set  
 
VAS SPIS to be presented on Table 14.2-5.3 are, in order, SPIS(0-12), SPIS(0-24), SPIS(0-48), SPIS(24-48), 
SPIS(48-72), and SPIS(0-72). Do not break an SPIS’s statistics across pages.  
 
 
 


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Table 14.2-6: Analysis of Pain-free Subjects at Assessment Timepoints - Efficacy Analysis Set 
 
Timepoint 
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
Baseline 
 
 
 
  Pain-Free 
n (%) 
xx (xx.x) 
xx (xx.x) 
  Pained 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Treatment Difference [1] 
xx.x 
 
 
95% CI for Difference [1] 
(xx.x, xx.x) 
 
 
p-value [2] 
0.xxxx 
 
 
 
 
 
Etc. 
 
 
 
  Pain-Free 
n (%) 
xx (xx.x) 
xx (xx.x) 
  Pained 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Treatment Difference [1] 
xx.x 
 
 
95% CI for Difference [1] 
(xx.x, xx.x) 
 
 
p-value [2] 
0.xxxx 
 
 
 
 
 
[1] Pain-Free Treatment difference (EXPAREL – placebo) and 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. 
Pain-free = VAS score ≤ 1.5 and no prior rescue medication use and all prior VAS scores ≤ 1.5. 
 
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, in order, Baseline, PACU and 6, 12, 24, 36, 48, 
60, and 72 hours.  Do not split a timepoint across pages.   
 


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Table 14.2-7: Analysis of Opioid-Free Subjects through 24 and 72 hours - Efficacy Analysis Set 
 
Time Interval 
  Opioid Use 
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
0-24 
 
 
 
    Yes  
n (%) 
xx (xx.x) 
xx (xx.x) 
    No 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Treatment Difference [1] 
xx.x 
 
 
95% CI for Difference [1] 
(xx.x, xx.x) 
 
 
p-value [2] 
0.xxxx 
 
 
 
 
 
0-72 
 
 
 
    Yes  
n (%) 
xx (xx.x) 
xx (xx.x) 
    No 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Treatment Difference [1] 
xx.x 
 
 
95% CI for Difference [1] 
(xx.x, xx.x) 
 
 
p-value [2] 
0.xxxx 
 
 
 
 
 
[1] Opioid-Free Treatment difference (EXPAREL – placebo) and 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. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Use the indicated mock-up for the following tables: 
 
 
 
 


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Table 14.2-8: Analysis of Overall Benefit of Analgesia Total Score by Timepoint and Question - Efficacy 
Analysis Set  
 
Timepoint 
  Question 
 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo 
[N=XX] 
 
 
 
 
 
24 hours 
 
 
 
 
  Total Score 
Summary  
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
p-value[1] 
0.xxx 
 
 
Score 
 
 
 
 
0 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
1 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
2 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
… 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
… 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
  1. Current Pain 
Summary  
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
Score 
 
 
 
 
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) 
 
 
 
 
 
Total score = sum of scores from questions 1 to 6 plus 4 minus question 7 score.  
[1] p-value from Kruskal-Wallis test. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 


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Note to programmer:  Timepoints to appear on this table, in order, are 24 and 72 hours, and Day 10.  
Questions to appear on this table, in order, are ‘Total Score’, ‘1. Current Pain’, ‘2. Vomiting’, ‘3. 
Itching’, ‘4. Sweating’, ‘5. Freezing’, ‘6. Dizziness’, ‘7. Satisfaction’. Do not split a question’s 
statistics across pages. P-Values should only be generated for ‘Total score’.   
Note to programmer: Use the indicated mock-up for the following tables: 
 
 
 
 


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Table 14.2-9: Analysis of Satisfaction with Postsurgical Pain Control Questionnaire Score by Timepoint - 
Efficacy Analysis Set  
 
 
Timepoint 
Score 
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
 
24 hours 
Summary  
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
p-value[1] 
0.xxx 
 
 
Score 
 
 
 
 
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) 
 
 
 
 
 
[1] p-value from the Kruskal-Wallis test. 
 
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 24 and 72 hours and Day 10.  Do not split 
timepoint across pages.  
 
 
 


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Table 14.2-10.1: Analysis of Time to Discharge Ready - Efficacy Analysis Set 
 
Assessment Time 
  Discharge Ready 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo 
[N=XX] 
 
 
 
 
12 hours 
 
 
 
  No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
Time to Discharge Ready 
 
 
 
  Quartiles [1] 
 
 
 
    First (25% Discharge Ready) 
Estimate  
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
    Median (50% Discharge Ready) 
Estimate 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
    Third (75% Discharge Ready) 
Estimate 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
  Minimum 
Observed 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx 
 
 
 
 
  p-value [2] 
 
0.xxxx 
 
 
 
 
 
 
 
* indicates censored observation 
 
CI = confidence interval 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from Log-rank test comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer:  Assessments Time to be presented are 12, 24, 36, 48, 60, and 72 hours.  
 
 
 
 


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Table 14.2-10.2: Summary of Discharge Ready at Assessment - Efficacy Analysis Set 
 
Assessment Time 
  Discharge Ready 
Statistic 
EXPAREL 133 mg  
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
12 hours 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
24 hours 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
36 hours 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
48 hours 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
60 hours 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
72 hours 
 
 
 
    No  
n (%) 
xx (xx.x) 
xx (xx.x) 
    Yes 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Note to programmer: Do not split timepoint across pages.  
 
 
 


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Table 14.2-11: Analysis of Number of Unscheduled Phone Calls or Office Visits Related to Pain - Efficacy 
Analysis Set 
 
 
Statistic 
EXPAREL 133 mg 
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
Count Summary 
n 
xx 
xx 
 
Mean 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
 
Minimum 
xx.x 
xx.x 
 
Median 
xx 
xx 
 
Maximum 
xx 
xx 
 
p-value[1] 
0.xxx 
 
 
 
 
 
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) 
 
 
 
 
[1] p-value from Kruskal-Wallis test. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Distribution should present all counts up to the highest number of unscheduled visits 
(phone calls + office visits) related to pain in the data (U).  
 
 
 


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Note to programmer:  For the following region summaries, ‘Site:’ will be replaced with ‘Region:’ in the 
statistical models, row labels, footnotes and by lines of summaries as appropriate.  When summarizing by 
region, the regions are, in order of appearance, US and ROW.  There will be no overall region summary 
presented on these tables. 
 
Use template 14.2-1.1.1 for tables: 
 
Table 14.2-12.1.1.1: Region Analysis of AUC of VAS Pain Intensity Scores through 48 hours – Efficacy 
Analysis Set - Multiple Imputation Results 
 
Table 14.12-1.2.1: Region Analysis of AUC of VAS Pain Intensity Scores through 48 hours – Per-protocol 
Analysis Set - Multiple Imputation Results 
 
Use template 14.2-2.1.1 for table: 
 
Table 14.2-12.2.1.1: Region Analysis of Postsurgical Total Opioid Consumption (MED mg) through 48 hours – 
Efficacy Analysis Set 
 
Use template 14.2-2.1.2 for table: 
 
Table 14.2-12.2.1.2: Region Summary of Total Opioid Consumption (MED mg) through 48 hours by Region - 
Efficacy Analysis Set 
 
Use template 14.2-2.1.3 for table: 
 
Table 14.2-12.2.1.3: Region Summary of Total Opioid Consumption (MED mg) by Time Period - Efficacy Analysis 
Set 
 
Use template 14.2-2.1.4 for table: 
 
Table 14.2-12.2.1.4: Region Summary of the Number of Times Opioid (Rescue) Medication was used by Subject - 
Efficacy Analysis Set 
 
Use template 14.2-2.1.1 for table: 
 
Table 14.2-12.2.2.1: Region Analysis of Postsurgical Total Opioid Consumption (MED mg) through 48 hours – 
Per-protocol Analysis Set 
 
Use template 14.2-2.1.2 for table: 
 


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Table 14.2-12.2.2.2: Region Summary of Total Opioid Consumption (MED mg) through 48 hours by Site - Per-
protocol Analysis Set 
 
Use template 14.2-2.1.3 for table: 
 
Table 14.2-12.2.2.3: Region Summary of Total Opioid Consumption (MED mg) by Time Period - Per-protocol 
Analysis Set 
 
Use template 14.2-2.1.4 for table: 
 
Table 14.2-12.2.2.4: Region Summary of the Number of Times Opioid (Rescue) Medication was used by Subject - 
Per-protocol Analysis Set 
 
Use template 14.2-3.1.1 for table: 
 
Table 14.2-12.3.1.1: Region Analysis of Opioid-Free Subjects through 48 hours - Efficacy Analysis Set 
 
Use template 14.2-3.1.2 for table: 
 
Table 14.2-12.3.1.2: Region Summary of Opioid-Free Subjects through 48 hours by Site - Efficacy Analysis 
Set 
 
Use template 14.2-3.1.1 for table: 
 
Table 14.2-12.3.2.1: Region Analysis of Opioid-Free Subjects through 48 hours - Per-protocol Analysis Set 
 
Use template 14.2-3.1.2 for table: 
 
Table 14.2-12.3.2.2: Region Summary of Opioid-Free Subjects through 48 hours by Site - Per-protocol 
Analysis Set 
 
 
 
 
 
 
 
 
 
 
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Table 14.3-1.1.1: Summary of Clinical Laboratory Data by Timepoint – Hematology - Safety Analysis Set 
Laboratory parameter (units) 
EXPAREL 
 
 
Timepoint 
Value 
Statistic 
133 mg 
[N=XXX] 
266 mg 
[N=XXX] 
All 
EXPAREL 
[N=XXX] 
Placebo 
[N=XXX] 
Total 
[N=XXX] 
 
 
 
 
 
 
 
 
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Day 10 
Baseline [1] 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Change  
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
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. Timepoints to appear on this table are, in order of 
appearance, Baseline (prior to surgery) and Day 10.  Do not split timepoint statistics across pages.  See 


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protocol for list of lab analytes.  Analytes should be sorted in alphabetical order.  Use this mock-up for 
the following tables: 
 
Table 14.3-1.1.2: Summary of Clinical Laboratory Data by Timepoint – Chemistry - Safety Analysis Set 
Table 14.3-1.1.3.1: Summary of Clinical Laboratory Data by Timepoint – Urinalysis - Safety Analysis Set 
 
For urinalysis results only numeric results will appear on this table. 
 
 


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(Page X of Y) 
Protocol: 402-C-327 
Table 14.3-1.1.3.2: Tabulation of Clinical Laboratory Data by Timepoint – Urinalysis - Safety Analysis Set 
 
 
 
 
EXPAREL 
 
 
Analyte 
  Timepoint 
Category Statistic 
133 mg 
[N=XXX] 
266 mg 
[N=XXX] 
All EXPAREL 
[N=XXX] 
Placebo 
[N=XXX] 
Total 
[N=XXX] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analyte 1 Baseline [1] Cat 1 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
Day 10 
Cat 1 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Analyte 2 Baseline [1] Cat 1 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
Day 10 
Cat 1 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) 
xxx (xx.x%) xxx (xx.x%) 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[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. Timepoints to appear on this table are, in order of 
appearance, Baseline (prior to surgery) and Day 10.  Do not split timepoint statistics across pages, if 
possible.  Present all avaliable lab analytes. Categories are the superset of those reported in the data 
for both timepoints combined.  All categories should appear for both timepoints with zeros (0) as counts 
where needed. 
 
 


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Protocol: 402-C-327 
Table 14.3-1.2.1: Tabulation of Clinical Laboratory Range by Timepoint – Hematology - Safety Analysis Set 
Laboratory parameter (units) 
EXPAREL 
 
 
Timepoint 
Normal 
Range 
Statistic 
133 mg 
[N=XXX] 
266 mg 
[N=XXX] 
All EXPAREL 
[N=XXX] 
Placebo 
[N=XXX] 
Total 
[N=XXX] 
 
 
 
 
 
 
 
 
Baseline 
Below 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Normal 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Above 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
Day 10 
Below 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Normal 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Above 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (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)and Day 10.  Do not split timepoint statistics across pages.  
Present all avaliable analytes.  Analytes should be sorted in alphabetical order.  Use this mock-up for the 
following tables: 
 
Table 14.3-1.2.2: Tabulation of Clinical Laboratory Range by Timepoint – Chemistry - Safety Analysis Set 
Table 14.3-1.2.3: Tabulation of Clinical Laboratory Range by Timepoint – Urinalysis - Safety Analysis Set 
 
 


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(Page X of Y) 
Protocol: 402-C-327 
Table 14.3-1.3.1: Shift Table for Clinical Laboratory Data by Timepoint – Hematology - Safety Analysis Set 
 
 
Baseline 
 
Normal Range 
EXPAREL All EXPAREL [N=XXX] 
Placebo [N=XXX] 
Analyte 
Day 10 
Below 
Normal 
Above 
Below 
Normal 
Above 
 
 
 
 
 
 
 
 
Analyte 1 
Below 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Above 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Analyte 2 
Below 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Above 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Analyte 3 
Below 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Above 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
ETC. 
Below 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Above 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
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.  Do not split an analyte across pages.  EXPAREL 133 mg and 
EXPAREL 266 mg will appear on separate pages.  All analytes for an EXPAREL group (combined, 133 mg, 266 mg) 
should appear on consecutive pages before starting the next EXPAREL group. Analytes should be sorted in 
alphabetical order.  Use this mock-up for the following tables: 
 
Table 14.3-1.3.2: Shift Table for Clinical Laboratory Data by Timepoint – Chemistry - Safety Analysis Set 
Table 14.3-1.3.3: Shift Table for Clinical Laboratory Data by Timepoint – Urinalysis - Safety Analysis Set 
 
 
 


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Protocol: 402-C-327 
Table 14.3-2.1: Summary of Vital Signs by Timepoint – Safety Analysis Set 
Heart Rate (bpm) 
EXPAREL 
 
 
Timepoint 
Value 
Statistic 
133 mg 
[N=XXX] 
266 mg 
[N=XXX] 
All 
EXPAREL 
[N=XXX] 
Placebo 
[N=XXX] 
Total 
[N=XXX] 
 
 
 
 
 
 
 
 
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
PACU 
Baseline [1] 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Change  
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
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 ‘Heart Rate (bpm)’, ‘Systolic Blood 
Pressure (mmHg)’ and ‘Diastolic Blood Pressure (mmHg)’. Timepoints to appear on this table are, in order of 


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appearance, Baseline (prior to surgery), PACU, and 6, 12, 24, 36, 48, 60, and 72 hours, and Days 7 and 10.  
Do not split timepoint statistics across pages. 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-327 
Table 14.3-2.2: Summary of Potentially Clinically Significant Abnormal Vital Signs – Safety Analysis Set 
Heart Rate (bpm) 
EXPAREL 
 
 
Timepoint 
Criteria 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All EXPAREL 
[N=XX] 
n (%) 
Placebo 
[N=XX]  
n (%) 
Total 
[N=XXX]  
n (%) 
Baseline 
<= 50 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Decrease >= 15 
NA 
NA 
NA 
NA 
NA 
 
<= 50 & Decrease >= 15 
NA 
NA 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
>= 120 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 15 
NA 
NA 
NA 
NA 
NA 
 
>= 120 & Increase >= 15 
NA 
NA 
NA 
NA 
NA 
 
 
 
 
 
 
 
Any Time 
<= 50 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
After 
Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Baseline 
<= 50 & Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
>= 120 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
>= 120 & Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Etc. 
<= 50 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
<= 50 & Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
>= 120 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
>= 120 & Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


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Protocol: 402-C-327 
Table 14.3-2.2: Summary of Potentially Clinically Significant Abnormal Vital Signs – Safety Analysis Set 
Systolic Blood Pressure (mmHg) 
EXPAREL 
 
 
Timepoint 
Criteria 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All EXPAREL 
[N=XX] 
n (%) 
Placebo 
[N=XX]  
n (%) 
Total 
[N=XXX]  
n (%) 
Baseline 
<= 90 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Decrease >= 20 
NA 
NA 
NA 
NA 
NA 
 
<= 90 & Decrease >= 20 
NA 
NA 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
>= 180 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 20 
NA 
NA 
NA 
NA 
NA 
 
>= 180 & Increase >= 20 
NA 
NA 
NA 
NA 
NA 
 
 
 
 
 
 
 
Any Time 
<= 90 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
After 
Decrease >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Baseline 
<= 90 & Decrease >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
>= 180 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
>= 180 & Increase >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Etc. 
<= 90 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Decrease >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
<= 90 & Decrease >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
>= 180 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
>= 180 & Increase >= 20 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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(Page X of Y) 
Protocol: 402-C-327 
Table 14.3-2.2: Summary of Potentially Clinically Significant Abnormal Vital Signs – Safety Analysis Set 
Diastolic Blood Pressure (mmHg) 
EXPAREL 
 
 
Timepoint 
Criteria 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All EXPAREL 
[N=XX] 
n (%) 
Placebo 
[N=XX]  
n (%) 
Total 
[N=XXX]  
n (%) 
Baseline 
<= 50 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Decrease >= 15 
NA 
NA 
NA 
NA 
NA 
 
<= 50 & Decrease >= 15 
NA 
NA 
NA 
NA 
NA 
 
 
 
 
 
 
 
 
>= 105 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 15 
NA 
NA 
NA 
NA 
NA 
 
>= 105 & Increase >= 15 
NA 
NA 
NA 
NA 
NA 
 
 
 
 
 
 
 
Any Time 
<= 50 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
After 
Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Baseline 
<= 50 & Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
>= 105 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
>= 105 & Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Etc. 
<= 50 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
<= 50 & Decrease >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
>= 105 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
>= 105 & Increase >= 15 
xx (xx.x%) 
xx (xx.x%) 
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), Any Time After Baseline, PACU and, 6, 12, 24, 36, 48, 60, and 72 
hours and Days 7 and 10.  Do not split timepoint statistics across pages. 
 
 


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(Page X of Y) 
Protocol: 402-C-327 
Table 14.3-3.1: Summary of Electrocardiogram Interpretation – Investigator Read - Safety Analysis Set 
 
 
EXPAREL 
 
 
 
Time Point 
Interpretation 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 
EXPAREL 
[N=XX] 
n (%) 
Placebo 
[N=XX]  
n (%) 
Total 
[N=XXX]  
n (%) 
 
 
 
 
 
 
Baseline (Prior to Surgery) 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Any Time After Baseline 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
At Tmax* 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N/A 
N/A 
 
Abnormal, NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N/A 
N/A 
 
Abnormal, CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N/A 
N/A 
 
 
 
 
 
 
 
Etc. 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
*QuantPharm LLC indicated that the results of the interim PK analysis showed a median Tmax of 48 hours for 
the 133 mg EXPAREL group and a median Tmax of 60 hours for the 266 mg EXPAREL group. The ‘at Tmax’ 
timepoint is the time nearest in absolute value to the population PK estimated median Tmax. 
NCS = not clinically significant 
 
CS = clinically significant 
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 any time after baseline, At Tmax, PACU, and 6, 12, 24, 36, 48, 
60, and 72 hours, and Days 7 and 10.  Do not split a timepoint across pages.  For the timepoint ‘any time 
after baseline’ report the worst interpretation reported at any timepoint but baseline.  For the ‘at Tmax’ 
timepoint, report the interpretation at the time of Tmax for those subjects with Tmax reported and median 
Tmax for those subjects without Tmax. 
 
 
 


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Table 14.3-3.2: Shift Table for Electrocardiogram Interpretation – Investigator Read - Safety Analysis Set 
 
 
Baseline 
 
 
EXPAREL All EXPAREL [N=XXX] 
Placebo [N=XXX] 
 
 
 
Abnormal 
 
Abnormal 
Time Point 
Interpretation 
Normal 
NCS 
CS 
Normal 
NCS 
CS 
 
 
 
 
 
 
 
 
Any Time  
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
After 
NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Baseline 
CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
At Tmax* 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N/A 
N/A 
N/A 
 
NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N/A 
N/A 
N/A 
 
CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N/A 
N/A 
N/A 
 
 
 
 
 
 
 
 
Etc. 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
*QuantPharm LLC indicated that the results of the interim PK analysis showed a median Tmax of 48 hours for 
the 133 mg EXPAREL group and a median Tmax of 60 hours for the 266 mg EXPAREL group. The ‘at Tmax’ 
timepoint is the time nearest in absolute value to the population PK estimated median Tmax. 
NCS = not clinically significant 
 
CS = clinically significant 
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 any time after baseline, At Tmax, PACU, and 6, 12, 24, 36, 48, 
60, and 72 hours, and Days 7 and 10.  Do not split a timepoint across pages.  For the timepoint ‘any time 
after baseline’ report the worst interpretation reported at any timepoint but baseline.  For the ‘at Tmax’ 
timepoint, report the interpretation at the time of Tmax for those subjects with Tmax reported and median 
Tmax for those subjects without Tmax.  EXPAREL 133 mg and EXPAREL 266 mg will appear on separate pages.  
All timepoints for an EXPAREL group (All EXPAREL, 133 mg, 266 mg) should appear on consecutive pages before 
starting the next EXPAREL group. 


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Table 14.3-4: Summary of Neurological Assessments by Timepoint- Safety Analysis Set  
 
 
 
EXPAREL 
 
 
Timepoint Assessment 
 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All EXPAREL 
[N=XX] 
n (%) 
Placebo 
[N=XX]  
n (%) 
Total 
[N=XXX]  
n (%) 
Baseline (Prior to Surgery) 
 
 
 
 
 
 
 
Subject Oriented 
No 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
 
 
Numb lips, tongue or mouth 
No 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
 
 
Metallic taste 
No 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
 
 
Hearing problems 
No 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
 
 
Vision problems 
No 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
 
 
Muscle twitching 
No 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
Yes 
XX (XX.X) 
XX (XX.X) 
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 any time after baseline, PACU and, 6, 12, 24, 36, 48, 60, and 
72 hours and Days 7 and 10. Put one timepoint per page.  For the timepoint ‘any time after baseline’ if 
there is at least one ‘yes’ at any timepoint other than baseline, the subject will be a ‘yes’. 
 
 


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Table 14.3-5.1: Tabulation of Sensation Tests – Safety Analysis Set 
 
Location: location-name 
EXPAREL 
 
 
Timepoint 
Sensation 
 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
Total 
[N=XXX]  
n (%) 
 
 
 
 
 
 
 
 
Baseline 
Cold  
Absent 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Present xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Pinprick 
Absent 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Present xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Light Touch 
Absent 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Present xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
Etc. 
Cold 
Absent 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Present xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Pinprick 
Absent 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Present xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Light Touch 
Absent 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Present xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’. Timepoints to appear on this table are, in order, are: Baseline, 15, 30 and 45 
minutes and 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours.  Do not split a timepoint across pages. 
 
 


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Table 14.3-5.2: Summary of Sensation Loss and Return by Timepoint – Safety Analysis Set 
 
Location: location-name  
EXPAREL 
 
 
Timepoint 
Sensation 
 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
Total 
[N=XXX]  
n (%) 
 
 
 
 
 
 
 
 
At Any Time 
Any 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
CPL 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
CP 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
CL 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
PL 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Cold (C) 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Pinprick (P) 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Light Touch (L) 
Loss 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Return 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
Loss is the absence of sensation 
Return is the presence of sensation after a loss of sensation 
Sensation: CPL = All; CP = cold & pinprick; CL = cold & light touch; PL = pinprick & light touch 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’.  Timepoints to appear on this table are, in order, are: At Any Time, 15, 30 
and 45 minutes, and 6, 9, 12, 18, 24, 36, 48, 60, and 72 hours.  For ‘at any time’ timepoint subjects’ 


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experiencing a loss/return at any time during the study will be counted only once. For ‘any’ sensation, 
subjects’ experiencing a loss/return for at least one of the sensation at that timepoint will be counted 
only once.  Do not split a timepoint across pages. 
 
 


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Table 14.3-5.3.1: Analysis of Time to First Sensation Loss – Safety Analysis Set 
 
Location: location-name  
EXPAREL 
 
Sensation 
Statistic 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
 
 
 
 
 
 
Loss 
 
 
 
 
 
  Ever 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Never* 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
Time to First Loss (hrs) 
 
 
 
 
 
  Quartiles [1] 
 
 
 
 
 
    First (25%) 
Estimate  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Median (50%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Third (75%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
  Minimum 
Observed 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx* 
xx.xx 
xx.xx 
  p-value [2] 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
Loss: absence of at least one of cold, pinprick or light touch sensation. 
* = censored 
Time to sensation loss is the time from end of surgery to first loss of sensation. 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from log-rank test comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’.   
 


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Table 14.3-5.3.2: Analysis of Time to Last Sensation Loss – Safety Analysis Set 
 
Location: location-name  
EXPAREL 
 
Sensation 
Statistic 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
 
 
 
 
 
 
Time to Last Loss (hrs) 
 
 
 
 
 
  Quartiles [1] 
 
 
 
 
 
    First (25%) 
Estimate  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Median (50%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Third (75%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
  Minimum 
Observed 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx* 
xx.xx 
xx.xx 
  p-value [2] 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
Loss: absence of at least one of cold, pinprick or light touch sensation. 
* = censored 
Return: all 3 (cold, pinprick and light touch) sensations are present after loss of sensation 
Time to sensation return is the time from first sensation loss to first sensation return. 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from log-rank test comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’.  If a subject meets the loss criteria at any timepoint, the subject will be 
counted in ‘loss ever’ category; otherwise the subject will be counted in ‘loss never’ category.  Note time 
to last loss will only be provided if more than 10% of the subjects in a treatment arm have more than 1 
sensation loss-return cycle.    


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Table 14.3-5.4.1: Analysis of Time to First Sensation Return – Safety Analysis Set 
 
Location: location-name  
EXPAREL 
 
Sensation 
Statistic 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
 
 
 
 
 
 
Loss Ever 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Return 
 
 
 
 
 
  Ever 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Never* 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
Time to First Return (hrs) 
 
 
 
 
 
  Quartiles [1] 
 
 
 
 
 
    First (25%) 
Estimate  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Median (50%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Third (75%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
  Minimum 
Observed 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx* 
xx.xx 
xx.xx 
  p-value [2] 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
Loss: absence of at least one of cold, pinprick or light touch sensation. 
* = censored 
Return: all 3 (cold, pinprick and light touch) sensations are present after loss of sensation 
Time to sensation return is the time from first sensation loss to first sensation return. 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from log-rank test comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’.  This table based on only those subjects who lost sensation (ie, the loss ever 
row is the population appearing in analyses).  
 


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Table 14.3-5.4.2: Analysis of Time to Last Sensation Return – Safety Analysis Set 
 
Location: location-name  
 
EXPAREL 
 
Sensation 
Statistic 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
 
 
 
 
 
 
Time to Last Return (hrs) 
 
 
 
 
 
  Quartiles [1] 
 
 
 
 
 
    First (25%) 
Estimate  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Median (50%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
    Third (75%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
  Minimum 
Observed 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx* 
xx.xx 
xx.xx 
  p-value [2] 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
Loss: absence of at least one of cold, pinprick or light touch sensation. 
* = censored 
Return: all 3 (cold, pinprick and light touch) sensations are present after loss of sensation 
Time to sensation return is the time from first sensation loss to first sensation return. 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from log-rank test with terms for treatment comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’. ‘Loss Ever’ counts on this table should agree with ‘loss ever’ counts on Table 
14.3-5.1.1. If a subject meets the return criteria at any time, the subject will be counted in ‘return 
ever’ category; otherwise the subject will be counted in the ‘return never’ category.  The sum of ‘return 
ever’ and ‘return never’ should add up to ‘loss ever’; subjects who did not experience a loss of sensation 
cannot have a return of sensation.  Only subjects experiencing a ‘loss ever’ will contribute to the body of 
this table.  Note time to last return will only be provided if more than 10% of the subjects in a treatment 
arm have more than 1 sensation loss-return cycle. 
 
 


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Table 14.3-5.5: Summary of Duration (hrs) of Sensation Loss – Safety Analysis Set 
 
Location: location-name  
 
EXPAREL 
 
 
Statistic 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
 
 
 
 
 
 
Total Duration  
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Cycle 1 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Etc. 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Duration is the time between loss and return of sensation. 
Total duration is the sum, within a subject, of all sensation loss-return cycles. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’. Only subjects experiencing a sensation loss will contribute to the body of 
this table.  Note summaries of cycles will only be provided if more than 10% of the subjects in a treatment 
arm have more than 1 sensation loss-return cycle. 


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Table 14.3-5.6: Summary of the Number of Sensation Loss-Return Cycles - Safety Analysis Set 
 
Location: location-name 
EXPAREL 
 
 
Statistic 
133 mg 
[N=XX] 
266 mg 
[N=XX] 
All EXPAREL 
[N=XX] 
Placebo  
[N=XX] 
 
 
 
 
 
 
Count Summary 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
 
Median 
xx 
xx 
xx 
xx 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Count Distribution 
 
 
 
 
 
  0  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  1 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  2 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  3 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  4 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  5 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  … 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  U 
n (%) 
xx (xx.x) 
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: Locations to appear on this table, in order, are ‘Shoulder’, ‘Forearm’, ‘5th finger’, 
’Middle finger’ and ‘Thumb’. Distribution should present all counts up to the highest number of loss-return 
cycles in the data (U). Only subjects experiencing a sensation loss will contribute to the body of this 
table.  This table will only be provided if at least 1 subject has more than 1 sensation loss-return cycle. 
 
 
 


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Table 14.3-6.1: Summary of Motor Function Loss and Return by Timepoint – Safety Analysis Set 
 
 
EXPAREL 
 
 
Timepoint 
133 mg 
[N=XXX] 
n (%) 
266 mg 
[N=XXX]  
n (%) 
All 
EXPAREL 
[N=XXX]  
n (%) 
Placebo 
[N=XXX]  
n (%) 
Total 
[N=XXX]  
n (%) 
 
 
 
 
 
 
At Any Time 
 
 
 
 
 
  Loss 
 
 
 
 
 
    Thumb abduction (radial nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
    Thumb adduction (ulnar nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
    Thumb opposition (median nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
    Elbow flexion (musculocutaneous nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
Return 
 
 
 
 
 
    Elbow flexion (musculocutaneous nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
    Thumb adduction (ulnar nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
    Thumb opposition (median nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
    Elbow flexion (musculocutaneous nerve) 
xx (xx.x%) 
xx (xx.x%) xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 
 
Loss: Lovett scale score < 3 in at least one of the motor function assessments 
Return: Lovett scale score returns to 3 or more in any motor function assessment. 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Locations to appear on this table, in order, are Thumb abduction (radial nerve), Thumb 
adduction (ulnar nerve), Thumb opposition (median nerve), and Elbow flexion (musculocutaneous nerve). 
Timepoints to appear on this table are, in order, are: At Any Time, 15, 30 and 45 minutes and 6, 9, 12, 18, 
24, 36, 48, 60, and 72 hours.   
 
 


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Table 14.3-6.2: Analysis of Time to Onset of Motor Function Loss - Efficacy Analysis Set 
 
Location: location-name (nerve name) 
 
EXPAREL 
 
 
Statistic 
133 mg 
[N=XX] 
266 mg 
[N=XX] 
Placebo 
[N=XX] 
 
 
 
 
 
Number of Subjects with 
 
 
 
 
  Motor Function Loss 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No Motor Function Loss 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Time to Loss 
 
 
 
 
  Quartiles [1] 
 
 
 
 
    First (25%) 
Estimate  
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
 
    Median (50%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
 
    Third (75%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
 
  Minimum 
Observed 
xx.xx 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx* 
xx.xx 
 
 
 
 
 
  p-value [2] 
 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
Locations to appear on this table, in order, are Thumb abduction (radial nerve), Thumb adduction (ulnar 
nerve), Thumb opposition (median nerve), and Elbow flexion (musculocutaneous nerve). 
Loss: Lovett scale score < 3 in at least one of the motor function assessments 
 
* indicates censored observation 
 
CI = confidence interval 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from log-rank test comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Table 14.3-6.3: Analysis of Time to Return of Motor Function - Efficacy Analysis Set 
 
Location: location-name (nerve name) 
 
EXPAREL 
 
 
Statistic 
133 mg 
[N=XX] 
266 mg 
[N=XX] 
Placebo 
[N=XX] 
 
 
 
 
 
Number of Subjects with 
 
 
 
 
  Motor Function Return 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No Motor Function Return 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Time to Return 
 
 
 
 
  Quartiles [1] 
 
 
 
 
    First (25%) 
Estimate  
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
 
    Median (50%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
 
    Third (75%) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
 
 
  Minimum 
Observed 
xx.xx 
xx.xx 
xx.xx 
  Maximum 
Observed 
xx.xx* 
xx.xx* 
xx.xx 
 
 
 
 
 
  p-value [2] 
 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
Locations to appear on this table, in order, are Thumb abduction (radial nerve), Thumb adduction (ulnar 
nerve), Thumb opposition (median nerve), and Elbow flexion (musculocutaneous nerve). 
Return: Lovett scale score returns to 3 or more in any motor function assessment. 
* indicates censored observation 
 
CI = confidence interval 
[1] Estimates from Kaplan-Meier analysis.  
[2] p-value from log-rank test with terms for treatment comparing EXPAREL to placebo. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


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Table 14.3-6.4: Summary of Motor Function Assessments by Timepoint – Safety Analysis Set 
 
Active Flexion (degrees) 
EXPAREL 
 
 
Timepoint 
Value 
Statistic 
133 mg 
[N=XXX] 
266 mg 
[N=XXX] 
All EXPAREL 
[N=XXX] 
Placebo 
[N=XXX] 
Total 
[N=XXX] 
 
 
 
 
 
 
 
 
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
15 min 
Baseline [1] 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Actual 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Change  
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
xx 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
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 
 


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Table 14.3-7.1.1: Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
 
EXPAREL 
 
 
Number of 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 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) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
  At least one Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
  At least one Serious 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Subjects Discontinued due to TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Died on Study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Related TEAEs are those AEs indicated as ‘possible’, ‘probable’ or ‘definite’ related by the investigator 
on the AE CRF. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Only present overall sites. All categories on this table should appear, even if not 
present in the data. 
 


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Table 14.3-7.1.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
 
EXPAREL 
 
 
System Organ Class 
  Preferred Term 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 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) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
SOC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
SOC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT2.1 
xx (xx.x) 
xx (xx.x) 
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) 
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 14.3-7.1.3: Summary of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) - 
Safety Analysis Set  
Table 14.3-7.1.4: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) Leading to Study 
Withdrawal - Safety Analysis Set 
Table 14.3-7.1.5: 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. 
 
 


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Table 14.3-7.1.6: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Severity - Safety 
Analysis Set 
 
 
EXPAREL 
 
 
System Organ Class 
  Preferred Term 
Severity 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 
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) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
SOC1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
  PT1.1 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
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 
 
 
 
 


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Table 14.3-7.1.7: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Relationship to 
Study Drug - Safety Analysis Set 
 
 
EXPAREL 
 
 
System Organ Class 
  Preferred Term 
Relation 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 
EXPAREL 
[N=XX] 
n (%) 
Placebo  
[N=XX]  
n (%) 
Total  
[N=XX] 
n (%) 
 
 
 
 
 
 
 
Subjects with at least one TEAE 
Unrelated 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Unlikely 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Possible 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Probable 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Definite 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
SOC1 
Unrelated 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Unlikely 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Possible 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Probable 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Definite 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
  PT1.1 
Unrelated 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Unlikely 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Possible 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Probable 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
Definite 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
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 
 
 


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Note to programmer: Only present overall sites. 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.”  Use indicated mock-up for the following tables:  
 
Use mock-up 14.7-1.1 
Table 14.3-7.2.1: Overview of Serious Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set  
Use mock-up 14.7-1.2 
Table 14.3-7.2.2: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) - Safety 
Analysis Set  
Use mock-up 14.7-1.3 
Table 14.3-7.2.3: Summary of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) - Safety Analysis Set  
Use mock-up 14.7-1.4 
Table 14.3-7.2.4: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) Leading to 
Study Withdrawal - Safety Analysis Set  
Use mock-up 14.7-1.5 
Table 14.3-7.2.5: Summary of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) Leading to Study Withdrawal - Safety Analysis Set  
Use mock-up 14.7-1.6 
Table 14.3-7.2.6: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) Resulting in 
Death - Safety Analysis Set  
Use mock-up 14.7-1.7 
Table 14.3-7.2.7: Summary of Incidence of Study Drug-Related Serious Treatment-Emergent Adverse Events 
(TEAEs) Resulting in Death - Safety Analysis Set 
 
  
Use mock-up 14.7-1.1 
Table 14.3-7.3.1: Overview of Treatment-Emergent Adverse Events (TEAEs) of Special Interest - Safety 
Analysis Set  
Use mock-up 14.7-1.2 
Table 14.3-7.3.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest - 
Safety Analysis Set  
Use mock-up 14.7-1.3 
Table 14.3-7.3.3: Summary of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) of 
Special Interest - Safety Analysis Set  
Use mock-up 14.7-1.4 
Table 14.3-7.3.4: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
Leading to Study Withdrawal - Safety Analysis Set  
Use mock-up 14.7-1.5 


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Table 14.3-7.3.5: Summary of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) of 
Special Interest Leading to Study Withdrawal - Safety Analysis Set  
Use mock-up 14.7-1.6 
Table 14.3-7.3.6: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
Resulting in Death - Safety Analysis Set  
Use mock-up 14.7-1.7 
Table 14.3-7.3.7: Summary of Incidence of Study Drug-Related Treatment-Emergent Adverse Events (TEAEs) of 
Special Interest Resulting in Death - Safety Analysis Set 
 
 
 


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Note to programmer: Use mock-up 14.1-4.1 for tables: 
 
Table 14.3-8.1: Incidence of Prior Medications – Safety Analysis Set.  
 
On this table change the footnote ‘Intraoperatives medications are those indicated as such by the 
investigator’ to read ‘Prior medications are those stopped before start of study drug administration.’ 
 
Table 14.3-8.2: Incidence of Concomitant Medications – Safety Analysis Set.  
 
On this table change the footnote ‘Intraoperatives medications are those indicated as such by the 
investigator’ to read ‘Concomitant medications are those taken between the start of study drug 
administration and discharge from study and are not designated intraoperative medications.’ 
 
 
 
 


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Note to programmer: For the following tables, only present US and ROW regions; there is no overall regions 
group.  All of the following mock-ups will put the region as a by-line title in the table.  
 
Use mock-up 14.3-5.1 for table: 
 
Table 14.3-9.1.1: Region Tabulation of Sensation Tests – Safety Analysis Set  
 
Use mock-up 14.3-5.2 for table: 
 
Table 14.3-9.1.2: Region Summary of Sensation Loss and Return by Timepoint – Safety Analysis Set 
 
Use mock-up 14.3-5.3 for table: 
 
Table 14.3-9.1.3: Region Analysis of Time to Sensation Loss – Safety Analysis Set 
 
Use mock-up 14.3-5.4 for table: 
 
Table 14.3-9.1.4: Region Analysis of Time to Sensation Return – Safety Analysis Set 
 
Use mock-up 14.3-5.5 for table: 
 
Table 14.3-9.1.5: Region Summary of Duration (hrs) of Sensation Loss – Safety Analysis Set 
 
Use mock-up 14.3-6.1 for table: 
 
Table 14.3-9.2.1: Region Summary of Active Motor Function Loss and Return by Timepoint – Safety Analysis 
Set 
 
Use mock-up 14.3-6.2 for table: 
 
Table 14.3-9.2.2: Region Analysis of Time to Onset of Motor Function Loss - Efficacy Analysis Set 
 
Use mock-up 14.3-6.3 for table: 
Table 14.3-9.2.3: Region Analysis of Time to Return of Motor Function - Efficacy Analysis Set 
 
Use mock-up 14.3-6.4 for table: 
 
Table 14.3-9.2.4: Region Summary of Motor Function Assessments by Timepoint – Safety Analysis Set 


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Table 14.3-9.3.1: Region Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
Region: US 
EXPAREL 
 
 
Number of 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 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) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
  At least one Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
  At least one Serious 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Subjects Discontinued due to TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Died on Study 
xx (xx.x) 
xx (xx.x) 
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 US and ROW regions; there is no overall regions group. All categories on 
this table should appear, even if not present in the data. 
 


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Table 14.3-9.3.2: Region Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) - Safety 
Analysis Set 
Region:  
EXPAREL 
 
 
System Organ Class 
  Preferred Term 
133 mg 
[N=XX] 
n (%) 
266 mg 
[N=XX] 
n (%) 
All 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) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
SOC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
SOC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  PT2.1 
xx (xx.x) 
xx (xx.x) 
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) 
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 US and ROW regions; there is no overall regions group. Use this template 
for table: 
 
Table 14.3-9.3.3: Region Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) - Safety 
Analysis Set 
 
 
 


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15. 
TABLE OF CONTENTS FOR LISTING MOCK-UPS 
LISTING 16.2-1: SUBJECT DISPOSITION – ALL SUBJECTS 
129 
LISTING 16.2-2: RANDOMIZATION AND ANALYSIS SETS – ALL SUBJECTS 
130 
LISTING 16.2-3: DEMOGRAPHICS – ALL SUBJECTS 
131 
LISTING 16.2-4: HEIGHT AND WEIGHT – ALL SUBJECTS 
132 
LISTING 16.2-5: SURGERY – ALL SUBJECTS 
133 
LISTING 16.2-6: VISUAL ANALOG SCALE (VAS) – ALL SUBJECTS 
134 
LISTING 16.2-7.1: RESCUE MEDICATION TOTAL DOSE (MED MG) AND OPIOID-FREE STATUS 
- ALL SUBJECTS 
135 
LISTING 16.2-7.2: RESCUE MEDICATION – ALL SUBJECTS 
136 
LISTING 16.2-8: OVERALL BENEFIT OF ANALGESIA – ALL SUBJECTS 
137 
LISTING 16.2-9: SUBJECT SATISFACTION WITH POST-SURGICAL PAIN CONTROL – ALL 
SUBJECTS 
138 
LISTING 16.2-10: MODIFIED POST-ANESTHESIA DISCHARGE SCORING SYSTEM (MPADSS)– 
ALL SUBJECTS 
139 
LISTING 16.2-11: DAY 29 PHONE CALL – ALL SUBJECTS 
140 
LISTING 16.2-12: HEMATOLOGY – ALL SUBJECTS 
141 
LISTING 16.2-13: CHEMISTRY – ALL SUBJECTS 
141 
LISTING 16.2-14.1: URINALYSIS – NUMERIC RESULTS – ALL SUBJECTS 
141 
LISTING 16.2-14.2: URINALYSIS – CHARACTER RESULTS – ALL SUBJECTS 
142 
LISTING 16.2-15: VITAL SIGNS ASSESSMENT – ALL SUBJECTS 
143 
LISTING 16.2-16: ELECTROCARDIOGRAM FINDINGS – INVESTIGATOR ASSESSMENT – ALL 
SUBJECTS 
144 
LISTING 16.2-17: NEUROLOGICAL ASSESSMENT – ALL SUBJECTS 
145 
LISTING 16.2-18.1: SENSORY FUNCTION ASSESSMENT – ALL SUBJECTS (PART 1 OF 3) 
146 
LISTING 16.2-18.1: SENSORY FUNCTION ASSESSMENT – ALL SUBJECTS (PART 2 OF 3) 
147 
LISTING 16.2-18.1: SENSORY FUNCTION ASSESSMENT – ALL SUBJECTS (PART 3 OF 3) 
148 
LISTING 16.2-18.2: TIME TO LOSS AND RETURN OF SENSORY FUNCTION – ALL SUBJECTS 149 
LISTING 16.2-19.1: MOTOR FUNCTION ASSESSMENT – ALL SUBJECTS 
150 
LISTING 16.2-19.2: TIME TO LOSS AND RETURN OF MOTOR FUNCTION – ALL SUBJECTS 
151 
LISTING 16.2-20.1: ALL ADVERSE EVENTS – ALL SUBJECTS 
152 
LISTING 16.2-20.2.1: TREATMENT-EMERGENT ADVERSE EVENTS – ALL SUBJECTS 
152 
LISTING 16.2-20.2.2: TREATMENT-EMERGENT STUDY DRUG RELATED ADVERSE EVENTS – 
ALL SUBJECTS 
152 
LISTING 16.2-20.3: ALL SERIOUS ADVERSE EVENTS – ALL SUBJECTS 
152 
LISTING 16.2-20.4.1: TREATMENT-EMERGENT SERIOUS ADVERSE EVENTS – ALL SUBJECTS152 
LISTING 16.2-20.4.2: TREATMENT-EMERGENT STUDY DRUG RELATED SERIOUS ADVERSE 
EVENTS – ALL SUBJECTS 
152 


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LISTING 16.2-20.5.1: TREATMENT-EMERGENT ADVERSE EVENTS OF SPECIAL INTEREST – 
ALL SUBJECTS 
152 
LISTING 16.2-20.5.2: TREATMENT-EMERGENT STUDY DRUG RELATED ADVERSE EVENTS 
OF SPECIAL INTEREST – ALL SUBJECTS 
152 
LISTING 16.2-21.1: ALL PRIOR AND CONCOMITANT MEDICATIONS – ALL SUBJECTS 
153 
LISTING 16.2-21.2: PRIOR MEDICATIONS – ALL SUBJECTS 
153 
LISTING 16.2-21.3: CONCOMITANT MEDICATIONS – ALL SUBJECTS 
153 
LISTING 16.2-22: MEDICAL HISTORY – ALL SUBJECTS 
154 
LISTING 16.2-23: INTRAOPERATIVE MEDICATIONS – ALL SUBJECTS 
155 
LISTING 16.2-24: STUDY DRUG ADMINISTRATION – ALL SUBJECTS 
156 
LISTING 16.2-25: URINE DRUG SCREEN, ALCOHOL BLOOD TEST AND PREGNANCY TEST – 
ALL SUBJECTS 
157 
LISTING 16.2-26: ADMISSION AND DISCHARGE – ALL SUBJECTS 
158 
LISTING 16.2-27: UNIQUE ADVERSE EVENTS TERMS AND ASSOCIATED CODED TERMS 
159 
LISTING 16.2-28: UNIQUE MEDICATION TERMS AND ASSOCIATED CODED TERMS 
160 
LISTING 16.2-29: PROTOCOL DEVIATIONS – ALL SUBJECTS 
161 


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Listing 16.2-1: Subject Disposition – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site Subject 
Date of 
Last Visit End of Study Status 
Specify 
 
 
 
 
 
XXX 
XXX-YYYY DDMONYYYY  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
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. 
 
 


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Listing 16.2-2: Randomization and Analysis Sets – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
Randomization 
Protocol 
Amendment 
Analysis Set 
Site 
Subject 
Date and Time 
Number 
Safety 
Efficacy 
Per-protocol 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXXXX 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Analysis set will by ‘Y’ if subject in set, blank otherwise.  
 


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Listing 16.2-3: Demographics – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
Subject 
Birth  
Date 
Age 
(yrs) 
 
Dominant 
Hand 
 
 
ASA 
Class 
 
 
Site 
Number 
Init. 
Sex 
Race 
Ethnicity 
Region 
Country 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
AMZ 
DDMONYYYY 
XX 
X 
XXXXX 
XXXXXXXXXXX XXXXXXXXX 
X 
XXX 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If race is ‘other’ then race should be ‘Other: other-specify-text’.  
 
 


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Listing 16.2-4: Height and Weight – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
 
 
 
Body Mass 
Site 
Subject 
 
Height and Weight 
Collection Date 
Height (cm) 
Weight (kg) 
Index 
(kg/m2) 
 
 
 
 
 
 
XXX 
XXX-YYYY 
 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Listing 16.2-5: Surgery – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site 
Subject 
Date 
Start 
Time 
Stop 
Time 
Duration 
(hrs) 
Location 
Incision 
Length 
(cm) 
Anesthesia Type 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
X.X 
XXXXX 
XX.X 
XXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If anesthesia type is ‘other’ then text should read ‘other: specify-text’. 
 
 
 
 


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Listing 16.2-6: Visual Analog Scale (VAS) – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
Time From Dose 
 
 
  
Site 
Subject 
Date Time 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(hrs) 
VAS 
(cm) 
Pain-Free 
  
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
Pain-free is VAS ≤ 1.5 cm and no prior rescue medication use. 
VAS: 0=No pain to 10=Worst Pain Imaginable 
 
ND=Not Done  NA=Not Applicable 
* = out of window 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by VAS collection date and time. If VAS 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 if it can be avoided.  Pain-free will have Y if VAS ≤ 1.5 otherwise 
blank.  An asterisk (*) will be placed next to the deviation if an assessment is out of window.  See Table 
of Time and Events for windows.


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Listing 16.2-7.1: Rescue Medication Total Dose (MED mg) and Opioid-free Status - All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site 
Subject 
48 hrs 
24 hrs 
72 hrs 
24-48hrs 
48-72hrs 
Opioid-Free 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
XXXX.X 
XXXX.X 
XXXX.X 
XXXX.X 
XXXX.X 
NO 
XXX 
XXX-YYYY 
- 
- 
- 
- 
- 
YES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total dose is dose from end of surgery through timepoint. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’.  Sort by date and 
time within subject. 
 
 


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Listing 16.2-7.2: Rescue Medication – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site 
Subject 
Date and Time 
Time to  
Rescue (hr) 
Medication 
Dose 
(units) 
Conversion 
Factor 
Dose 
(MED 
mg) 
Route 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX XX(XXXX) 
X.XX 
XXX.X 
XXXXXXX  
 
 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX XX(XXXX) 
X.XX 
XXX.X 
XXXXXXX  
 
 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX XX(XXXX) 
X.XX 
XXX.X 
XXXXXXX  
 
 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX XX(XXXX) 
X.XX 
XXX.X 
XXXXXXX  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time to rescue is time from end of surgery to rescue medication dose. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’.  Sort by date and 
time within subject. 
 
 
 
 
 


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Listing 16.2-8: Overall Benefit of Analgesia – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
Assessment 
Question 
 
Site 
Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
1 
2 
3 
4 
5 
6 
7 
Total 
Score 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
24 
XX.X 
XX.X 
X 
X 
X 
X 
X 
X 
X 
XX 
 
 
DDMONYYYYTHH:MM 
72 
XX.X 
XX.X 
X 
X 
X 
X 
X 
X 
X 
XX 
 
 
DDMONYYYYTHH:MM 
240 (D10) 
XXX.X 
XX.X 
X 
X 
X 
X 
X 
X 
X 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total score = sum of questions 1 to 6 scores minus question 7 score plus 4. 
1) Please rate your current pain at rest on a scale between 0=minimal pain and 4=maximum imaginable pain 
2) Please grade any distress and bother from vomiting in the past 24 h (0=not at all to 4=very much) 
3) Please grade any distress and bother from itching in the past 24 h (0=not at all to 4=very much)  
4) Please grade any distress and bother from sweating in the past 24 h (0=not at all to 4=very much) 
5) Please grade any distress and bother from freezing in the past 24 h (0=not at all to 4=very much) 
6) Please grade any distress and bother from dizziness in the past 24 h (0=not at all to 4=very much) 
7) How satisfied are you with your pain treatment during in the past 24 h (0=not at all to 4=very much) 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject.  
 
 


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Listing 16.2-9: Subject Satisfaction with Post-Surgical Pain Control – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site 
Subject 
Assessment 
Date and Time 
Rating 
Score 
    
 
 
 
 
 
XXX 
XXX-YYYY 
24 hr 
DDMONYYYYTHH:MM 
EXTREMELY DISSATISFIED 
1 
    
 
 
72 hr 
DDMONYYYYTHH:MM 
DISSATISFIED 
2 
    
 
 
Day 10 
DDMONYYYYTHH:MM 
NEITHER SATISFIED NOR DISSATISFIED 
3 
    
 
 
 
 
 
 
    
XXX 
XXX-YYYY 
24 hr 
DDMONYYYYTHH:MM 
SATISFIED 
4 
    
 
 
72 hr 
DDMONYYYYTHH:MM 
EXTREMELY SATISIFIED 
5 
    
 
 
Day 10 
DDMONYYYYTHH:MM 
EXTREMELY SATISIFIED 
5 
    
 
 
 
 
 
 
    
Etc. 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
Time to rescue is time from end of surgery to rescue medication dose. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. 
 
 


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Listing 16.2-10: Modified Post-Anesthesia Discharge Scoring System (MPADSS)– All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
Assessment 
Question 
 
Site 
Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
1 
2 
3 
4 
5 
Total 
Score 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
24 
XX.X 
XX.X 
X 
X 
X 
X 
X 
XX 
 
 
DDMONYYYYTHH:MM 
72 
XX.X 
XX.X 
X 
X 
X 
X 
X 
XX 
 
 
DDMONYYYYTHH:MM 
240 (D10) 
XXX.X 
XX.X 
X 
X 
X 
X 
X 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window 
Total score = sum of scores. 
1) Vital signs: 2 = ≤ 20%; 1 = 20-40%; 0 = >40% of preoperative value. 
2) Ambulation: 2 = steady gait/no dizziness; 1 = with assistance; 0 = none/dizziness 
3) Nausea and Vomiting: 2 = minimal; 1 = moderate; 0 = severe 
4) Pain: 2 = minimal; 1 = moderate; 0 = severe 
5) Surgical bleeding: 2 = minimal; 1 = moderate; 0 = severe  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject.  
 
 


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Protocol: 402-C-327 
Listing 16.2-11: Day 29 Phone Call – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
 
 
 
 
Number of pain-related 
 
Site 
Subject 
Date 
Schedule 
(days) 
Actual 
(days) 
Deviation 
(days) 
Phone 
Calls 
Visits 
Total 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYY 
29 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXX 
XXX-YYYY 
DDMONYYYY 
29 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXX 
XXX-YYYY 
DDMONYYYY 
29 
XX.X 
XX.X 
XX 
XX 
XXXX 
 
 
 
 
 
 
 
 
 
Total = sum of calls and visits. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject.  
 
 
 


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Listing 16.2-12: Hematology – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
 
 
 
 
Normal Range 
 
 
 
Site Subject 
Visit 
Date and Time 
Analyte (units) 
Low 
High 
Result Change Flag 
 
 
 
 
 
XXX 
XXX-YYYY Screening DDMONYYYYTHH:MM XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
H 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
L 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
DDMONYYYYTHH:MM XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
L 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 10 
DDMONYYYYTHH:MM XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
XX.X 
 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
XX.X 
 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
XX.X 
L 
 
 
 
 
XXXXXXXXXXXXXXXX (units) 
xxx.xx xxx.xx xxx.xx 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
Flag: L=below normal range; H=above normal range. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject and analyte alphabetically within date.  Change is 
only calculated for Day 10 visit. Use this mock-up for the following listings: 
 
Listing 16.2-13: Chemistry – All Subjects 
Listing 16.2-14.1: Urinalysis – Numeric Results – All Subjects 
 
 
 
 
 
 


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Listing 16.2-14.2: Urinalysis – Character Results – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
Site 
Subject 
Visit 
Date and Time 
Analyte  
Normal Criteria 
Result 
Flag 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
Screening 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
A 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
A 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 10 
DDMONYYYYTHH:MM 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
XXXXXXXXXXXXXXXX  
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
 
Flag: A = abnormal. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject and analyte alphabetically within date. 
 
 
 


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Listing 16.2-15: Vital Signs Assessment – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
 
 
 
 
Heart Rate 
Blood Pressure (mmHg) 
 
 
Assessment 
 (bpm) 
Systolic 
Diastolic 
Site Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Actual Change Actual Change Actual Change 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Screening 
- 
- 
XX 
- 
XXX 
- 
XX 
- 
 
 
DDMONYYYYTHH:MM 
Baseline 
- 
- 
XX 
- 
XXX 
- 
XX 
- 
 
 
DDMONYYYYTHH:MM 
PACU 
- 
- 
XX 
XX 
XXX 
-X 
XX 
X 
 
 
DDMONYYYYTHH:MM 
6 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
 
 
DDMONYYYYTHH:MM 
12 
XXX.XX 
XXX 
XX 
XX 
XXX 
X 
XX 
X 
 
 
DDMONYYYYTHH:MM 
24 
XXX.XX 
XXX 
XX 
XX 
XXX 
-X 
XX 
X 
 
 
DDMONYYYYTHH:MM 
36 
XXX.XX 
XXX 
XX 
XX 
XXX 
X 
XX 
X 
 
 
DDMONYYYYTHH:MM 
48 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
 
 
DDMONYYYYTHH:MM 
60 
XXX.XX 
XXX 
XX 
XX 
XXX 
-X 
XX 
X 
 
 
DDMONYYYYTHH:MM 
66 
XXX.XX 
XXX 
XX 
XX 
XXX 
-X 
XX 
-X 
 
 
DDMONYYYYTHH:MM 
72 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
X 
 
 
DDMONYYYYTHH:MM 
120 (D5) 
XXX.XX 
XXX 
XX 
XX 
XXX 
X 
XX 
-X 
 
 
DDMONYYYYTHH:MM 
240 (D10) XXX.XX 
XXX 
XX 
-XX 
XXX 
-X 
XX 
X 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window 
 
 
Change is change from baseline (Preop). 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window.  See Table of Time and Events for windows. 
  
 
 


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Listing 16.2-16: Electrocardiogram Findings – Investigator Assessment – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
Assessment 
 
Site Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
Finding 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Screening 
- 
- 
Normal 
 
 
DDMONYYYYTHH:MM 
Preop 
- 
- 
Abnormal, clinically significant 
 
 
DDMONYYYYTHH:MM 
PACU 
- 
- 
Abnormal, not clinically significant 
 
 
DDMONYYYYTHH:MM 
6 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
12 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
24 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
36 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
48 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
60 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
66 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
72 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
120 (D5) 
XXX.XX 
XXX 
Normal 
 
 
DDMONYYYYTHH:MM 
240 (D10) 
XXX.XX 
XXX 
Normal 
 
 
 
 
 
 
 
*=out of window 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window.  See Table of Time and Events for windows. 
 
 


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Protocol: 402-C-327 
Listing 16.2-17: Neurological Assessment – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
Assessment 
Question 
Site 
Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Screening 
- 
- 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
Preop 
- 
- 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
PACU 
- 
- 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
6 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
12 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
24 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
36 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
48 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
60 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
66 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
72 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
120 (D5) 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
240 (D10) 
XXX.XX 
XXX 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window 
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 not related to the use of eye glasses? 
6) Are your muscles twitching? 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window.  See Table of Time and Events for windows. 
 
 
 
 
 


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Protocol: 402-C-327 
Listing 16.2-18.1: Sensory Function Assessment – All Subjects (Part 1 of 3) 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
Assessment 
Axillary Nerve 
Musculocutaneous 
Nerve 
Site Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Cold 
Pin- 
prick 
Light 
Touch 
Cold 
Pin- 
prick 
Light 
Touch 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM Screening 
- 
- 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
Baseline 
- 
- 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
PACU 
- 
- 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
6 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
9 
XXX.XX 
XXX 
-L 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
12 
XXX.XX 
XXX 
- 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
18 
XXX.XX 
XXX 
- 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
24 
XXX.XX 
XXX 
- 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
36 
XXX.XX 
XXX 
- 
-L 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
48 
XXX.XX 
XXX 
+R 
+R 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
60 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
72 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
120 (D5) 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 240 (D10) XXX.XX 
XXX 
+ 
+ 
+ 
-L 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
Unsched. 
- 
- 
+ 
+ 
+ 
- 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window 
‘-/+‘=Absent/Present; L/R=Loss/Return of sensation 
Unsched=Unscheduled 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window.  See Table of Time and Events for windows.  
 
 


Pacira Pharmaceuticals, Inc. 
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EXPAREL 
Statistical Analysis Plan 
 
Document No. <  > 
 
CONFIDENTIAL 
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26Jun2017 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-327 
Listing 16.2-18.1: Sensory Function Assessment – All Subjects (Part 2 of 3) 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
Assessment 
Median Nerve 
Ulnar Nerve 
Site Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Cold 
Pin- 
prick 
Light 
Touch 
Cold 
Pin- 
prick 
Light 
Touch 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM Screening 
- 
- 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
Baseline 
- 
- 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
PACU 
- 
- 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
6 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
9 
XXX.XX 
XXX 
-L 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
12 
XXX.XX 
XXX 
- 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
18 
XXX.XX 
XXX 
- 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
24 
XXX.XX 
XXX 
- 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
36 
XXX.XX 
XXX 
- 
-L 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
48 
XXX.XX 
XXX 
+R 
+R 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
60 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
72 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
120 (D5) 
XXX.XX 
XXX 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
DDMONYYYYTHH:MM 240 (D10) XXX.XX 
XXX 
+ 
+ 
+ 
-L 
+ 
+ 
 
 
DDMONYYYYTHH:MM 
Unsched. 
- 
- 
+ 
+ 
+ 
- 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window 
‘-/+‘=Absent/Present; L/R=Loss/Return of sensation 
Unsched=Unscheduled 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window.  See Table of Time and Events for windows. 
 
 


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26Jun2017 
 
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(Page X of Y) 
Protocol: 402-C-327 
Listing 16.2-18.1: Sensory Function Assessment – All Subjects (Part 3 of 3) 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
 
Assessment 
Radial Nerve 
 
Site Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Cold 
Pin- 
prick 
Light 
Touch 
 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM Screening 
- 
- 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
Baseline 
- 
- 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
PACU 
- 
- 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
6 
XXX.XX 
XXX 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
9 
XXX.XX 
XXX 
-L 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
12 
XXX.XX 
XXX 
- 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
18 
XXX.XX 
XXX 
- 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
24 
XXX.XX 
XXX 
- 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
36 
XXX.XX 
XXX 
- 
-L 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
48 
XXX.XX 
XXX 
+R 
+R 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
60 
XXX.XX 
XXX 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
72 
XXX.XX 
XXX 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
120 (D5) 
XXX.XX 
XXX 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 240 (D10) XXX.XX 
XXX 
+ 
+ 
+ 
 
 
 
 
 
DDMONYYYYTHH:MM 
Unsched. 
- 
- 
+ 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window 
‘-/+‘=Absent/Present; L/R=Loss/Return of sensation 
Unsched=Unscheduled 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window.  See Table of Time and Events for windows. 
 
 
 
 


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Statistical Analysis Plan 
 
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26Jun2017 
 
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Protocol: 402-C-327 
Listing 16.2-18.2: Time to Loss and Return of Sensory Function – All Subjects  
TREATMENT: treatment-name 
 
 
Loss-Return 
Date and Time of 
Time to (hrs) 
Site 
Subject 
Cycle Number Location 
Dose 
Loss 
Return 
Loss 
[1] 
Return 
[2] 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
1 
XXXXXXX 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
 
 
2 
 
- 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
 
 
… 
 
- 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
 
 
n 
 
- 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM* 
XXX.X XXX.X* 
 
 
Total 
 
- 
- 
- 
- 
D.D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Time to loss is the time from start of study drug administration to loss of sensation 
[2] Time to return is time the time from most recent loss of sensation to return of sensation 
*=Censored return (time of last sensory assessment)Source: list SAS datasets used to create table 
 
DDMONY
SAS X.Y 
 
program_name 
 
Note to programmer: Locations are axillary, musculo., median, ulnar and radial.  Sort by date and time 
within subject. In total row, L is the total number of times subject lost sensation, R is total number of 
times subject had return of sensation; and D.D is sum of durations from all cycles.  Some subjects may have 
more losses of sensation than returns. 
 
 
 
 


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Protocol: 402-C-327 
Listing 16.2-19.1: Motor Function Assessment – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
Assessment 
Thumb 
Elbow 
Flexion 
Site Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Abduct 
Adduct 
Oppos 
 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
Screening 
- 
- 
X 
- 
X 
- 
 
 
DDMONYYYYTHH:MM 
Baseline 
- 
- 
X 
- 
X 
- 
 
 
DDMONYYYYTHH:MM 
PACU 
- 
- 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
6 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
9 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
12 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
18 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
24 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
36 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
48 
XXX.XX 
XXX 
XL 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
60 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
72 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
120 (D%) 
XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
240 (D10) XXX.XX 
XXX 
X 
X 
X 
X 
 
 
DDMONYYYYTHH:MM 
Unsched. 
- 
- 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
*=out of window 
L=Loss of function/R=Return of function 
Unsched=Unscheduled 
Abduct=Abduction 
Adduct=adduction 
Oppos=opposition 
0=no evidence of contractility;  
 
1=evidence of slight contractility;  
2=complete range of motion without gravity;  
 
3=complete range of motion with gravity;  
4=complete range of motion against gravity with some  resistance;  
5=complete range of motion against gravity with full  resistance. 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window.  See Table of Time and Events for windows.  


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Listing 16.2-19.2: Time to Loss and Return of Motor Function – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
Loss-Return 
Date and Time of 
Time (hrs) to 
Site Subject 
Cycle 
Number 
Assessment 
Dose 
Loss 
Return 
Loss 
[1] 
Return 
[2] 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
1 
Abduct 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
 
 
2 
Flexion 
- 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
 
 
… 
 
- 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
 
 
n 
 
- 
DDMONYYYYTHH:MM DDMONYYYYTHH:MM* 
XXX.X 
XXX.X* 
 
 
Total 
 
- 
- 
- 
- 
D.D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Time to loss is the time from start of study drug  administration to loss of motor function 
[2] Time to return is time the time from most recent loss of to return of motor function 
Total Return is the time from first loss to last return of motor function. 
*=Censored return (time of last motor assessment) 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
Note to programmer: Assessments are Abduct, Adduct, Oppos and Flexion.  Sort by date and time within 
subject. In total row, D.D is the time from first loss of motor function to last return of motor function  
Some subjects may have more losses of motor function than returns.  
 
 
 


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Listing 16.2-20.1: All Adverse Events – All Subjects 
Treatment: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
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.  Use this template for the following listings: 
Listing 16.2-20.2.1: Treatment-emergent Adverse Events – All Subjects  
Listing 16.2-20.2.2: Treatment-emergent Study Drug Related Adverse Events – All Subjects  
Listing 16.2-20.3: All Serious Adverse Events – All Subjects  
Listing 16.2-20.4.1: Treatment-emergent Serious Adverse Events – All Subjects  
Listing 16.2-20.4.2: Treatment-emergent Study Drug Related Serious Adverse Events – All Subjects  
Listing 16.2-20.5.1: Treatment-emergent Adverse Events of Special Interest – All Subjects  
Listing 16.2-20.5.2: Treatment-emergent Study Drug Related Adverse Events of Special Interest – All 
Subjects 
 
 
 


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Listing 16.2-21.1: All Prior and Concomitant Medications – All Subjects 
Treatment: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
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 a 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 16.2-21.2: Prior Medications – All Subjects  
Listing 16.2-21.3: Concomitant Medications – All Subjects 
 
 
 


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Listing 16.2-22: Medical History – All Subjects 
Treatment: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site Subject 
Data Type 
Data 
XXX 
XXX-YYYY Start 
DDMONYYYY 
 
 
Stop 
DDMONYYYY 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
    History Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
Start 
DDMONYYYY 
 
 
Stop 
DDMONYYYY 
 
 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
 
 
  Preferred 
  XXXXXXXXXXXXXXXXXXXX 
 
 
    History Verbatim 
    XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Listing 16.2-23: Intraoperative Medications – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site 
Subject 
Administered 
Name 
Dose 
Unit 
Route 
   
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
YES 
OPIOID-NAME 
XXX.XX 
(UNITS) 
XXXX 
   
XXX 
XXX-YYYY 
NO 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-327 
Listing 16.2-24: Study Drug Administration – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site 
Subject 
Date 
Start 
Time 
Stop 
Time 
Total Volume 
(mL) 
    
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XXX 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
 
 
 
 
 
 
    
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Listing 16.2-25: Urine Drug Screen, Alcohol Blood Test and Pregnancy Test – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site 
Subject 
Visit 
Urine Drug 
Blood 
Alcohol 
Pregnancy 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
Day 0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
Day 0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
Day 0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
XXX 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
Day 0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 
 
 
 
 


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Listing 16.2-26: Admission and Discharge – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
 
 
Date and Time 
 
Site 
Subject 
Admission 
Discharge 
 
 
 
 
 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
 
XXX 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
 
 
 
 
 
 
*=out of window 
Total score = sum of scores. 
1) Vital signs: 2 = ≤ 20%; 1 = 20-40%; 0 = >40% of preoperative value. 
2) Ambulation: 2 = steady gait/no dizziness; 1 = with assistance; 0 = none/dizziness 
3) Nausea and Vomiting: 2 = minimal; 1 = moderate; 0 = severe 
4) Pain: 2 = minimal; 1 = moderate; 0 = severe 
5) Surgical bleeding: 2 = minimal; 1 = moderate; 0 = severe  
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y 
 
program_name 
 
 


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Listing 16.2-27: 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. 
 
 
 


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Listing 16.2-28: 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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Listing 16.2-29: Protocol Deviations – All Subjects 
TREATMENT: treatment-name 
  Surgery: surgery-type 
    Nerve Block: nerve-block type 
Site Subject Important 
Date 
Description 
 
 
 
 
 
XXX XXX-YYYY 
XXX 
DDMONYYYYTHH:MM XXXXXXXXXXXXXXXXXX 
 
 
 
DDMONYYYYTHH:MM XXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Categories: Important, might significantly impact; Not-Important, none to minimal impact on study outcomes. 
Important:   
Source: list SAS datasets used to create listing 
 
DDMONYYYYTHH:MM  
SAS X.Y 
 
program_name 
 
Note to programmer: Subjects may have multiple deviations.  Sort deviations by treatment, surgery type, 
nerve block type, site, subject, then category ‘Important’ followed by ‘Not-Important’ and finally 
important (‘YES’ then ‘NO’).  Date may or may not include time. 


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16. 
TABLE OF CONTENTS FOR FIGURE MOCK-UPS 
FIGURE 1.1: PLOT OF MEAN PAIN INTENSITY SCORE (VAS) VS TIME THROUGH 48 HOURS – 
EFFICACY ANALYSIS SET 
167 
FIGURE 1.2: PLOT OF MEAN PAIN INTENSITY SCORE (VAS) VS TIME THROUGH 48 HOURS – 
PER-PROTOCOL ANALYSIS SET 
167 
FIGURE 2.1: PLOT OF MEAN PAIN INTENSITY SCORE (VAS) VS TIME THROUGH 72 HOURS – 
EFFICACY ANALYSIS SET 
167 
FIGURE 2.2: PLOT OF MEAN PAIN INTENSITY SCORE (VAS) VS TIME THROUGH 72 HOURS – 
PER-PROTOCOL ANALYSIS SET 
167 
FIGURE 3.1: PLOT OF INDIVIDUAL SUBJECT PAIN INTENSITY SCORE (VAS) VS TIME 
THROUGH 48 HOURS – EFFICACY ANALYSIS SET 
167 
FIGURE 3.2: PLOT OF INDIVIDUAL SUBJECT PAIN INTENSITY SCORE (VAS) VS TIME 
THROUGH 48 HOURS – PER-PROTOCOL ANALYSIS SET 
167 
FIGURE 4.1: PLOT OF INDIVIDUAL SUBJECT PAIN INTENSITY SCORE (VAS) VS TIME 
THROUGH 72 HOURS – EFFICACY ANALYSIS SET 
167 
FIGURE 4.2: PLOT OF INDIVIDUAL SUBJECT PAIN INTENSITY SCORE (VAS) VS TIME 
THROUGH 72 HOURS – PER-PROTOCOL ANALYSIS SET 
167 
 


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Figure Mock-up 1 
  


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Figure Mock-up 2
 


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Figure Mock-up 3 
 
Pain Intensity Score (VAS)
0
1
2
3
4
5
6
7
8
9
10
Time (hours)
-5
0
5
10
15
20
25
30
35
40
45
50
55
Treatment=EXPAREL XXX mg surgery=XXXXXXXXXXXXXXXXXXXXXX Subject=XXX-XXX-XXXX
Gray bars indicate rescue medication windows
VAS - Actual
VAS - Imputed


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Figure Mock-up 4 
 
Pain Intensity Score (VAS)
0
1
2
3
4
5
6
7
8
9
10
Time (hours)
-5
5
15
25
35
45
55
65
75
85
95
105
115
125
Treatment=EXPAREL XXX mg surgery=XXXXXXXXXXXXXXXXXXXXXX Subject=XXX-XXX-XXXX
Gray bars indicate rescue medication windows
VAS - Actual
VAS - Imputed


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Note to programmers:    Note the colors and symbols used in the figure mock-ups are not correct per the SAP 
description; all figures created should use the SAP defined colors and symbols. In figure mock-ups 3 and 4: 
the gray bars highlight the rescue medication windows for that subject; the time axes are set to ensure the 
entire period is captured and doesn’t end at the limits of the figure.  Use the indicated figure mock-up 
for the following figures.  
 
Use Figure mock-up 1 for the following (do not include EXPAREL 266 mg): 
Figure 1.1: Plot of Mean Pain Intensity Score (VAS) vs Time through 48 hours – Efficacy Analysis Set  
Figure 1.2: Plot of Mean Pain Intensity Score (VAS) vs Time through 48 hours – Per-protocol Analysis Set  
 
Use Figure mock-up 2 for the following (do not include EXPAREL 266 mg and the x-axis should track through 
76 hours): 
Figure 2.1: Plot of Mean Pain Intensity Score (VAS) vs Time through 72 hours – Efficacy Analysis Set  
Figure 2.2: Plot of Mean Pain Intensity Score (VAS) vs Time through 72 hours – Per-protocol Analysis Set  
 
Use Figure mock-up 3 for the following (do not include EXPAREL 266 mg subjects, use actual hours since the 
end of surgery and not scheduled hours, include all VAS scores collected, include the following footnote 
“RCR = Rotator Cuff Repair; TSA = Total Shoulder Arthoplasty;”): 
Figure 3.1: Plot of Individual Subject Pain Intensity Score (VAS) vs Time through 48 hours – Efficacy 
Analysis Set  
Figure 3.2: Plot of Individual Subject Pain Intensity Score (VAS) vs Time through 48 hours – Per-Protocol 
Analysis Set  
 
Use Figure mock-up 4 for the following (do not include EXPAREL 266 mg subjects, use actual hours since the 
end of surgery and not scheduled hours, include all VAS scores collected, the x-axis should track through 
76 hours, include the following footnote “RCR = Rotator Cuff Repair; TSA = Total Shoulder Arthoplasty;”): 
Figure 4.1: Plot of Individual Subject Pain Intensity Score (VAS) vs Time through 72 hours – Efficacy 
Analysis Set 
Figure 4.2: Plot of Individual Subject Pain Intensity Score (VAS) vs Time through 72 hours – Per-Protocol 
Analysis Set