Clinical trial NCT03853694
Conditions: Elective Cesarean Section Pain Management
Keywords: bupivacaine EXPAREL analgesic TAP Block C-Section Cesarean Section elective c-section TAP
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2019-03-04; Completion date: 2020-01-16
Enrollment: 167 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare total opioid consumption by subjects in different treatment groups.

Another purpose of this study is to assess how well EXPAREL works, collect any safety data and assess your satisfaction using EXPAREL.

Detailed description:
This is a Phase-4, multicenter, randomized, active-controlled study in approximately 182 adult women undergoing elective C-section. All subjects will remain in the hospital for up to 72 hours post surgery.

Subjects will be screened within 30 days prior to surgery. During the screening visit, subjects will be assessed for any past or present medical conditions that in the opinion of the investigator would preclude them from study participation.

After the Informed Consent Form (ICF) is signed, a medical history, surgical history, physical examination, 12-lead electrocardiogram (ECG), vital sign measurements, alcohol breath test and urine drug screen, and clinical laboratory tests (hematology and chemistry) will be performed.

On Day 1, prior to the C-section, eligible subjects will be randomized in a 1:1:1 ratio into one of the three treatment groups listed below:

* Group 1: 150 mcg Duramorph® (SOC arm)+ postoperative multi-modal pain regimen as defined in this protocol. No EXPAREL TAP infiltration following skin-incision closure.
* Group 2: 50 mcg Duramorph + EXPAREL TAP infiltration following skin-incision closure + postoperative multi-modal pain regimen as defined in this protocol.
* Group 3: EXPAREL TAP infiltration following skin-incision closure + postoperative multi-modal pain regimen as defined in this protocol. No Duramorph.

Rescue Medication will be provided, as needed, for all subjects.

Subjects will remain in the hospital for up to 72 hours after surgery.

Total opioid burden and Pain intensity scores using a 10 cm Visual Analog Scale (VAS) will be collected.

Daily pain intensity score (VAS) and all pain medications will be collected through Day 14.

A phone call will be made to each subject on Day 14 and Day 30.

Arms: arm 1: 150 mcg Duramorph® + postoperative multi-modal pain regimen. No EXPAREL TAP infiltration arm 2: 50 mcg Duramorph + EXPAREL TAP infiltration + postoperative multi-modal pain regimen. arm 3: EXPAREL TAP infiltration + postoperative multi-modal pain regimen. No Duramorph.
Interventions: intervention 1: 50 mcg Duramorph+ EXPAREL + multi-modal pain regimen intervention 2: 150 mcg Duramorph + multi-modal pain regimen intervention 3: Exparel TAP + multi-modal pain regimen
Intervention descriptions: intervention 1: Intrathecal injection of 50 mcg Duramorph + EXPAREL administered via TAP infiltration + multi-modal pain regimen. intervention 2: Intrathecal injection of 150 mcg Duramorph + multi-modal pain regimen. intervention 3: EXPAREL administered via TAP infiltration + multi-modal pain regimen.

Protocol documents:
Prot_002.pdf: 
 
 
 
 
 
 
Clinical Study Protocol 
A Multicenter, Randomized, Active-Controlled Study to Evaluate the Efficacy 
and Safety of EXPAREL When Administered via Infiltration into the 
Transversus Abdominis Plane versus Standard of Care in Subjects 
Undergoing Elective Cesarean Section (CHOICE) 
 
Protocol No.: 402-C-414 
EudraCT No.: Not applicable 
IND No.: 069,198 
Study Phase: 4 
Study Drug: EXPAREL® (bupivacaine liposome injectable suspension) 
Original Protocol Date: 16-Aug-2018 
Amendment 1 Date: 15-Nov-2018 
Amendment 2 Date:   07-Feb-2019 
Study Sites: Multicenter study in North America 
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. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
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07-Feb-2019 
 
 
 
SIGNATURE PAGE
 
 
 
 
 
 
13-Feb-2019 
 
 
 
 
 
 
Michael Rozycki, PhD 
Sr Vice President, Regulatory Affairs 
Date 
 
13-Feb-2019 
 
 
 
 
 
 
 
Julia Yang, MD 
Vice President, Clinical Research 
Date 
 
13-Feb-2019 
 
 
 
 
 
Igor Grachev, MD, PhD 
Sr Medical Director 
Clinical Research and Development 
Date 
 
 
14-Feb-2019 
 
 
 
 
 
 
Vincent Yu, PhD
Sr Director, Biometrics 
Date 
15-Feb-2019 
Richard Scranton, MD, MPH 
Chief Medical Officer 
Date 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
3 of 73 
07-Feb-2019 
 
 
 
 
2.  SYNOPSIS 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Title of Study: A Multicenter, Randomized, Active-Controlled Study to Evaluate the Efficacy and Safety of 
EXPAREL When Administered via Infiltration into the Transversus Abdominis Plane versus Standard of Care in 
Subjects Undergoing Elective Cesarean Section (CHOICE) 
Principal investigator: To be determined 
Study Center(s): Multicenter study in North America 
Publications (Reference): None 
Objectives: 
Primary objective: To compare total opioid consumption through 72 hours following EXPAREL infiltration into the 
transversus abdominis plane (TAP) with standard of care (SOC) in subjects undergoing an elective cesarean section 
(C-section). 
Secondary objective: To assess efficacy and safety parameters and participant satisfaction. 
Methodology: 
This is a Phase 4, multicenter, randomized, active-controlled study in approximately 182 adult subjects undergoing 
elective C-section. All subjects will remain in the hospital for up to 72 hours postsurgery. 
Obtaining Informed Consent 
Potential participants may provide informed consent up to 30 days before their scheduled surgery. If a subject can 
only be screened on the day of surgery, the consent process should be started at least 24 hours prior to the day of 
surgery in order to ensure ample time for the subject to review the informed consent form (ICF) and have all her 
questions answered by the investigator/study staff prior to providing informed consent. Screening procedures that are 
SOC at the institution may be completed prior to written informed consent.  Any screening procedures that are not 
SOC must be completed after written informed consent is provided and prior to surgery. 
Screening 
Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be allowed but is 
discouraged. If a subject can only be screened on the day of surgery, the informed consent process must still be  
started at least 24 hours prior to the conduct of any screening procedures that are not considered SOC at the institution 
and such procedures may not be performed until written informed consent is provided. All screening procedures that 
are not SOC must be performed and documented within the 30-day time window (inclusive of the day of surgery for 
those subjects who can only be screened on the day of surgery) as described here. During the screening visit, subjects 
will be assessed for any past or present medical conditions that, in the opinion of the investigator, would preclude them 
from study participation. 
After the ICF is signed, medical history, surgical history, physical examination (according to the investigational site’s 
SOC), 12-lead electrocardiogram, vital sign measurements, alcohol breath test and urine drug screen, and clinical 
laboratory tests (hematology and chemistry) will be performed. The Surgical Fear Questionnaire (SFQ) will be 
administered during screening. 
Day of Surgery 
Pre-operative medications: Use of pre-operative analgesics (e.g., opioid medications, Tylenol® [acetaminophen], non- 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
4 of 73 
07-Feb-2019 
 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
steroidal anti-inflammatory drugs [NSAIDs]) is prohibited. 
On Day 1, prior to the C-section, pulse oximetry will be measured and eligible subjects will be randomized in a 1:1:1 
ratio into one of the three treatment groups listed below: 
• 
Group 1: 150 mcg Duramorph® (SOC arm). No EXPAREL TAP infiltration following skin-incision 
closure. 
Subjects randomized to Group 1 will receive an intrathecal injection of 150 mcg preservative-free morphine 
for spinal injection (e.g., Duramorph) in conjunction with single-shot spinal anesthesia using 1.4 to 1.6 mL 
bupivacaine hydrochloride (HCl) 0.75% and 15 mcg fentanyl. Postoperative pain management will follow 
the multimodal pain regimen as defined in this protocol.. 
• 
Group 2: 50 mcg Duramorph + EXPAREL TAP infiltration following skin-incision closure + postoperative 
multimodal pain regimen as defined in this protocol. 
Subjects randomized to Group 2 will receive an intrathecal injection of 50 mcg preservative-free morphine 
for spinal injection (e.g., Duramorph) in conjunction with single-shot spinal anesthesia using 1.4 to 1.6 mL 
bupivacaine HCl 0.75%. If deemed necessary by the investigator, intrathecal fentanyl can be given prior to 
incision for the C-section. If intrathecal fentanyl is used, the dose of 15 mcg fentanyl, date, and time of the 
usage must be recorded. In addition, Group 2 subjects will receive EXPAREL TAP infiltration following 
skin-incision closure plus postoperative multimodal pain regimen. 
• 
Group 3: EXPAREL TAP infiltration following skin-incision closure + postoperative multimodal pain 
regimen as defined in this protocol. No Duramorph. 
Subjects randomized to Group 3 will NOT receive Duramorph as a spinal injection. This group will receive 
single-shot spinal anesthesia using 1.4 to 1.6 mL bupivacaine HCl 0.75%. If deemed necessary by the 
investigator, intrathecal fentanyl can be given prior to incision for the C-section. If intrathecal fentanyl is 
used, the dose of 15 mcg fentanyl, date, and time of the usage must be recorded. In addition, Group 3 
subjects will receive EXPAREL TAP infiltration following skin-incision closure plus postoperative 
multimodal pain regimen. 
In all treatment groups, a combined spinal epidural (CSE) anesthesia technique may also be used provided the epidural 
component is not used. Subjects who receive the epidural component of the CSE anesthesia must be immediately 
withdrawn from the study. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
5 of 73 
07-Feb-2019 
 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Study Schema 
 
TAP=transversus abdominis plane 
Intraoperative medications: The intraoperative use of ketamine and midazolam (Versed®) is discouraged but may be 
permitted if clinically indicated based on the investigator’s discretion (all medications must be appropriately recorded 
[i.e., drug, dose, and route of administration]). Prophylactic use of dexamethasone for prevention of nausea and 
vomiting is prohibited. 
For Groups 2 and 3, after delivery of the baby and prior to the TAP infiltration, a small amount of lidocaine (<2 mL) 
may be administered subcutaneously to form a skin wheal over the area of the needle insertion site. A 2-point classic 
TAP block, in 2 steps (see Pharmacy Binder), must be performed under ultrasound guidance and must be performed  
no more than 90 minutes after skin-incision closure of the C-section. A confirmatory ultrasound image or video will 
be taken of each side of the abdomen after the TAP needle position has been established and following infiltration of 
study drug. 
TAP infiltration (Groups 2 and 3): The TAP infiltration includes two steps: (1) TAP needle placement and saline 
hydrodissection and (2) study drug mixture infiltration into the TAP.  Each step must be performed on one side of the 
abdomen and must be repeated on the contralateral side to complete the bilateral, 2-point TAP required for the study. 
For complete, step-by-step instructions on performing the TAP infiltration under ultrasound guidance, please refer to 
the Pharmacy Binder. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
6 of 73 
07-Feb-2019 
 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Postsurgical Analgesia: Participant-controlled analgesia is not permitted. 
The following multimodal pain regimens will be used for all treatment groups. The date, time, and dose of all 
standardized multimodal pain medications administered must be recorded. 
All Subjects in Groups 1, 2, and 3: 
At the time of skin-incision closure (Note: it is very important that these be administered at the time of skin-incision 
closure and not prior to or before the end of surgery): 
• 
Intravenous (IV) ketorolac 30 mg (1 dose) 
• 
IV acetaminophen 1000 mg (1 dose) 
Beginning 6 hours after skin-incision closure: 
• 
IV ketorolac 30 mg beginning 6 hours from the administration of IV ketorolac at the time of skin-incision 
closure and then every 6 hours (q6h) for the next 18 hours (i.e., total of 120 mg as four 30-mg doses over first 
24 hours from the time of skin-incision closure) 
• 
IV acetaminophen 1000 mg beginning 6 hours from the administration of IV acetaminophen at the time of 
skin-incision closure and then every 6 hours (q6h) for the next 18 hours (i.e., total of 4000 mg as four 1000- 
mg doses over first 24 hours from the time of skin-incision closure) 
• 
Scheduled oral (PO) Tylenol® (acetaminophen) 975 mg beginning 6 hours from the administration of the last 
dose of IV acetaminophen and q6h for up to 72 hours or hospital discharge (whichever occurs first) 
• 
Scheduled PO ibuprofen 600 mg beginning 6 hours from the administration of the last dose of IV ketorolac 
and then q6h for up to 72 hours or hospital discharge (whichever occurs first) 
This multimodal pain regimen is a requirement for all subjects in the study and is not subject to investigator 
discretion. The date, time, and dose of all standardized multimodal pain medications administered must be recorded. 
Note: The scheduled PO medication will be administered on a q6h schedule only till hospital discharge. 
Rescue Medication: When breakthrough pain occurs, the study staff or the floor nurses on duty will need to ensure 
that the study subject is strictly following the protocol-specific multimodal pain regimen schedule (q6h as defined in 
the protocol) before considering the use of the opioids as a rescue, especially in cases where the visual analog scale 
(VAS) score is relatively low. Subjects should receive opioid rescue pain medication only upon request for 
breakthrough pain. 
Postsurgical rescue medication will comprise PO immediate-release oxycodone (initiated at 5 mg as needed [PRN]). If 
the 5 mg oxycodone is not sufficient for pain management, subject can receive a dose of 10 mg PRN. If a subject is 
unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine (initiated at 1 to 2 mg) or 
hydromorphone (initiated at 0.3 to 0.5 mg) may be administered PRN. 
All surgical and postsurgical opioid and other analgesics (pain medications) administered must be documented 
through Day 14 postsurgery. Additionally, an unscheduled pain intensity score using a 10 cm VAS (see Appendix 1) 
must be completed immediately prior to any rescue medication while in the hospital. 
Permitted medications for the prevention and treatment of possible adverse events (AEs) of medications include the 
following (to be used at the discretion of the study site principal investigator): 
• 
Ondansetron 4 mg IV immediately after delivery of the baby 
• 
Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for intraoperative and 
postoperative nausea and vomiting 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
7 of 73 
07-Feb-2019 
 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
• 
Metoclopramide 10 mg PO PRN for nausea and vomiting 
• 
Nalbuphine IV 2.5 mg PRN for pruritus 
• 
Naloxone IV 50 to 100 mcg PRN for pruritus 
Postsurgical Assessments 
Subjects will remain in the hospital for up to 72 hours after surgery. Postsurgical assessments will include: 
• 
Opioid use 
• 
Date and time to first bowel movement 
-Total opioid burden 
• 
Itching using Numeric Rating Scale (NRS) of 0 to 10 (see 
-Time to first opioid use 
Appendix 10) 
• 
Date and time of first unassisted ambulation 
• 
Subject's satisfaction with postsurgical pain control 
• 
Pain intensity scores using a 10 cm VAS 
(see Appendix 3) 
(see Appendix 1) at rest (general and site of 
• 
Recovery from Cesarean Section scale (RCSS; 
injection) 
 
see Appendix 4) 
• 
Discharge readiness (see Appendix 2) 
• 
Calls to physician about pain (see Appendix 8) 
• 
Opioid Related Symptom Distress scale 
• 
Total time in post-anesthesia care unit (PACU) 
(ORSDS; see Appendix 7) 
• 
Persistent opioid use at Day 30 (see Appendix 9) 
• 
Emergency department visits 
While in the hospital, subjects will be provided with an electronic patient-reported outcome (ePRO) device and will 
use the device to record all scheduled and unscheduled VAS scores. For all scheduled assessments and unscheduled 
assessments in the hospital, subjects will assess “How much pain are you experiencing right now in general?” and 
“How much pain are you experiencing at the site of the incision”; a vertical mark will be placed on the VAS line to 
indicate the level of pain experienced at the time of assessment. If a subject is discharged prior to a scheduled VAS 
assessment, a member of the study site staff will contact the subject to remind her to complete the scheduled VAS 
assessment at the scheduled time and to record the assessment in the device, which the subjects will take home with 
them to continue to record study assessments at home. 
At hospital discharge, the subject will be instructed to record in the device their daily pain intensity score (VAS) and 
all pain medications taken following hospital discharge through Day 14. 
At home, the subject will assess pain intensity at rest each day at noon (± 4 hours). This assessment should capture 
her worst pain at rest in the prior 24 hours by assessing “What was your worst pain since your last pain assessment?” 
(i.e., from noon on the previous day to the current assessment). At the same time, the subject should record any pain 
medication (medication name, date, time, and dose) taken in the prior 24 hours. 
A phone call will be made to each subject on Day 14 for safety purposes and to inquire as to whether the subject has 
made any unscheduled phone calls or office visits related to pain, experienced any hospital readmission, or 
experienced an emergency room visit since hospital discharge. AEs and serious adverse events (SAEs) will be 
recorded from the time the ICF is signed through Day 14. Any concomitant medications to treat AEs through Day 14 
will also be recorded. On Day 30, a phone call will be made to ask the subjects about persistent opioid use. 
Number of Subjects (Planned): Approximately 182 subjects are planned for enrollment into the study. Subjects who 
are withdrawn or discontinued prior to completing the study may be replaced. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
8 of 73 
07-Feb-2019 
 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Eligibility Criteria: 
Note: Based on the World Health Organization (WHO) Guidance: Breastfeeding and Maternal Medication, 
Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs, bupivacaine is compatible with 
breastfeeding; therefore, there are no restrictions in this study regarding the participation of women who wish to 
breastfeed following treatment with study drug. 
Inclusion Criteria: 
1. Females 18 years of age and older at screening 
2. Term pregnancies of 37 to 42 weeks gestation scheduled to undergo elective C-section 
3. American Society of Anesthesiologists physical status 1, 2, or 3 
4. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments 
Exclusion Criteria: 
1. Subjects who, in the opinion of the study site principal investigator, have a high-risk pregnancy (e.g., multiple 
gestations, pregnancy resulting from in vitro fertilization, end-term prolonged bed rest required for medical 
reasons) 
2. Subjects with an unstable pregnancy-induced medical condition or complication (e.g., gestational diabetes, 
hypertension, pre-eclampsia, chorioamnionitis) 
3. Subjects with 3 or more prior C-sections (a subject is eligible if the index C-section is the third case for that 
subject) 
4. Pre-pregnancy body mass index >50 kg/m2 or otherwise not anatomically appropriate to undergo a TAP block 
5. Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative 
is not named in the protocol (e.g., amide-type local anesthetics, opioids, bupivacaine, NSAIDs, spinal anesthesia) 
6. Planned concurrent surgical procedure with the exception of salpingo-oophorectomy or tubal ligation 
7. Severely impaired renal or hepatic function (for example, serum creatinine level >2 mg/dL [176.8 µmol/L], blood 
urea nitrogen level >50 mg/dL [17.9 mmol/L], serum aspartate aminotransferase level >3 times the upper limit of 
normal [ULN], or serum alanine aminotransferase level >3 times the ULN) 
8. Subjects at an increased risk for bleeding or a coagulation disorder (defined as platelet count less than 
80,000 × 103/mm3 or international normalized ratio greater than 1.5) 
9. Concurrent painful physical condition that may require analgesic treatment (such as long-term, consistent use of 
opioids) in the postsurgical period for pain that is not strictly related to the surgery and which may confound the 
postsurgical assessments 
10. Clinically significant medical disease in either the mother or baby that, in the opinion of the investigator, would 
make participation in a clinical study inappropriate. This includes any psychiatric or other disease in the mother 
that would constitute a contraindication to participation in the study or cause the mother to be unable to comply 
with the study requirements. 
11. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within 
the past 2 years 
12. Administration of an investigational drug within 30 days or 5 elimination half-lives of such investigational drug, 
whichever is longer, prior to study drug administration, or planned administration of another investigational 
product or procedure during the subject’s participation in this study 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
9 of 73 
07-Feb-2019 
 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
13. Previous participation in an EXPAREL study 
In addition, the subject will be ineligible to receive study drug and will be withdrawn from the study if she meets the 
following criteria during surgery: 
14. Any clinically significant event or condition uncovered during the surgery (e.g., excessive bleeding, acute sepsis) 
that might render the subject medically unstable or complicate the subject’s postsurgical course 
15. Receives the epidural component of CSE anesthesia during participation in the study 
Test Product, Dose, Mode of Administration, and Lot Numbers: 
Name: EXPAREL (bupivacaine liposome injectable suspension) and bupivacaine HCl 0.5% (Groups 2 and 3) 
Active Ingredient: Bupivacaine, 1.3%, 13.3 mg/mL 
Dosage: See Pharmacy Binder 
Lot Number: To be determined 
Reference Product, Dose, Mode of Administration, and Lot Numbers: 
Name: Duramorph® (150 mcg); Institutional site SOC 
Duration of Subject Participation in Study: 
Participation will begin upon signing of the ICF. No more than 30 days should pass between signing the ICF and 
surgery. The time from study drug administration through the end of participation is 30 ± 3 days. Therefore, each 
subject may participate in the study for a maximum of 66 days. 
Efficacy Assessments: 
The following efficacy measurements will be performed at the times specified after closure of the C-section skin 
incision: 
• 
Date and time of administration, and amount of all postsurgical opioid rescue medication taken through Day 14 
• 
Pain intensity scores at rest (general and at incision site) using a 10 cm VAS at 12, 24, 48, and 72 hours after 
surgery (see Appendix 1) and then once daily (at noon ± 4 hours) through Day 14 
Note 1: For pain intensity scores at 12, 24, 48, or 72 hours, if the subject is sleeping, do not wake her to assess 
pain. If she awakens within the assessment window (i.e., 1 hour for the 12- and 24-hour assessments, 2 hours 
for the 48-hour assessments, and 4 hours for the 72-hour assessments), a pain score may be collected then. 
Note 2: An unscheduled VAS score is also required immediately prior to administration of any rescue 
medication while in the hospital. 
Note 3: If a subject is discharged prior to any of the scheduled VAS assessments to be collected at 12 to 
72 hours after surgery, a member of the study site staff will telephone the subject at the appropriate scheduled 
times (i.e., the time of each assessment scheduled to be collected that occurs after hospital discharge) to remind 
her to complete the VAS and to record the scheduled assessments in the ePRO device. This will ensure that, for 
any subjects discharged prior to 72 hours, all VAS assessments required for calculation of the study endpoints 
are captured. These phone calls will only occur if a subject is discharged prior to 72 hours. 
• 
Total time in PACU 
• 
Date and time of first unassisted ambulation 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 CHOICE (C-Section) 
Clinical Study Protocol Amendment 2 
CONFIDENTIAL 
10 of 73 
07-Feb-2019 
 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
• 
Date and time to first bowel movement 
• 
Itching using an NRS of 0 to 10 (see Appendix 10) 
• 
SFQ at screening (see Appendix 6) 
• 
ORSDS questionnaire at 24, 48, and 72 hours after surgery (see Appendix 7) 
• 
Subject satisfaction with postsurgical pain control using a 5-point Likert scale (see Appendix 3) 
• 
RCSS at 24, 48, and 72 hours or at hospital discharge, whichever occurs first (see Appendix 4) 
• 
Discharge readiness at 24, 48, and 72 hours, or at hospital discharge, or until the subject attains a score of 9, 
whichever occurs first (see Appendix 2) 
• 
Unscheduled phone calls or office visits related to pain after discharge through Day 14 
• 
Persistent opioid use at Day 30 (see Appendix 9) 
Efficacy Endpoints: 
Primary Efficacy Endpoint: 
• 
Total postsurgical opioid consumption in morphine equivalents through 72 hours or hospital discharge 
Secondary Efficacy Endpoints: 
• 
Time to first postsurgical opioid rescue medication 
• 
Percentage of opioid-free subjects through 72 hours or hospital discharge 
• 
Incidence and severity of itching (NRS of 0 to 10) 
• 
ORSDS at 24, 48, and 72 hours after surgery 
• 
The VAS pain, general and at incision site (at rest), through 72 hours or hospital discharge prior to any physical 
therapy or physical activity/mobilization 
• 
Proportion of subjects discharge-ready at 24, 48, and 72 hours, or at hospital discharge, or until the subject 
attains a score of 9, whichever occurs first 
• 
Overall assessment of subject’s satisfaction with pain control at 72 hours or at hospital discharge, whichever 
occurs first 
• 
Integrated rank assessment using the VAS pain intensity score (at rest) and the total amount of postsurgical 
opioids consumed through 72 hours or hospital discharge 
Exploratory efficacy endpoints may include (but may not be limited to): 
• 
Total opioid use from 72 hrs to Day 14 
• 
Time to and date of first unassisted ambulation 
• 
Length of hospital stay 
• 
Number of unscheduled phone calls or office visits related to pain from discharge through Day 14 
• 
Emergency department visits 
• 
Persistent opioid use at Day 30 
Safety Assessments: 
Adverse events (AEs/SAEs) will be monitored and recorded from the time the ICF is signed through Day 14. Vital 


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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 Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
signs (blood pressure, heart rate, respiratory rate, and temperature) and pulse oximetry will be monitored and recorded. 
Safety Endpoints: 
Incidence of treatment-emergent AEs and SAEs will be assessed from the start of anesthesia through Day 14. 
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 for all subjects who receive study drug. Efficacy 
and safety endpoint analyses will be described in the SAP. 
Determination of Sample Size: 
Assuming a log-normal distribution for total opioid consumption with a 70% coefficient of variation, 5% alpha, an 
equal randomization ratio, and 80% power, a total of 77 subjects per treatment group will be sufficient to detect a 
25% reduction in total opioid consumption. Assuming 5% of the subjects are not evaluable and one of the two 
EXPAREL groups will be dropped after interim analysis when a total of 60 subjects are treated, a total sample size of 
approximately 182 treated subjects is needed. This sample size will be re-evaluated after the interim analysis. 
After approximately 20 subjects per treatment group are randomized and treated (i.e., a total of 60 patients are treated 
in this study), an interim analysis will be conducted to evaluate and compare the clinical efficacy/safety and health 
economics benefits between the two EXPAREL groups against the SOC control group. The primary purpose of this 
interim analysis is to select one EXPAREL treatment group out of the two EXPAREL treatment groups to continue for 
the rest of this study. The second purpose of this interim analysis is to evaluate the sample size assumptions and the 
selection of the primary/secondary endpoints. Full details on the planned or additional interim analysis will be covered 
in a prospective interim analysis plan. 


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Table 1.  Assessment Schedule (Screening through 72 hours after Surgery) 
 
Study Procedure 
Within 30 days 
of scheduled 
surgery 
Screening 
(up to 30 days prior 
to day of surgery) 
Day 1 
Hours after Surgery 
OR 
PACU 12 hr 
(± 1hr) 
24 hr 
(± 1hr) 
48 hr 
(± 2hr) 
72 hr 
(± 4hr) 
Explain study purpose and procedures; obtain signed ICF 
X1 
X1 
Assess/confirm eligibility 
X 
X 
Record/confirm medical and surgical history 
X 
X 
Record prior and concomitant medications 
X 
X 
Record demographics and baseline characteristics 
X 
Measure vital signs (blood pressure, heart rate, respiratory rate, 
and temperature) 
X2 
X 
X11 
X 
X 
X3 
Measure pulse oximetry per SOC10 
Physical examination (according to the investigational site’s 
SOC) 
X 
X 
Drug screen/alcohol test 
X 
Clinical laboratory tests (hematology and chemistry; 
Appendix 5)4 
X 
12-lead electrocardiogram 
X 
Explain ePRO device and expectations of the subject regarding 
the device 
X 
Randomize subject and prepare study drug 
X 
Administer intrathecal preservative-free morphine injection in 
conjunction with single-shot spinal anesthesia per the treatment 
group (Section 13.4) 
X 
Record surgery start and stop times 
X 
Perform TAP needle placement and saline hydrodissection under 
ultrasound guidance using up to 10 mL normal saline (per the 
treatment group) 
X 
Capture ultrasound image or video of the TAP needle placement 
after saline hydrodissection 
X 
Perform 2-point classic TAP infiltration no more than 90 min 
after skin-incision closure of the C-section (per the treatment 
group) 
X 
Take ultrasound image of the 2-point classic TAP needle 
placement after study drug infiltration 
X 
Record start and stop times of study drug infiltration 
X 
Record intraoperative opioid medications administered and 
doses 
X 
 
 
 


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Study Procedure 
Within 30 days 
of scheduled 
surgery 
Screening 
(up to 30 days prior 
to day of surgery) 
Day 1 
Hours after Surgery 
OR 
PACU 12 hr 
(± 1hr) 
24 hr 
(± 1hr) 
48 hr 
(± 2hr) 
72 hr 
(± 4hr) 
Record date, time in and out of the PACU 
X 
Record SFQ (Appendix 6) 
X 
Record scheduled 10 cm VAS pain intensity scores (General 
and Site of Incision) at rest through ePRO5,6,7 (Appendix 1) 
X 
X 
X 
X 
Record 10 cm VAS pain intensity (through ePRO) immediately 
prior to any postsurgical opioid medication administered 
while in the hospital (Appendix 1) 
X 
X 
X 
X 
X 
Record date, time, and dose of all postsurgical pain medication8 
X 
X 
X 
X 
X 
Record date, time, and dose of all standardized multimodal pain 
medications administered 
X 
X 
X 
X 
X 
Record date and time of first unassisted ambulation 
X 
X 
X 
X 
X 
Record date and time of first bowel movement 
X 
X 
X 
X 
X 
Assess itching (Numeric Rating Scale of 0 to 10) 
X 
X11 
X 
X 
X 
X 
Record overall rating of subject’s satisfaction with postsurgical 
pain control through ePRO (Appendix 3) 
X3 
Record RCSS through ePRO (Appendix 4) 
X 
X 
X3 
Record ORSDS through ePRO (Appendix 7) 
X 
X 
X 
Assess discharge readiness9 (Appendix 2) 
X 
X 
X 
Record concomitant medications for treatment of AEs 
X 
X 
X 
X 
X 
X 
X 
Record AEs/SAEs (starting at signing of ICF) 
X 
X 
X 
X 
X 
X 
X 
1. 
Potential participants may provide informed consent up to 30 days before their scheduled surgery.  If a subject can only be screened on the day of surgery, the consent process 
must be started at least 24 hours prior to the day of surgery in order to ensure ample time for the subject to review the ICF and have all her questions answered by the 
investigator/study staff prior to providing informed consent.  Screening procedures that are SOC at the institution may be completed prior to written informed consent.  Any 
screening procedures that are not SOC, must be completed after written informed consent is provided and prior to surgery. 
If a subject can only be screened on the day of surgery, the informed consent process must still be started at least 24 hours prior to the conduct of any screening procedures 
that are not considered SOC at the institution and such procedures may not be performed until written informed consent is provided. 
2. 
Vital signs at screening will include height, weight, blood pressure, heart rate, respiratory rate, and temperature. 
3. 
At 72 hours postsurgery or prior to hospital discharge, whichever occurs first. 
4. 
Clinical laboratory tests will be conducted in accordance with the investigator’s SOC, including direct bilirubin; either gamma-glutamyl transpeptidase and lactate 
dehydrogenase or alanine transaminase and aspartate transaminase; and either serum creatinine or blood urea nitrogen. 
5. 
To assess pain intensity (VAS) general and at incision site at rest, the subject should rest quietly in a supine or seated position that does not exacerbate her postsurgical pain 
for 3-5 minutes before entering the pain score. This assessment should not be completed immediately following assessment of ambulation. 
6. 
If a subject is discharged prior to any of the scheduled VAS assessments (general and at incision site) to be collected at 12 to 72 hours after surgery, a member of the study 
site staff will contact the subject at the appropriate scheduled times (i.e., the time of each assessment scheduled to be collected that occurs after hospital discharge) to remind 
her to complete the VAS and ORSDS assessments and to record the scheduled assessments in the device.  This will ensure that, for any subject discharged prior to 72 hours, 
all VAS and ORSDS assessments required for calculation of the study endpoints are captured.  These phone calls will only be made if a subject is discharged prior to 
72 hours. 


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Study Procedure 
Within 30 days 
of scheduled 
surgery 
Screening 
(up to 30 days prior 
to day of surgery) 
Day 1 
Hours after Surgery 
OR 
PACU 12 hr 
(± 1hr) 
24 hr 
(± 1hr) 
48 hr 
(± 2hr) 
72 hr 
(± 4hr) 
7. 
For pain intensity scores at 12, 24, 48, or 72 hours, if the subject is sleeping, do not wake her to assess pain. If she awakens within the assessment window (i.e., 1 hour for the 
12- and 24-hour assessments, 2 hours for the 48-hour assessments, and 4 hours for the 72-hour assessments), a pain score may be collected then. 
8. 
Subjects should only receive opioid pain medication (e.g., morphine, hydromorphone [Dilaudid], oxycodone) upon request for breakthrough pain. 
9. 
Discharge readiness will be assessed at 24, 48, and 72 hours, or hospital discharge, or until the subject attains score of 9, whichever occurs first. 
10. Pulse oximetry measured once prior to surgery and per your site’s SOC from surgery end up to 24 hours. 
11. Assess vital signs (blood pressure, heart rate, respiratory rate, and temperature) and itching in PACU prior to PACU discharge. 
Note: No more than 30 days should pass between signing of the ICF and performance of the surgery.  Screening on the day of surgery will be permitted but is discouraged. 
Note: The end of surgery is defined as the time of skin-incision closure of the C-section wound (following delivery and prior to TAP infiltration). 
AE=adverse event; C-section=cesarean section; ePRO=electronic patient-reported outcome; hr=hour(s); ICF=informed consent form; OR=operating room; ORSDS=Opioid 
Related Symptom Distress scale; PACU=post-anesthesia care unit; RCSS=Recovery from Cesarean Section scale; SAE=serious adverse event; SFQ=Surgical Fear Questionnaire; 
SOC=standard of care; TAP= transversus abdominis plane; VAS=visual analog scale 


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Table 2.  Assessment Schedule (Hospital Discharge through Day 30) 
 
Study Procedure 
Hospital 
Discharge 
Day 14 
(±3 d) Call 
Day 30 (±3 d) 
Call 
Measure vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
X1 
Provide the ePRO device, addressed and stamped packaging material, and instructions for use 
X 
Record scheduled 10 cm VAS pain intensity scores (general and site of incision) at rest through ePRO (Appendix 
1) 
X 
Record date, time, and dose of all standardized postsurgical pain medication through ePRO4 
Record date, time, and dose of all standardized multimodal pain medications administered 
X 
Record overall rating of subject’s satisfaction with postsurgical pain control through ePRO (Appendix 3) 
X1 
Record RCSS3 through ePRO (Appendix 4) 
X1 
Assess discharge readiness2 (Appendix 2) 
X1 
Record date and time of hospital discharge 
X 
Record persistent opioid use (see Appendix 9) 
X 
Document whether the subject has made any unscheduled phone calls or office visits related to pain, experienced 
any hospital readmission, or experienced an emergency room visit since hospital discharge (Appendix 8) 
X 
Remind subject to return the ePRO device in the provided addressed and stamped packaging material 
X 
Record concomitant medications for treatment of AEs 
X 
X 
Record AEs/SAEs (starting at signing of ICF) 
X 
X 
1. 
At 72 hours postsurgery or prior to hospital discharge, whichever occurs first. 
2. 
Discharge readiness will be assessed at 24, 48, and 72 hours, or hospital discharge, or until the subject attains score of 9, whichever occurs first. 
3. 
RCSS at 24, 48, and 72 hours or at hospital discharge, whichever occurs first (see Appendix 4) 
4. 
Following hospital discharge, the subject will record her daily use of pain medication, if any, in the ePRO. 
Note: The end of surgery is defined as the time of skin-closure of the C-section wound (following delivery and prior to TAP infiltration). 
AE=adverse event; C-section=cesarean section; d=day; ePRO=electronic patient-reported outcome; ICF=informed consent form; ORSDS=Opioid Related Symptom Distress scale; 
RCSS=Recovery from Cesarean Section scale; SAE=serious adverse event; VAS=visual analog scale 


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3. TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................................ II 
2. 
SYNOPSIS ..................................................................................................................... 3 
3. 
TABLE OF CONTENTS ............................................................................................. 16 
4. 
LIST OF ACRONYMS/ABBREVIATIONS .............................................................. 20 
5. 
ETHICS ........................................................................................................................ 21 
5.1. 
Institutional Review Board/Independent Ethics Committee ....................................... 21 
5.2. 
Ethical Conduct of the Study ......................................................................................21 
5.3. 
Subject Information and Consent ................................................................................. 21 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE ................. 22 
7. 
INTRODUCTION ........................................................................................................ 23 
7.1. 
Indication ...................................................................................................................... 23 
7.2. 
Current Therapies/Treatments ....................................................................................23 
7.3. 
EXPAREL (Bupivacaine Liposome Injectable Suspension) ...................................... 24 
7.4. 
Summary of Human Experience with EXPAREL ......................................................24 
8. 
OBJECTIVES ............................................................................................................... 25 
8.1. 
Primary Objective .......................................................................................................25 
8.2. 
Secondary Objectives ................................................................................................... 25 
9. 
OVERALL STUDY DESIGN AND PLAN ................................................................ 26 
9.1. 
Study Design................................................................................................................. 26 
9.1.1. Duration of the Study and Subject Participation ......................................................... 30 
9.1.2. Study Stopping Rules ..................................................................................................30 
9.2. 
Discussion of Study Design ......................................................................................... 31 
10. 
STUDY POPULATION .............................................................................................. 32 
10.1. 
Inclusion Criteria .......................................................................................................... 32 
10.2. 
Exclusion Criteria ......................................................................................................... 32 
10.3. 
Removal of Subjects from Therapy or Assessment ....................................................33 
10.3.1. Withdrawal Secondary to Adverse Events ..................................................................34 
10.3.2. Voluntary or Study Investigator Withdrawal ............................................................... 34 
11. 
TREATMENTS ............................................................................................................ 35 
11.1. 
Treatment to be Administered ...................................................................................... 35 
11.1.1. EXPAREL Administration Considerations ................................................................. 36 
 
 
 


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11.1.2. Intrathecal Morphine Administration Considerations ................................................. 36 
11.2. 
Identity of the Investigational Products ....................................................................... 37 
11.2.1. Description of EXPAREL...........................................................................................37 
11.2.2. Description of Reference Product ................................................................................ 37 
11.3. 
Method of Assigning Subjects to Treatment ............................................................... 37 
11.3.1. Randomization Scheme ................................................................................................ 37 
11.3.2. Randomization Procedures ........................................................................................... 37 
11.3.3. Replacement of Subjects .............................................................................................37 
11.4. 
Selection of Doses in the Study ..................................................................................37 
11.5. 
Prior and Concomitant Therapy and Medications ....................................................... 38 
11.5.1. Prior Therapy and Medications .................................................................................... 38 
11.5.2. Restricted Therapy and Medications During Surgery .................................................38 
11.5.3. Permitted Therapy or Medications after Surgery ........................................................38 
11.6. 
Treatment Compliance ................................................................................................. 40 
11.7. 
Accountability of Study Drug .....................................................................................40 
12. 
STUDY ENDPOINTS AND MEASUREMENTS ..................................................... 41 
12.1. 
Efficacy Measurements ................................................................................................ 41 
12.2. 
Efficacy Endpoints ......................................................................................................42 
12.2.1. Primary Efficacy Endpoint .........................................................................................42 
12.2.2. Secondary Efficacy Endpoints ....................................................................................42 
12.2.3. Exploratory Efficacy Endpoints ..................................................................................42 
12.3. 
Safety Assessments ...................................................................................................... 43 
12.4. 
Safety Endpoints .........................................................................................................43 
12.5. 
Appropriateness of Measures ....................................................................................... 43 
13. 
STUDY PROCEDURES .............................................................................................. 44 
13.1. 
Instructions for Conducting Procedures and Measures ............................................... 44 
13.1.1. Electronic Patient Reported Outcome Device .............................................................44 
13.1.2. Pain Intensity Assessments .........................................................................................45 
13.1.3. Itching Assessments ....................................................................................................45 
13.1.4. Subject Satisfaction with Postsurgical Pain Control ...................................................45 
13.1.5. Recovery from Cesarean Section Scale ....................................................................... 45 
13.1.6. Discharge Readiness ...................................................................................................46 


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13.1.7. Opioid Related Symptom Distress scale (ORSDS) ....................................................46 
13.1.8. Surgical Fear Questionnaire (SFQ) .............................................................................. 46 
13.1.9. Calls to Physician ......................................................................................................... 46 
13.1.10. Persistent Opioid Use ...............................................................................................46 
13.2. 
Obtaining Informed Consent .......................................................................................46 
13.3. 
Screening/Baseline Procedures .................................................................................... 46 
13.4. 
Day 1 - Operating Room .............................................................................................47 
13.5. 
Day 1 - Post-Anesthesia Care Unit .............................................................................48 
13.6. 
Day 1 - Prior to PACU Discharge ................................................................................ 48 
13.7. 
Days 1-3 (0-72 Hours After Surgery/Hospital Discharge) .......................................... 49 
13.8. 
After Hospital Discharge Through Day 14 .................................................................50 
13.9. 
Day 14 Phone Call ........................................................................................................ 50 
13.10. Day 30 Phone Call ........................................................................................................ 50 
14. 
ADVERSE EVENT REPORTING .............................................................................. 51 
14.1. 
Adverse Events ...........................................................................................................51 
14.1.1. Definitions of Adverse Event ......................................................................................51 
14.1.2. Recording Adverse Events ..........................................................................................52 
14.1.3. Severity of Adverse Events .........................................................................................52 
14.1.4. Relationship of Adverse Events to Study Drug ..........................................................53 
14.1.5. Outcome of Adverse Events .......................................................................................53 
14.1.6. Action Taken with Subject Because of an Adverse Event .......................................... 54 
14.2. 
Serious Adverse Events ..............................................................................................54 
14.2.1. Definition of a Serious Adverse Event ........................................................................ 54 
14.2.2. Reporting Serious Adverse Events ............................................................................... 55 
15. 
STATISTICAL METHODS .......................................................................................56 
15.1. 
Study Objective ............................................................................................................ 56 
15.2. 
Study Endpoints ..........................................................................................................56 
15.3. 
Determination of Sample Size ....................................................................................56 
15.4. 
Analysis Populations ...................................................................................................56 
15.5. 
Handling Subject Dropouts and Discontinuations ....................................................... 56 
15.6. 
Statistical Analyses ....................................................................................................... 56 
15.6.1. Baseline Characteristics................................................................................................ 56 


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15.6.2. Study Compliance .......................................................................................................57 
15.6.3. Efficacy Analyses ......................................................................................................... 57 
15.6.4. Safety Analyses ............................................................................................................ 57 
15.7. 
Significance Testing ....................................................................................................57 
15.8. 
Interim Analyses ........................................................................................................... 58 
16. 
REFERENCES ............................................................................................................. 59 
17. 
INVESTIGATOR AGREEMENT ............................................................................... 61 
18. 
APPENDICES .............................................................................................................. 62 
18.1. 
Appendix 1: Subject’s Reported Pain (Visual Analog Scale) at Rest ......................... 63 
18.2. 
Appendix 2: Discharge Readiness ............................................................................... 64 
18.3. 
Appendix 3: Subject Satisfaction with Postsurgical Pain Control .............................. 65 
18.4. 
Appendix 4: Recovery from Cesarean Section Scale (RCSS) .................................... 66 
18.5. 
Appendix 5: Clinical Laboratory Tests ........................................................................ 67 
18.6. 
Appendix 6: Surgical Fear Questionnaire (SFQ) ......................................................... 68 
18.7. 
Appendix 7: Opioid Related Symptom Distress Scale (ORSDS) ............................... 70 
18.8. 
Appendix 8: Calls to Physician (Single Question) ......................................................71 
18.9. 
Appendix 9: Persistent Opioid Use .............................................................................72 
18.10. Appendix 10: Numeric Rating Scale ..........................................................................73 
 
 
LIST OF TABLES 
Table 1.  Assessment Schedule (Screening through 72 hours after Surgery) ................................. 12 
Table 2.  Assessment Schedule (Hospital Discharge through Day 30) ..........................................15 


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4. LIST OF ACRONYMS/ABBREVIATIONS 
 
 
AE 
Adverse event 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
CSE 
Combined spinal epidural 
C-section 
Cesarean section 
d 
Day 
ePRO 
Electronic patient-reported outcome 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
hr 
Hour(s) 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
MMT 
Multi-modal therapy 
NRS 
Numeric rating scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
q6h 
Every 6 hours 
OR 
Operating room 
ORSDS 
Opioid Related Symptom Distress scale 
PACU 
Post-anesthesia care unit 
PO 
Oral 
PRN 
As needed 
RCSS 
Recovery from Cesarean Section scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SFQ 
Surgical Fear Questionnaire 
SOC 
Standard of care 
TAP 
Transversus abdominis plane 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog scale 
WHO 
World Health Organization 
 
 


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5. ETHICS 
5.1. Institutional Review Board/Independent Ethics Committee 
Prior to enrolling subjects into this study, each study site will obtain the approval of an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that complies with the 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and/or the United 
States (US) Food and Drug Administration (FDA) Title 21 Code of Federal Regulations (CFR) 
Part 56. Attention is directed to the basic elements that are required to be incorporated into the 
informed consent form (ICF) under 21 CFR Part 50.25 and ICH GCP. 
5.2. Ethical Conduct of the Study 
This study will be conducted in accordance with the clinical research guidelines established by 
the FDA Title 21 CFR, Parts 50, 54, 56, and 312, and the ICH GCP. Study documents will be 
maintained in accordance with applicable regulations. 
5.3. Subject Information and Consent 
Before a subject undergoes any study-specific screening procedures, the investigator or designee 
will thoroughly explain to the subject the purpose of the study, the associated procedures, and 
any expected effects and potential adverse reactions.  A copy of the IRB-approved ICF will be 
provided to the subject, who will be given sufficient time and opportunity to inquire about the 
details of the study and decide whether or not to participate.  The subject, and the study staff with 
whom 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 she is completely free to decline entry into the 
study and may withdraw from the study at any time, for any reason, without risking her medical 
care. Similarly, the investigator and/or Pacira Pharmaceuticals, Inc. (Pacira) will be free to 
withdraw the subject at any time for safety or administrative reasons. Any other requirements 
necessary for the protection of the human rights of the subject will also be explained, according 
to the current ICH GCP (E6) and the Declaration of Helsinki (1964, and as amended through 
2000 [Edinburgh]). 


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


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7. INTRODUCTION 
7.1. Indication 
EXPAREL® was developed to extend pain relief with a single-dose administration without the 
use of indwelling catheters and to decrease the requirement for supplemental opioid medications. 
EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local 
analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional 
analgesia. 
Effective postsurgical pain control is a critical element in patient recovery following surgery, 
as the majority of patients may experience significant pain, particularly in the first few days. 
Improved postsurgical pain management contributes to better healing, faster patient mobilization, 
shortened hospital stays, and reduced healthcare costs (American Society of Anesthesiologists 
Task Force on Pain Management 1995). 
7.2. Current Therapies/Treatments 
Current modalities of postoperative analgesia include wound infiltration with local anesthetics 
combined with the systemic administration of analgesics (multimodal therapy).  Multimodal 
therapy usually includes opioid medications, which have considerable drawbacks, including time 
and resources required for monitoring opioid-related side effects. A reduction in the use of 
postoperative opioids is desirable to decrease the incidence and severity of opioid-induced 
adverse events (AEs), such as respiratory depression, nausea, vomiting, constipation, 
somnolence, pruritus, and urinary retention. 
With over 70 million surgeries performed annually in the US, postoperative pain is a ubiquitous 
condition among the US 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 [PO] intake, etc.), and conserve healthcare 
resources.  As such, the Joint Commission on Accreditation of Healthcare Organizations requires 
that all healthcare facilities practice adequate pain management and monitor opioid-related AEs 
(Apfelbaum 2003). 
Opioid analgesics have long been established to be the most effective agents used for the 
management of moderate to severe postoperative pain and are currently considered the mainstay 
of treatment.  Opioid-only regimens are common and intravenous (IV) patient-controlled 
analgesia is a widely used delivery system for morphine sulfate.  AEs 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 


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AEs, 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 AEs 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; however, it has a limited duration 
of action after local administration, usually less than 8 hours. EXPAREL (Pacira 
Pharmaceuticals, Inc., Parsippany, New Jersey) 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. 
7.4. Summary of Human Experience with EXPAREL 
Pacira has conducted more than 36 clinical studies and one observational follow-up study to 
investigate EXPAREL.  Across these studies, over 1800 human subjects received EXPAREL at 
doses ranging from 2 mg to 665 mg (equivalent to 2 mg to 750 mg bupivacaine hydrochloride 
[HCl]) administered by various routes: local infiltration into the surgical site, subcutaneous, 
perineural (or nerve block), and epidural.  EXPAREL has been generally well tolerated and, in 
active comparator studies, AEs occurred at a similar rate as the corresponding bupivacaine HCl 
controls. 
EXPAREL was initially approved by the US FDA in 2011 for single-dose administration into the 
surgical site to produce postsurgical analgesia.  The indication was amended and approved by the 
US FDA in 2018 to read: “EXPAREL is indicated for single-dose infiltration in adults to 
produce postsurgical local analgesia and as an interscalene brachial plexus block to produce 
postsurgical regional analgesia.” Since its approval, EXPAREL has been administered to over 
4 million patients in the US. 
Following the initial approval of EXPAREL, numerous clinical studies were conducted in which 
EXPAREL was administered via various routes of administration, including infiltration into the 
transversus abdominis plane (TAP) (Sternlicht 2014, Feierman 2014). 
Please see the EXPAREL Full Prescribing Information (2018) for complete safety information 
regarding EXPAREL (liposome bupivacaine injectable suspension): 
https://www.exparel.com/hcp/prescriptioninformation.pdf. 


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8. OBJECTIVES 
8.1. Primary Objective 
To compare total opioid consumption through 72 hours following EXPAREL infiltration into the 
TAP with standard of care (SOC) in subjects undergoing an elective cesarean section 
(C-section). 
8.2. Secondary Objectives 
To assess efficacy and safety parameters and participant satisfaction. 


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9. OVERALL STUDY DESIGN AND PLAN 
9.1. Study Design 
This is a Phase 4, multicenter, randomized, active-controlled study in approximately 182 adult 
subjects.  Subjects who are withdrawn or discontinued prior to completing the study may be 
replaced. 
Obtaining Informed Consent 
Potential participants may provide informed consent up to 30 days before their scheduled 
surgery.  If a subject can only be screened on the day of surgery, the consent process must be 
started at least 24 hours prior to the day of surgery in order to ensure ample time for the subject 
to review the ICF and have all her questions answered by the investigator/study staff prior to 
providing informed consent.  Screening procedures that are SOC at the institution may be 
completed prior to written informed consent.  Any screening procedures that are not SOC must 
be completed after written informed consent is provided and prior to surgery (see Section 13.3). 
Screening 
Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be 
allowed but is discouraged.  If a subject can only be screened on the day of surgery, the informed 
consent process must still be started at least 24 hours prior to the conduct of any screening 
procedures that are not considered SOC at the institution and such procedures may not be 
performed until written informed consent is provided.  All screening procedures that are not SOC 
must be performed and documented within the 30-day time window (inclusive of the day of 
surgery for those subjects who can only be screened on the day of surgery) as described here. 
During the screening visit, subjects will be assessed for any past or present medical conditions 
that, in the opinion of the investigator, would preclude them from study participation. 
After the ICF is signed, medical history, surgical history, physical examination (according to the 
investigational site’s SOC), 12-lead electrocardiogram, vital sign measurements, alcohol breath 
test and urine drug screen, and clinical laboratory tests (hematology and chemistry) will be 
performed.  The Surgical Fear Questionnaire (SFQ) will be administered during screening. 
Day of Surgery 
Pre-operative medications: Use of pre-operative analgesics (e.g., opioid medications, Tylenol® 
(acetaminophen), non-steroidal anti-inflammatory drugs [NSAIDs]) is prohibited. 
On Day 1, prior to the C-section, pulse oximetry will be measured and eligible subjects will be 
randomized in a 1:1:1 ratio into one of the three treatment groups listed below: 
• Group 1: 150 mcg Duramorph® (SOC arm).  No EXPAREL TAP infiltration following 
skin-incision closure. 
Subjects randomized to Group 1 will receive an intrathecal injection of 150 mcg 
preservative-free morphine for spinal injection (e.g., Duramorph) in conjunction with 


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single-shot spinal anesthesia using 1.4 to 1.6 mL bupivacaine HCl 0.75% and 15 mcg 
fentanyl. Postoperative pain management will follow the multimodal pain regimen as 
defined in this protocol. 
• Group 2: 50 mcg Duramorph + EXPAREL TAP infiltration following skin-incision 
closure + postoperative multimodal pain regimen as defined in this protocol. 
Subjects randomized to Group 2 will receive an intrathecal injection of 50 mcg 
preservative-free morphine for spinal injection (e.g., Duramorph) in conjunction with 
single-shot spinal anesthesia using 1.4 to 1.6 mL bupivacaine HCl 0.75%.  If deemed 
necessary by the investigator, intrathecal fentanyl can be given prior to incision for the 
C-section.  If intrathecal fentanyl is used, the dose of 15 mcg fentanyl, date, and time of 
the usage must be recorded.  In addition, Group 2 subjects will receive EXPAREL TAP 
infiltration following skin-incision closure plus postoperative multimodal pain regimen. 
• Group 3: EXPAREL TAP infiltration following skin-incision closure + postoperative 
multimodal pain regimen as defined in this protocol.  No Duramorph. 
Subjects randomized to Group 3 will NOT receive Duramorph as a spinal injection.  This 
group will receive single-shot spinal anesthesia using 1.4 to 1.6 mL bupivacaine HCl 
0.75%.  If deemed necessary by the investigator, intrathecal fentanyl can be given prior to 
incision for the C-section.  If intrathecal fentanyl is used, the dose of 15 mcg fentanyl, 
date, and time of the usage must be recorded.  In addition, Group 3 subjects will receive 
EXPAREL TAP infiltration following skin-incision closure plus postoperative 
multimodal pain regimen. 
In all treatment groups, a combined spinal epidural (CSE) anesthesia technique may also be used 
provided the epidural component is not used.  Subjects who receive the epidural component of 
the CSE anesthesia must be immediately withdrawn from the study. 
Intraoperative medications: The intraoperative use of ketamine and midazolam (Versed®) is 
discouraged but may be permitted if clinically indicated based on the investigator’s discretion 
(all medications must be appropriately recorded [i.e., drug, dose, and route of administration]). 
Prophylactic use of dexamethasone for prevention of nausea and vomiting is prohibited. 
For Groups 2 and 3, after delivery of the baby and prior to the TAP infiltration, a small amount 
of lidocaine (<2 mL) may be administered subcutaneously to form a skin wheal over the area of 
the needle insertion site.  A 2-point classic TAP block, in 2 steps (see Pharmacy Binder), must be 
performed under ultrasound guidance and must be performed no more than 90 minutes after 
skin-incision closure of the C-section. A confirmatory ultrasound image or video will be taken 
of each side of the abdomen after the TAP needle position has been established and following 
infiltration of study drug. 
TAP infiltration (Groups 2 and 3): The TAP infiltration includes two steps: (1) TAP needle 
placement and saline hydrodissection and (2) study drug mixture infiltration into the TAP.  Each 
step must be performed on one side of the abdomen and must be repeated on the contralateral 


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side to complete the bilateral, 2-point TAP required for the study. For complete, step-by-step 
instructions on performing the TAP infiltration under ultrasound guidance, please refer to the 
Pharmacy Binder. 
Postsurgical Analgesia: Patient-controlled analgesia is not permitted. 
The following multimodal pain regimens will be used for all treatment groups.  The date, time, 
and dose of all standardized multimodal pain medications administered must be recorded. 
All Subjects in Groups 1, 2, and 3: 
At the time of skin-incision closure (Note: it is very important that these be administered at the 
time of skin-incision closure and not prior to or before the end of surgery): 
• Intravenous (IV) ketorolac 30 mg (1 dose) 
• IV acetaminophen 1000 mg (1 dose) 
Beginning 6 hours after skin-incision closure: 
• IV ketorolac 30 mg beginning 6 hours from the administration of IV ketorolac at the time 
of skin-incision closure and then every 6 hours (q6h) for the next 18 hours (i.e., total of 
120 mg as four 30-mg doses over first 24 hours from the time of skin-incision closure) 
• IV acetaminophen 1000 mg beginning 6 hours from the administration of IV 
acetaminophen at the time of skin-incision closure and then every 6 hours (q6h) for the 
next 18 hours (i.e., total of 4000 mg as four 1000-mg doses over first 24 hours from the 
time of skin-incision closure) 
• Scheduled PO Tylenol® (acetaminophen) 975 mg beginning 6 hours from the 
administration of the last dose of IV acetaminophen and q6h for up to 72 hours or 
hospital discharge (whichever occurs first) 
• Scheduled PO ibuprofen 600 mg beginning 6 hours from the administration of the last 
dose of IV ketorolac and then q6h for up to 72 hours or hospital discharge (whichever 
occurs first) 
This multimodal pain regimen is a requirement for all subjects in the study and is not subject 
to investigator discretion.  The date, time, and dose of all standardized multimodal pain 
medications administered must be recorded.  Note:  The scheduled PO medication will be 
administered on a q6h schedule only till hospital discharge. 
Rescue Medication: When breakthrough pain occurs, the study staff or the floor nurses on duty 
will need to ensure that the study subject is strictly following the protocol-specific multimodal 
pain regimen schedule (q6h as defined in the protocol) before considering the use of the opioids 
as a rescue, especially in cases where the visual analog scale (VAS) score is relatively low. 
Subjects should receive opioid rescue pain medication only upon request for breakthrough pain. 
Postsurgical rescue medication will comprise PO immediate-release oxycodone (initiated at 
5 mg as needed [PRN]).  If the 5 mg oxycodone is not sufficient for pain management, subject 


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can receive a dose of 10 mg PRN.  If a subject is unable to tolerate PO medication or fails the PO 
oxycodone rescue, IV morphine (initiated at 1-2 mg) or hydromorphone (initiated at 0.3-0.5 mg) 
may be administered PRN.  All surgical and postsurgical opioid and other analgesics (pain 
medications) administered must be documented through Day 14 postsurgery.  Additionally, an 
unscheduled pain intensity score using a 10 cm VAS (see Appendix 1) must be completed 
immediately prior to any rescue medication while in the hospital. 
Permitted medications for the prevention and treatment of possible AEs of medications include 
the following (to be administered at the discretion of the study site principal investigator): 
• Ondansetron 4 mg IV immediately after delivery of the baby 
• Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for 
intraoperative and postoperative nausea and vomiting 
• Metoclopramide 10 mg PO PRN for nausea and vomiting 
• Nalbuphine IV 2.5 mg PRN for pruritus 
• Naloxone IV 50 to 100 mcg PRN for pruritus 
Postsurgical Assessments 
Subjects will remain in the hospital for up to 72 hours after surgery.  Postsurgical assessments 
will include: 
 
• Opioid use 
-total opioid burden 
-time to first opioid use 
• Date and time of first unassisted 
ambulation 
• Pain intensity scores using a 10 cm 
VAS (see Appendix 1) at rest 
(general and site of injection) 
• Discharge readiness (see 
Appendix 2) 
• Opioid Related Symptom Distress 
scale (ORSDS; see Appendix 7) 
• Date and time to first bowel movement 
• Itching using Numeric Rating Scale (NRS) of 0 to 
10 (see Appendix 10) 
• Subject's satisfaction with postsurgical pain 
control (see Appendix 3) 
• Recovery from Cesarean Section scale (RCSS; 
see Appendix 4) 
• Calls to physician about pain (see Appendix 8) 
• Total time in post-anesthesia care unit (PACU) 
• Persistent opioid use at Day 30 (see Appendix 9) 
• Emergency department visits 
 
 
While in the hospital, subjects will be provided with an electronic patient-reported outcome 
(ePRO) device and will use the device to record all scheduled and unscheduled VAS scores.  For 
all scheduled assessments and unscheduled assessments in the hospital, subjects will assess, 
“How much pain are you experiencing right now in general?” and “How much pain are you 
experiencing at the site of the incision”, a vertical mark will be placed on the VAS line to 
indicate the level of pain experienced at the time of assessment.  If a subject is discharged prior 
to a scheduled VAS assessment, a member of the study site staff will contact the subject to 
remind her to complete the scheduled VAS assessment at the scheduled time and to record the 


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assessment in the device, which the subjects will take home with them to continue to record 
study assessments at home. 
At hospital discharge, the subject will be instructed to record in the device their daily pain 
intensity score (VAS) and all pain medications  taken  following hospital  discharge  through 
Day 14. 
At home, the subject will assess pain intensity at rest each day at noon (± 4 hours).  This 
assessment should capture her worst pain at rest in the prior 24 hours by assessing “What was 
your worst pain since your last pain assessment?” (i.e., from noon on the previous day to the 
current assessment).  At the same time, the subject should record any pain medication 
(medication name, date, time, and dose) taken in the prior 24 hours. 
A phone call will be made to each subject on Day 14 for safety purposes and to inquire as to 
whether the subject made any unscheduled phone calls or office visits related to pain, 
experienced any hospital readmission, or experienced an emergency room visit since hospital 
discharge. AEs and serious adverse events (SAEs) will be recorded from the time the ICF is 
signed through Day 14.  Any concomitant medications to treat AEs through Day 14 will also be 
recorded.  On Day 30, a phone call will be made to ask the subjects about persistent opioid use. 
9.1.1. 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 performance of the surgery.  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. 
9.1.2. Study Stopping Rules 
If Pacira, the investigator, or officials from regulatory authorities discover conditions during the 
study that indicate that the study or study site should be terminated, this action may be taken 
after Pacira has consulted with appropriate regulatory authorities and notified the investigator(s). 
The Pacira Medical Monitor and Pharmacovigilance team review all SAEs reported from Pacira 
clinical studies on an ongoing basis and in real time (i.e., as the events are reported). The 
Medical Monitor is responsible for temporarily halting the study if the type, frequency, or 
seriousness/severity of such events suggests a potential threat to the safety of the study 
participants.  If such action is taken, a thorough review of all available data will be performed. 
Based on the results of this review and discussions with investigators and/or regulatory 
authorities as warranted, the study may be restarted or permanently terminated. 
In addition, any death will be thoroughly reviewed and appropriate action taken. 


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9.2. Discussion of Study Design 
EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local 
analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional 
analgesia. 
This Phase 4, multicenter, randomized active-controlled study will evaluate the efficacy and 
safety of EXPAREL+bupivacaine infiltration into the TAP compared to the active SOC in 
subjects undergoing elective C-section. 
The physiology of pain involves multiple complex pathways and mechanisms and the successful 
management of pain requires the use of a combination of pain medications in a “balanced” or 
multimodal approach to achieve a state of balanced analgesia (White 2010). 
The practice of multimodal analgesia is being adopted across different patient-care pathways and 
is becoming the SOC at major surgery centers globally.  There is quite a variety of options of 
medications within the multimodal approach either in different combinations or when used  
alone.  In all cases, the goal is to reduce postoperative pain associated with surgery and reduce 
opioid use and opioid-related AEs.  In some cases, such an approach may also reduce the average 
length of hospital stay (Elvir-Lazo 2010). 
In addition, the dose-response relationship of intrathecal morphine for multimodal post-cesarean 
analgesia suggests that 50 mcg produces analgesia similar to that produced by either 100 mcg or 
150 mcg (Berger 2016), which provides the scientific support for the current study design. 
EXPAREL (liposomal bupivacaine injectable suspension) is an amide local anesthetic indicated 
for single-dose infiltration into the surgical site to produce postsurgical analgesia. This study is 
designed to assess the effectiveness of EXPAREL administered as a TAP block in a multimodal 
setting to reduce total postsurgical opioid consumption. All subjects in the study will be eligible 
to receive an opioid analgesic, if needed, to control breakthrough postsurgical pain as part of the 
multimodal approach to pain management. 


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10. 
Study Population 
Note:  Based on the World Health Organization (WHO) Guidance: Breastfeeding and Maternal 
Medication, Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs 
(WHO 2002), bupivacaine is compatible with breastfeeding; therefore, there are no restrictions in 
this study regarding the participation of women who wish to breastfeed following treatment with 
study drug. 
10.1. Inclusion Criteria 
Subjects eligible for study entry will meet all of the following criteria: 
1. Females 18 years of age and older at screening 
2. Term pregnancies of 37 to 42 weeks gestation scheduled to undergo elective C-section 
3. American Society of Anesthesiologists physical status 1, 2, or 3 
4. 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 she meets any one of the following criteria: 
1. Subjects who, in the opinion of the investigator, have a high-risk pregnancy 
(e.g., multiple gestations, pregnancy resulting from in vitro fertilization, end-term 
prolonged bed rest required for medical reasons) 
2. Subjects with an unstable pregnancy-induced medical condition or complication 
(e.g., gestational diabetes, hypertension, pre-eclampsia, chorioamnionitis) 
3. Subjects with 3 or more prior C-sections (subject is eligible if the index C-section is the 
third case for that subject) 
4. Pre-pregnancy body mass index >50 kg/m2 or otherwise not anatomically appropriate to 
undergo a TAP block 
5. Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications 
for which an alternative is not named in the protocol (e.g., amide-type local anesthetics, 
opioids, bupivacaine, NSAIDs, spinal anesthesia) 
6. Planned concurrent surgical procedure with the exception of salpingo-oophorectomy or 
tubal ligation 
7. Severely impaired renal or hepatic function (for example, serum creatinine level 
>2 mg/dL [176.8 µmol/L], blood urea nitrogen level >50 mg/dL [17.9 mmol/L], serum 
aspartate transaminase level >3 times the upper limit of normal [ULN], or serum alanine 
transaminase level >3 times the ULN) 


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8. Subjects at an increased risk for bleeding or a coagulation disorder (defined as platelet 
count less than 80, 000 × 103/mm3 or international normalized ratio greater than 1.5) 
9. Concurrent painful physical condition that may require analgesic treatment (such as 
long-term, consistent use of opioids) in the postsurgical period for pain that is not strictly 
related to the surgery and which may confound the postsurgical assessments 
10. Clinically significant medical disease in either the mother or baby that, in the opinion of 
the investigator, would make participation in a clinical study inappropriate.  This includes 
any psychiatric or other disease in the mother that would constitute a contraindication to 
participation in the study or cause the mother to be unable to comply with the study 
requirements. 
11. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription 
medicine(s), or alcohol within the past 2 years 
12. 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 
13. Previous participation in an EXPAREL study 
In addition, the subject will be ineligible to receive study drug and will be withdrawn from the 
study if she meets the following criteria during surgery: 
14. Any clinically significant event or condition uncovered during the surgery 
(e.g., excessive bleeding, acute sepsis) that might render the subject medically unstable or 
complicate the subject’s postsurgical course 
15. Receives the epidural component of CSE anesthesia during participation in the study 
10.3. Removal of Subjects from Therapy or Assessment 
Every reasonable effort shall be made to maintain subject compliance and participation in the 
study.  Reasons for discontinuation of any subject from the study will be recorded. 
If any clinically significant event or condition is uncovered during the surgery (e.g., excessive 
bleeding, acute sepsis), the subject should be withdrawn from the study and the event or 
condition should be reported as an AE or SAE. 
Additionally, any subjects who receive the epidural component of the CSE anesthesia must be 
immediately withdrawn from the study. 
If a subject withdraws from the study and has an ongoing AE, every effort must be made to 
follow up on such events until satisfactory resolution is obtained or further follow-up is 
otherwise no longer warranted. 


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10.3.1. Withdrawal Secondary to Adverse Events 
If a subject experiences an AE that renders her incapable of continuing with the remaining 
assessments 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.  If such a subject discontinues prior to hospital discharge, all assessments to be 
conducted at 72 hours/hospital discharge should be conducted as part of this final examination. 
If such a subject discontinues following hospital discharge, all information captured in the device 
should be collected and a final telephone call for safety should be made. 
Any subject who discontinues because of an AE should be instructed to notify the study 
personnel of any abnormalities and to come to the study site if medical evaluation is needed and 
the urgency of the situation permits.  Any subject exhibiting undesirable AEs will receive 
appropriate treatment at the discretion of the investigator until resolution of the AE. 
This study involves a single infiltration of study drug; therefore, subjects should not be 
terminated from the ongoing study assessments as long as they are willing and able to continue 
with the follow-up schedule according to the protocol. For emergencies and other unscheduled 
visits to a medical facility other than the study site, medical records must be obtained by the 
investigator and appropriate information captured in the subject’s case report form (CRF). 
10.3.2. Voluntary or Study Investigator Withdrawal 
Subjects are free to discontinue from the study at any time, without prejudice to future treatment. 
A subject may be discontinued from the study if she refuses EXPAREL infiltration or refuses to 
comply with study procedures.  Subjects should be encouraged to complete the study safety 
assessments.  Reasons for discontinuation from the study will be recorded. 
If a subject is discontinued by the investigator or voluntarily withdraws from the study after 
receiving the study drug, the subject will be asked to complete a final evaluation so that she can 
be withdrawn in a safe and orderly manner.  If such a subject discontinues prior to hospital 
discharge, all assessments to be conducted at 72 hours/hospital discharge should be conducted as 
part of this final examination.  If such a subject discontinues following hospital discharge, all 
information captured in the device should be collected and a final telephone call for safety 
should be made. 
After termination from the study, the subject may be followed for safety including monitoring of 
AEs through Day 14. 


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11. 
Treatments 
11.1. Treatment to be Administered 
There will be three treatment groups in this study.  On Day 1, prior to the C-section, eligible 
subjects will be randomized in a 1:1:1 ratio into one of the three treatment groups listed below: 
• Group 1: 150 mcg Duramorph® (SOC arm).  No EXPAREL TAP infiltration following 
skin-incision closure. 
Subjects randomized to Group 1 will receive an intrathecal injection of 150 mcg 
preservative-free morphine for spinal injection (e.g., Duramorph) in conjunction with 
single-shot spinal anesthesia using 1.4 to 1.6 mL bupivacaine HCl 0.75% and 15 mcg 
fentanyl.  Postoperative pain management will follow the multimodal pain regimen as 
defined in this protocol. 
• Group 2: 50 mcg Duramorph + EXPAREL TAP infiltration following skin-incision 
closure + postoperative multimodal pain regimen as defined in this protocol. 
Subjects randomized to Group 2 will receive an intrathecal injection of 50 mcg 
preservative-free morphine for spinal injection (e.g., Duramorph) in conjunction with 
single-shot spinal anesthesia using 1.4 to 1.6 mL bupivacaine HCl 0.75%.  If deemed 
necessary by the investigator, intrathecal fentanyl can be given prior to incision for the 
C-section. If intrathecal fentanyl is used, the dose of 15 mcg fentanyl, date and time of 
the usage must be recorded. In addition, Group 2 subjects will receive EXPAREL TAP 
infiltration following skin-incision closure plus postoperative multimodal pain regimen. 
• Group 3: EXPAREL TAP infiltration following skin-incision closure + postoperative 
multimodal pain regimen as defined in this protocol.  No Duramorph. 
Subjects randomized to Group 3 will NOT receive Duramorph as a spinal injection.  This 
group will receive single-shot spinal anesthesia using 1.4 to 1.6 mL bupivacaine HCl 
0.75%.  If deemed necessary by the investigator, intrathecal fentanyl can be given prior to 
incision for the C-section.  If intrathecal fentanyl is used, the dose of 15 mcg fentanyl, 
date and time of the usage must be recorded.  In addition, Group 3 subjects will receive 
EXPAREL TAP infiltration following skin-incision closure plus postoperative 
multimodal pain regimen. 
In all treatment groups, a CSE anesthesia technique may also be used provided the epidural 
component is not used.  Subjects who receive the epidural component of the CSE anesthesia 
must be immediately withdrawn from the study. 
Intraoperative medications: The intraoperative use of ketamine and midazolam (Versed®) is 
discouraged, but may be permitted if clinically indicated based on the investigator’s discretion 
(all medications must be appropriately recorded [i.e., drug, dose, and route of administration]). 
Prophylactic use of dexamethasone for prevention of nausea and vomiting is prohibited. 


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For Groups 2 and 3, after delivery of the baby and prior to the TAP infiltration, a small amount 
of lidocaine (<2 mL) may be administered subcutaneously to form a skin wheal over the area of 
the needle insertion site.  A 2-point classic TAP block, in 2 steps (see Pharmacy Binder), must be 
performed under ultrasound guidance and must be performed no more than 90 minutes after 
skin-incision closure of the C-section. A confirmatory ultrasound image or video will be taken 
of each side of the abdomen after the TAP needle position has been established and following 
infiltration of study drug. 
TAP infiltration (Groups 2 and 3):  The TAP infiltration includes two steps: (1) TAP needle 
placement and saline hydrodissection and (2) study drug mixture infiltration into the TAP. Each 
step must be performed on one side of the abdomen and must be repeated on the contralateral 
side to complete the bilateral, 2-point TAP required for the study.  For complete, step-by-step 
instructions on performing the TAP infiltration under ultrasound guidance, please refer to the 
Pharmacy Binder. 
11.1.1. EXPAREL Administration Considerations 
Because of the potential risk of severe adverse effects associated with the administration of 
bupivacaine, the study sites must be equipped to manage subjects with any evidence of cardiac, 
neurological, or respiratory toxicity. 
Administration of additional local anesthetics, including lidocaine, is prohibited and no agents 
other than bupivacaine HCl (as specified in the Pharmacy Binder) are to be admixed with 
EXPAREL.  Lidocaine and other local anesthetics are not permitted to be locally administered 
during the surgery because they are known to interact with EXPAREL resulting in the 
displacement of bupivacaine and elevated plasma levels. 
EXPAREL may not be administered to a subject if the vial has been open for more than 4 hours. 
In order to prevent EXPAREL from settling, gently inverting and re-inverting the syringe prior 
to administration is recommended. 
The maximum dosage of EXPAREL should not exceed 266 mg. 
11.1.2. Intrathecal Morphine Administration Considerations 
The most serious adverse effects encountered during administration of intrathecal 
morphine/hydromorphone are respiratory depression and/or respiratory arrest, which may be 
severe and could require intervention.  Naloxone injection and resuscitative equipment should be 
immediately available for administration in case of life-threatening or intolerable side effects and 
whenever intrathecal morphine therapy is being initiated. 
Intrathecal morphine is contraindicated in patients with medical conditions that would preclude 
the administration of opioids via the IV route, including an allergy to morphine/hydromorphone 
or other opiates, acute bronchial asthma, or upper airway obstruction. 
Morphine/hydromorphone, like all opioid analgesics, may cause severe hypotension in 


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individuals whose ability to maintain blood pressure is compromised by a depleted blood volume 
or a concurrent administration of drugs, such as phenothiazines or general anesthetics. 
11.2. Identity of the Investigational Products 
11.2.1. Description of EXPAREL 
EXPAREL (bupivacaine liposome injectable suspension) is formulated as a sterile, 
non-pyrogenic, white to off-white, preservative-free homogenous suspension of bupivacaine 
encapsulated into multivesicular liposomes (DepoFoam drug delivery system).  Bupivacaine is 
present at a nominal concentration of 13.3 mg/mL.  For the purpose of this study, EXPAREL 
will be provided in 20-mL, 1.3% (13.3 mg/mL) single-use, clear glass vials.  EXPAREL vials 
should be stored refrigerated at 2°C to 8°C (36°F to 46°F). 
11.2.2. Description of Reference Product 
Duramorph® (150 mcg): Institutional site SOC. 
11.3. Method of Assigning Subjects to Treatment 
11.3.1. Randomization Scheme 
This is an open-label study.  Subjects will be randomized in a 1:1:1 ratio into one of three 
treatment groups.  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 will be reused once assigned. 
11.3.2. Randomization Procedures 
Once a subject is identified as being qualified for the study in accordance with the eligibility 
criteria (see Section 10.1 and Section 10.2), and is at the study site for surgery, the research 
pharmacist or designee will obtain a randomization assignment.  The subject will be considered 
randomized into the study once the study treatment assignment is received. 
11.3.3. Replacement of Subjects 
Subjects who withdraw from the study before being randomized 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. 
11.4. Selection of Doses in the Study 
During the clinical development of EXPAREL, single doses ranging from 2 mg to 665 mg have 
been safely administered via various routes. Pharmacokinetic studies have shown that because 
EXPAREL releases bupivacaine gradually as the lipid structure breaks down, administration of 
EXPAREL 266 mg results in a maximum plasma concentration equivalent to that seen with 
standard bupivacaine 100 mg. Clinical studies have shown that, for wound infiltration, a total 


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dose of 266 mg (20 mL) of EXPAREL is safe and efficacious. Based on this experience, the 
FDA-approved marketed dose of 266 mg was deemed appropriate for this study. 
Intrathecal preservative-free morphine for spinal injection (e.g., Duramorph) is commonly used 
during C-section, usually at a dose between 0.1 mg and 0.2 mg.  The midpoint of 0.15 mg 
(150 mcg) is preferred by some anesthesiologists because it balances duration of analgesia 
(which may be shorter with a lower dose) and incidence of opioid-related AEs, such as nausea 
and vomiting (which may increase with a higher dose).  The study dose of 0.15 mg (150 mcg) of 
intrathecal morphine is also supported by a recent dose-finding study that sought to determine 
the effective analgesic dose for 90% of patients for both intrathecal morphine and 
hydromorphone in patient undergoing C-section (Sviggum 2016). 
11.5. Prior and Concomitant Therapy and Medications 
11.5.1. Prior Therapy and Medications 
Use of any of the following medications within the times specified before surgery is prohibited: 
long-acting opioid medication, NSAIDs, aspirin (except for low-dose aspirin used for 
cardioprotection) within 3 days, or Tylenol® (acetaminophen) or any opioid medication within 
24 hours. 
11.5.2. Restricted Therapy and Medications During Surgery 
As described in the EXPAREL Full Prescribing Information (2018), no agents are to be admixed 
with EXPAREL (e.g., epinephrine, dexamethasone, clonidine) other than bupivacaine. 
Lidocaine and other local anesthetics are not permitted to be locally administered during the 
surgery because they are known to interact with EXPAREL, resulting in the displacement of 
bupivacaine and elevated plasma levels. When a topical antiseptic is applied to the surgical site, 
the solutions should not be allowed to come in contact with each other (e.g., the area must be dry 
before EXPAREL is administered). Upon discovering use of any prohibited therapy and/or 
medication during or after surgery, the investigator should document all events that led to the 
deviation, write a note to file, and notify the Pacira Medical Monitor accordingly. 
11.5.3. Permitted Therapy or Medications after Surgery 
Patient-controlled analgesia is not permitted. 
The following multimodal pain regimens will be used for all treatment groups.  The date, time, 
and dose of all standardized multimodal pain medications administered must be recorded. 
All Patients in Groups 1, 2, and 3: 
At the time of skin-incision closure (Note: it is very important that these be administered at the 
time of skin-incision closure and not prior to or before the end of surgery): 
• Intravenous (IV) ketorolac 30 mg (1 dose) 
• IV acetaminophen 1000 mg (1 dose) 


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Beginning 6 hours after skin-incision closure: 
• IV ketorolac 30 mg beginning 6 hours from the administration of IV ketorolac at the time 
of skin-incision closure and then every 6 hours (q6h) for the next 18 hours (i.e., total of 
120 mg as four 30-mg doses over first 24 hours from the time of skin-incision closure) 
• IV acetaminophen 1000 mg beginning 6 hours from the administration of IV 
acetaminophen at the time of skin-incision closure and then every 6 hours (q6h) for the 
next 18 hours (i.e., total of 4000 mg as four 1000-mg doses over first 24 hours from the 
time of skin-incision closure) 
• Scheduled PO Tylenol® (acetaminophen) 975 mg beginning 6 hours from the 
administration of the last dose of IV acetaminophen and q6h for up to 72 hours or 
hospital discharge (whichever occurs first) 
• Scheduled PO ibuprofen 600 mg beginning 6 hours from the administration of the last 
dose of IV ketorolac and then q6h for up to 72 hours or hospital discharge (whichever 
occurs first) 
This multimodal pain regimen is a requirement for all subjects in the study and is not subject 
to investigator discretion.  The date, time, and dose of all standardized multimodal pain 
medications administered must be recorded.  Note: The scheduled PO medication will be 
administered on a q6h schedule only till hospital discharge. 
Rescue Medication: When breakthrough pain occurs, the study staff or the floor nurses on duty 
will need to ensure that the study subject is strictly following the protocol-specific multimodal 
pain regimen schedule (q6h as defined in the protocol) before considering the use of the opioids 
as a rescue.  Subjects should receive opioid rescue pain medication only upon request for 
breakthrough pain. 
Postsurgical rescue medication will comprise PO immediate-release oxycodone (initiated at 5 mg 
PRN).  If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV 
morphine (initiated at 1 to 2 mg) or hydromorphone (initiated at 0.3 to 0.5 mg) may be 
administered PRN.  If the 5 mg oxycodone is not sufficient for pain management, subject can 
receive a dose of 10 mg PRN.  If a subject is unable to tolerate PO medication or fails the PO 
oxycodone rescue, IV morphine (initiated at 1to 2 mg) or hydromorphone (initiated at 0.3 to 0.5 
mg) may be administered PRN. All surgical and postsurgical opioid and other analgesics 
(pain medications) administered must be documented through Day 14 postsurgery.  Additionally, 
an unscheduled pain intensity score using a 10 cm VAS (see Appendix 1) must be completed 
immediately prior to any rescue medication while in the hospital. 
Permitted medications for the prevention and treatment of possible AEs of medications include 
the following (to be administered at the discretion of the study site principal investigator): 
• Ondansetron 4 mg IV immediately after delivery of the baby 


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• Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for 
intraoperative and postoperative nausea and vomiting 
• Metoclopramide 10 mg PO PRN for nausea and vomiting 
• Nalbuphine IV 2.5 mg PRN for pruritus 
• Naloxone IV 50 to 100 mcg PRN for pruritus 
11.6. Treatment Compliance 
Study drug will be administered by the study staff; therefore, treatment compliance is ensured. 
11.7. Accountability of Study Drug 
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/or appropriate 
regulatory authorities at any time. A copy of the inventory records, drug accountability 
information, and notice of return or destruction will be returned to Pacira at the end of the study. 
Only authorized personnel identified 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 Measurements 
The following efficacy measurements will be performed at the times specified after closure of 
the C-section skin incision: 
• Date, time of administration, and amount of all postsurgical opioid rescue medication taken 
through Day 14 
• Pain intensity scores at rest (general and site of incision) using a 10 cm VAS at 12, 24, 48, 
and 72 hours after surgery (see Appendix 1) and then once daily (at noon ± 4 hours) 
through Day 14 
Note 1: For pain intensity scores at 12, 24, 48, or 72 hours, if the subject is sleeping, do not 
wake her to assess pain. If she awakens within the assessment window (i.e., 1 hour for the 
12- and 24-hour assessments, 2 hours for the 48-hour assessments, and 4 hours for the 
72-hour assessments), a pain score may be collected then. 
Note 2: An unscheduled VAS score is also required immediately prior to administration of 
any rescue medication while in the hospital. 
Note 3: If a subject is discharged prior to any of the scheduled VAS assessments to be 
collected at 12 to 72 hours after surgery, a member of the study site staff will telephone the 
subject at the appropriate scheduled times (i.e., the time of each assessment scheduled to be 
collected that occurs after hospital discharge) to remind her to complete the VAS and to 
record the scheduled assessments in the ePRO device.  This will ensure that, for any 
subjects discharged prior to 72 hours, all VAS assessments required for calculation of the 
study endpoints are captured.  These phone calls will only occur if a subject is discharged 
prior to 72 hours. 
• Total time in PACU 
• Date and time of first unassisted ambulation 
• Date and time of first bowel movement 
• 
Itching using an NRS of 0 to 10 (see Appendix 10) 
• SFQ at screening (see Appendix 6) 
• ORSDS at 24, 48, and 72 hours after surgery (see Appendix 7) 
• Subject satisfaction with postsurgical pain control using a 5-point Likert scale 
(see Appendix 3) 
• RCSS at 24, 48, and 72 hours or at hospital discharge, whichever occurs first 
(see Appendix 4) 


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• Discharge readiness at 24, 48, and 72 hours, or at hospital discharge, or until the subject 
attains a score of 9, whichever occurs first (see Appendix 2) 
• Unscheduled phone calls or office visits related to pain after discharge through Day 14 
• Persistent opioid use at Day 30 (see Appendix 9) 
12.2. Efficacy Endpoints 
12.2.1. Primary Efficacy Endpoint 
• Total postsurgical opioid consumption in morphine equivalents through 72 hours or 
hospital discharge 
12.2.2. Secondary Efficacy Endpoints 
• Time to first postsurgical opioid rescue medication 
• Percentage of opioid-free subjects through 72 hours or hospital discharge 
• Incidence and severity of itching (NRS of 0 to 10) 
• ORSDS at 24, 48, and 72 hours after surgery 
• The VAS pain, general and at incision site (at rest) through 72 hours or hospital discharge 
prior to any physical therapy or physical activity/mobilization 
• Proportion of subjects discharge-ready at 24, 48, and 72 hours or at hospital discharge, or 
until the subject attains a score of 9, whichever occurs first 
• Overall assessment of subject’s satisfaction with pain control at 72 hours or at hospital 
discharge, whichever occurs first 
• Integrated rank assessment using the VAS pain intensity score (at rest) and the total 
amount of postsurgical opioids consumed through 72 hours or hospital discharge 
12.2.3. Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints may include (but may not be limited to): 
• Total opioid use from 72 hrs to Day 14 
• Time to and date of first unassisted ambulation 
• Length of hospital stay 
• Number of unscheduled phone calls or office visits related to pain from discharge 
through Day 14. 
• Emergency department visits 
• Persistent opioid use at Day 30 


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12.3. Safety Assessments 
Adverse events (AEs/SAEs) will be monitored and recorded from the time the ICF is signed 
through Day 14.  Vital signs (blood pressure, heart rate, respiratory rate, and temperature) and 
pulse oximetry will be monitored and recorded. 
12.4. Safety Endpoints 
Incidence of treatment-emergent AEs (TEAEs) and SAEs will be assessed from the start of 
anesthesia through Day 14. 
12.5. Appropriateness of Measures 
Endpoints selected for this study were based on well-established clinical measurements used in 
peer-reviewed studies. 


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13. 
STUDY PROCEDURES 
A time and events schedule for all study procedures is provided in Table 1 and Table 2. 
13.1. Instructions for Conducting Procedures and Measures 
All assessments conducted after baseline will be timed from the completion of the last C-section 
skin-incision stitch (i.e., time of skin-incision closure of the C-section wound following delivery 
and prior to the TAP infiltration).  Day 1 is defined as the day on which study drug is 
administered.  The beginning of surgery is defined as the time of the first incision.  The end of 
surgery is defined as the time of closure of the C-section skin incision.  Postsurgical is defined as 
after the end of surgery. 
Subjects will be hospitalized for up to 72 hours after surgery. Postsurgical analgesia and 
collection of study data through hospital discharge will take place under the supervision of study 
staff. Following hospital discharge, the subject will record use of pain medication, if any, in the 
ePRO device.  Additionally, the subject will record a daily (at noon ± 4 hours) 10 cm VAS pain 
score at rest in the device daily from hospital discharge through Day 14.  This assessment should 
capture her worst pain at rest in the prior 24 hours by assessing, “What was your worst pain since 
your last pain assessment?” (i.e., from noon on the previous day to the current assessment).  At 
the same time, the subject should record any pain medication (medication name, dose, date, and 
time) taken in the prior 24 hours. 
Because the Day 14 assessment is a phone call, subjects will be provided with an addressed and 
stamped packaging material in which the device will be returned by the subject to the 
investigator. 
13.1.1. Electronic Patient Reported Outcome Device 
An ePRO device will be given to the subject at the first scheduled assessment; the option for the 
subject to record this event via a mobile app will also be provided. While in the hospital, the 
subject will use the device to record all scheduled VAS (general and incision site) (i.e., at 12, 24, 
48, and 72 hours) and ORSDS (i.e., at 24, 48, and 72 hours) assessments.  She will also use the 
device while in the hospital to record any unscheduled VAS assessments prior to receiving 
rescue medication. 
If a subject is discharged prior to any of the scheduled VAS assessments to be collected at 12 to 
72 hours after surgery or a scheduled ORSDS assessment to be collected at 24 to 72 hours after 
surgery, a member of the study site staff will contact the subject at the appropriate scheduled 
times (i.e., the time of each assessment scheduled to be collected that occurs after hospital 
discharge) to remind her to complete the VAS and ORSDS assessments and to record the 
scheduled assessments in the device, which will be provided to the subject at the time of hospital 
discharge. This will ensure that, for any subject discharged prior to 72 hours, all VAS and 
ORSDS assessments required for calculation of the study endpoints are captured.  These phone 
calls will only be made if a subject is discharged prior to 72 hours. 


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At hospital discharge, study personnel will use the device to record any pain medication 
provided to the subject for home use and any prescription provided for any pain medication to be 
filled following discharge.  This information should include medication name, dose, and 
instructions for use. 
At hospital discharge, the subject will be instructed to record a daily VAS pain intensity score 
and all pain medications taken following hospital discharge through Day 14 in the device. 
At home, the subject will assess pain intensity at rest each day at noon (± 4 hours).  This 
assessment should capture her worst pain at rest in the prior 24 hours by assessing, “What was 
your worst pain since your last pain assessment?” (i.e., from noon on the previous day to the 
current assessment).  At the same time, the subject should record any pain medication 
(date, time, and dose) taken in the prior 24 hours. 
13.1.2. Pain Intensity Assessments 
Pain intensity scores at rest using a 10 cm VAS at 12, 24, 48, and 72 hours (see Appendix 1) and 
once daily (at noon ± 4 hours) through Day 14. 
For pain intensity scores at 12, 24, 48, or 72 hours, if the subject is sleeping, do not wake her to 
assess pain.  If she awakens within the assessment window (i.e., 1 hour for the 12- and 24-hour 
assessments, 2 hours for the 48-hour assessments, and 4 hours for the 72-hour assessments), a 
pain score may be collected then.  See Section 13.1.1 regarding subjects discharged prior to 
72 hours. 
To assess pain intensity (VAS) at rest, the subject should rest quietly in a supine or seated 
position that does not exacerbate her postsurgical pain for 3 to 5 minutes before entering the pain 
score. 
13.1.3. Itching Assessments 
Subjects will be asked to rate the intensity of any itching they may have on a Numeric Rating 
Scale (NRS) from 0 to 10; 0 being no itching and 10 being worst itch (see Appendix 10).  Itching 
assessments will be performed at screening, in the PACU prior to PACU discharge, and at 
12 hours (±1 hour), 24 hours (±1 hour), 48 hours (±2 hours), and 72 hours (±4 hours). 
13.1.4. Subject Satisfaction with Postsurgical Pain Control 
Subject satisfaction with postsurgical pain control will be assessed using a 5-point Likert scale at 
72 hours or at hospital discharge, whichever occurs first (see Appendix 3). 
13.1.5. Recovery from Cesarean Section Scale 
Recovery from the C-section procedure will be assessed using the RCSS at 24, 48, and 72 hours 
or hospital discharge, whichever occurs first (see Appendix 4) 


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13.1.6. Discharge Readiness 
The subject’s discharge readiness will be assessed using the Modified Post Anesthesia Discharge 
Scoring System criteria (Chung 1995a; Chung 1995b; see Appendix 2). The discharge readiness 
assessment will be used for data collection only and is not intended to interfere with the 
investigational site’s policy for determining when the subject should be discharged from the 
hospital.  Discharge readiness will be assessed at 24, 48, and 72 hours or at hospital discharge or 
until the subject attains a score of 9, whichever occurs first. 
13.1.7. Opioid Related Symptom Distress scale (ORSDS) 
The subject’s opioid related symptom distress will be assessed using the ORSDS scale at 24, 48, 
and 72 hours (see Appendix 7). See Section 13.1.1 regarding subjects discharged prior to 
72 hours. 
13.1.8. Surgical Fear Questionnaire (SFQ) 
The subject’s attitudes toward pain prior to surgery will be recorded during screening or baseline 
(see Appendix 6). 
13.1.9. Calls to Physician 
Participants will record the number of calls made to their physician after discharge, for pain 
related to their surgery, to be collected on Day 14 (see Appendix 8). 
13.1.10. 
Persistent Opioid Use 
Participants will be asked if they are still taking opioids on Day 30 (see Appendix 9). 
13.2. Obtaining Informed Consent 
Potential participants may provide informed consent up to 30 days before their scheduled 
surgery.  If a subject can only be screened on the day of surgery, the consent process must be 
started at least 24 hours prior to the day of surgery in order to ensure ample time for the subject 
to review the ICF and have all her questions answered by the investigator/study staff prior to 
providing informed consent.  Screening procedures that are SOC at the institution may be 
completed prior to written informed consent.  Any screening procedures that are not SOC must 
be completed after written informed consent is provided and prior to surgery (see Section 13.3). 
13.3. Screening/Baseline Procedures 
Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be 
allowed but is discouraged.  If a subject can only be screened on the day of surgery, the informed 
consent process must still be started at least 24 hours prior to the conduct of any screening 
procedures that are not considered SOC at the institution and such procedures may not be 
performed until written informed consent is provided.  All screening procedures that are not SOC 
must be performed and documented within the 30-day time window (inclusive of the day of 
surgery for those subjects who can only be screened on the day of surgery) as described here. 


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The following screening/baseline procedures should be performed within 30 days prior to 
administration of study drug: 
• 
Explain study purpose and procedures 
• 
Obtain signed ICF, if not provided earlier 
• 
Assess eligibility 
• 
Record medical/surgical history 
• 
Record prior and concomitant medications 
• 
Record demographics and baseline characteristics 
• 
Explain to the subject that she will be provided with an ePRO device while in the hospital 
and that she will be expected to capture specific information in the device while in the 
hospital 
• 
Explain to the subject that she will be expected to capture specific information in the 
device after discharge through Day 14 
 
To be completed in the hospital 
• 
Measure vital signs (blood pressure, height, weight, heart rate, respiratory rate, and 
temperature) 
• 
Perform physical examination according to the investigational site’s SOC 
• 
Perform 12-lead electrocardiogram 
• 
Conduct urine drug screen and breath alcohol test 
• 
Clinical laboratory tests in accordance with the investigator’s SOC including 
(Appendix 5): 
1. Direct bilirubin 
2. Gamma-glutamyl transpeptidase and lactate dehydrogenase 
or 
Alanine transaminase and aspartate transaminase 
3. Serum creatinine 
or 
Blood urea nitrogen 
• 
Record SFQ (Appendix 6) 
• 
Assess itching (NRS of 0 to 10) (Appendix 10) 
• 
Record AEs/SAEs starting when the ICF is signed 
• 
Record concomitant medications for treatment of AEs 
13.4. Day 1 - Operating Room 
• 
Assess/confirm eligibility 


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• 
Confirm medical/surgical history 
• 
Update prior and concomitant medications 
• 
Measure vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
• 
Record pulse oximetry 
• 
Perform physical examination according to the investigational site’s SOC 
• 
Randomize subject and prepare study drug 
• 
Administer intrathecal preservative-free morphine injection in conjunction with 
single-shot spinal anesthesia per the treatment group.  A CSE anesthesia technique may 
also be used provided the epidural component is not used. Subjects who receive the 
epidural component of the CSE anesthesia must be immediately withdrawn from the 
study. 
• 
Record start and stop time of surgery (Note: end of surgery is defined as the closure of 
the C-section skin incision) 
• 
Record intraoperative opioids and other intraoperative medications administered and their 
doses 
• 
Record any AEs or SAEs 
• 
Record concomitant medications for treatment of AEs 
13.5. Day 1 - Post-Anesthesia Care Unit 
• 
Perform TAP needle placement and saline hydrodissection under ultrasound guidance 
using up to 10 mL normal saline (per the treatment group) 
• 
Capture ultrasound image or video of the TAP needle placement after saline 
hydrodissection 
• 
Perform 2-point classic TAP infiltration no more than 90 minutes after skin-incision 
closure of the C-section 
• 
Collect ultrasound image or video of 2-point TAP needle placement after infiltration of 
study drug 
• 
Record start and stop time of study drug infiltration 
13.6. Day 1 - Prior to PACU Discharge 
• 
Record date, time in, and time out of the PACU 
• 
Measure vital signs (blood pressure, heart rate, respiratory rate, and temperature) prior to 
PACU discharge 
• 
Record an unscheduled VAS pain intensity score before any postsurgical opioid 
medication while in the hospital 


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• 
Record pulse oximetry per SOC 
• 
Record date, time, and dose of all postsurgical opioid and other pain medication. 
Note: Subjects should only receive opioid pain medication (e.g., morphine, 
hydromorphone [Dilaudid], oxycodone) upon request for breakthrough pain. 
• 
Record date, time, and dose of all standardized multimodal pain medications 
administered 
• 
Record date and time of first unassisted ambulation 
• 
Record date and time of first bowel movement 
• 
Assess itching (NRS of 0 to 10) prior to PACU discharge (see Appendix 10) 
• 
Record any AEs or SAEs 
• 
Record concomitant medications for treatment of AEs 
13.7. Days 1-3 (0-72 Hours After Surgery/Hospital Discharge) 
• 
Provide the ePRO device to the subject prior to the first assessment scheduled to be 
recorded in the ePRO device (i.e., 12 hr VAS assessment). 
• 
Record scheduled pain intensity scores at rest using a 10 cm VAS (see Appendix 1) at 12, 
24, 48, and 72 hours.  If the subject is sleeping at 12, 24, 48, and 72 hours, do not wake 
her to assess pain.  If she awakens within the assessment window (i.e., 1 hour for the 
12-hour and 24-hour assessments, 2 hours for the 48-hour assessments, and 4 hours for 
the 72-hour assessments), a pain score may be collected. See Section 13.1.1 regarding 
subjects discharged prior to 72 hours. 
• 
Record pulse oximetry per SOC up to 24 hours 
• 
Record vital signs at 24, 48, and 72 hours or at the time of discharge, whichever occurs 
first 
• 
Record date, time, and dose of all standardized multimodal pain medications 
administered 
• 
Record an unscheduled VAS pain intensity score (general and site of incision) 
immediately before any postsurgical opioid medication while in the hospital 
• 
Record date, time, and dose of all postsurgical opioid and other pain medications 
administered through 72 hours. Note: Subjects should only receive opioid pain 
medication (morphine, hydromorphone [Dilaudid], oxycodone) upon request for 
breakthrough pain, PRN. 
• 
Record date and time of subject’s first unassisted ambulation 
• 
Record date and time of first bowel movement 
• 
Assess itching (NRS of 0 to 10) (Appendix 10) 


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• 
Record ORSDS (see Appendix 7) at 24, 48, and 72 hours. See Section 13.1.1 regarding 
subjects discharged prior to 72 hours. 
• 
Record discharge readiness (see Appendix 2) at 24, 48, and 72 hours or hospital 
discharge, or until the subject attains a score of 9, whichever occurs first 
• 
Record overall rating of subject’s satisfaction with postsurgical pain control at 72 hours 
or at hospital discharge, whichever occurs first 
• 
RCSS at 24, 48, and 72 hours or at hospital discharge, whichever occurs first 
(see Appendix 4) 
• 
Provide the stamped packaging material and instructions for use at the hospital discharge 
• 
Record date and time of hospital discharge 
• 
Record any AEs or SAEs 
• 
Record any concomitant medications for treatment of AEs 
13.8. After Hospital Discharge Through Day 14 
• 
Subjects will record VAS pain intensity scores at rest (see Appendix 1) in the device at 
noon (± 4 hours) each day through Day 14.  This assessment should capture the subject’s 
worst pain at rest in the prior 24 hours by assessing, “What was your worst pain since 
your last pain assessment?” (i.e., from noon on the previous day to the current 
assessment). 
• 
Subjects will record the use of pain medication, if any, in the device daily through 
Day 14. 
13.9. Day 14 Phone Call 
• 
Document whether the subject has made any unscheduled phone calls or office visits 
related to pain, experienced any hospital readmission, or experienced an emergency room 
visit since hospital discharge 
• 
Record any AEs or SAEs 
• 
Record any concomitant medications for treatment of AEs 
• 
Remind subject to return the device in the provided addressed and stamped packaging 
material 
13.10. Day 30 Phone Call 
Document whether the subject reports continued use of opioids. 


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14. 
ADVERSE EVENT REPORTING 
Consistent with the current regulatory guidance provided by the US CFR and the ICH GCP, 
AEs and SAEs are defined in Section 14.1.1 and Section 14.2.1, respectively. 
The concepts of AEs and SAEs represent regulatory instruments used to evaluate and monitor 
the safety of clinical study subjects.  Therefore, these terms only apply in light of their regulatory 
definition.  The term serious, in a regulatory sense, does not necessarily mean severe.  The SAE 
concept is primarily used 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 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 the 
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 has been signed and before the start of the study drug 
administration is identified as a pretreatment AE.  An AE that occurs after the administration of a 
study treatment is considered a TEAE. 
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. 
Suspected Adverse Reaction: Any AE for which there is a reasonable possibility that the drug 
caused the AE.  For the purposes of investigational new drug safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
AE. A suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any AE caused by a drug.  Suspected adverse reactions are a 
subset of all AEs for which there is a reasonable possibility that the drug caused the event. 


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14.1.2. Recording Adverse Events 
It is the responsibility of the investigator to document all AEs (i.e., pretreatment AEs and 
TEAEs) with an onset after the subject signs the ICF.  For the purpose of this study, all AEs that 
occur through Day 14 after surgery must be recorded regardless of whether or not they are 
considered related to study drug. Whenever feasible, AE terms should be documented as 
medical diagnoses (highest possible level of integration); otherwise, the AEs should be reported 
separately as individual signs or symptoms.  Only one AE per line should be recorded in the AE 
CRF.  For example, an AE of nausea and vomiting should be listed as two separate events: the 
event of nausea and the event of vomiting.  If a diagnosis is established after symptoms are 
recorded on the AE CRF, the diagnosis should be recorded and the symptoms collapsed 
(removed; i.e., lined through and initialed).  Whenever possible, abnormal laboratory results 
should be reported as their clinical corollary (e.g., low potassium should be recorded as 
hypokalemia). 
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 study drug, action taken for 
the AE, and the outcome of the AE, including the date and time of resolution, if applicable. 
14.1.3. Severity of Adverse Events 
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).  The event itself; however, 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. 


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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 for determining the AE’s causality to 
the study drug are provided below. 
Unrelated: 
A causal relationship between the study drug and the AE can be easily ruled out 
(e.g., based on the temporal sequence, absence of a reasonable pathophysiological 
mechanism, or direct evidence of actual cause) 
Unlikely: 
A clinical event with a temporal relationship to study drug administration, which 
makes a causal relationship improbable and in which other drugs, chemicals, or 
underlying disease provide a plausible explanation 
Possible: 
A clinical event with a reasonable time sequence to administration of the study drug 
but which could also be explained by a concurrent disease or other drugs or 
chemicals 
Probable: 
A clinical event with a reasonable time sequence to administration of the study drug 
unlikely to be attributed to a concurrent disease or other drugs or chemicals and 
which follows a clinically reasonable response on withdrawal (dechallenge) 
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: 
Not Recovered/ 
Not Resolved: 
The initial event resolved, but has a continuing abnormal condition 
as a result of the AE 
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 


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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 Because of 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, as suggested below: 
• None 
• Medication 
• Non-pharmaceutical therapy (The specific therapy used must be recorded in the CRF) 
• Discontinued from study 
• Other (The specific action taken must be recorded in the CRF) 
14.2. Serious Adverse Events 
14.2.1. Definition of a Serious Adverse Event 
Definition of an SAE: An AE is considered “serious” if, in the view of either the investigator or 
Sponsor, it results in any of the following outcomes: 
• Death1 
• A life-threatening 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 should make every effort to obtain and document the cause of death for all subjects 
who die during the study.  If, despite all efforts, the cause of death remains unknown, the AE 
should be documented as an “unspecified fatal event.” 
2Life-threatening:  An AE is considered life-threatening if, in the view of either the investigator 
or Sponsor, its occurrence places the subject at immediate risk of death.  It does not include an 
AE that, had it occurred in a more severe form, might have caused death. 
3Hospitalization:  It should be noted that hospitalization, in and of itself, does not represent an 
SAE.  It is the AE leading to the subject’s hospitalization that becomes “serious” when it 
requires inpatient care.  Consequently, an SAE should not be reported in cases of preplanned 
hospitalizations for a pre-existing condition that did not worsen during the study.  However, 
any medical condition that delays a subject’s discharge from the hospital (i.e., prolonged 
hospitalization) or requires the subject to be readmitted should be reported as an SAE. 


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4Persistent or significant incapacity:  A substantial disruption of a person’s ability to conduct 
normal life functions 
5Medically Significant: Important medical events that may not result in death, 
be life-threatening, or require hospitalization, may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medically significant events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
14.2.2. Reporting Serious Adverse Events 
Any SAE or death that occurs at any time after the subject signs the ICF through Day 14, 
whether or not related to EXPAREL, must be reported by the investigator or designee to Pacira 
Drug Safety either via email (drugsafety@pacira.com) or fax to 973-201-0649 within 24 hours of 
discovery.  In addition, the investigator or designee is encouraged to contact the Medical Monitor 
to discuss the case, PRN. 
Investigators should not wait to receive additional information to fully document the event 
before notifying Pacira Drug Safety or designee of the SAE.  The fax or email report should be 
followed by a full written summary using the SAE Form detailing relevant aspects of the SAE in 
question.  Where applicable, information from relevant hospital records and autopsy reports 
should be obtained and all patient-identifying information redacted prior to forwarding to Pacira. 
In the event of a fatal or life-threatening SAE, any required follow-up must be provided to Pacira 
Drug Safety or designee immediately.  The investigator will follow all SAEs until resolved or the 
condition stabilizes and further follow-up is not warranted. 
If the investigator is made aware of any SAEs after Day 14, these should also be reported to 
Pacira Drug Safety or designee provided the SAE is considered related to EXPAREL.  The site 
would then provide a completed SAE form within 1 business day and the event would be 
followed until resolution, or until adequate stabilization is met. 


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15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be developed for this study. 
15.1. Study Objective 
The primary objective of this study is to compare total opioid consumption through 72 hours 
following EXPAREL infiltration into the TAP with SOC in subjects undergoing an elective C- 
section. 
15.2. Study Endpoints 
The endpoints to be assessed in this study are listed in Section 12.2 (Efficacy Endpoints) and 
Section 12.4 (Safety Endpoints). 
15.3. Determination of Sample Size 
Assuming a log-normal distribution for total opioid consumption with a 70% coefficient of 
variation, 5% alpha, an equal randomization ratio, and 80% power, a total of 77 subjects per 
treatment group will be sufficient to detect a 25% reduction in total opioid consumption. 
Assuming 5% of the subjects are not evaluable and one of the two EXPAREL groups will be 
dropped after interim analysis when a total of 60 subjects are treated, a total sample size of 
approximately 182 treated subjects is needed.  This sample size will be re-evaluated after the 
interim analysis. 
15.4. Analysis Populations 
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 randomized subjects who undergo C-section.  All 
analyses based on the efficacy analysis set will be by randomized treatment regardless of the 
actual treatment received. 
The per-protocol efficacy analysis set will include all subjects in the efficacy analysis set who do 
not have any important protocol deviations.  All analyses based on the per-protocol analysis set 
will be by randomized treatment regardless of the actual treatment received. 
15.5. Handling Subject Dropouts and Discontinuations 
Methods for dealing with missing data will be described in the SAP. 
15.6. Statistical Analyses 
15.6.1. Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group. 


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15.6.2. Study Compliance 
The percentage of subject 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 
A comprehensive SAP will be developed for this study. Efficacy endpoint analyses will be 
conducted on the efficacy analysis set. The primary efficacy endpoint will also be analyzed 
using the per-protocol analysis set as a sensitivity analysis. 
Summary statistics (number, mean, median, standard deviation, minimum, and maximum) will 
be shown for each continuous measure of efficacy by treatment group.  The number and 
percentage of subjects in each category will be shown for each categorical measure of efficacy 
by treatment group.  For time to event measures of efficacy, medians and Kaplan-Meier 
estimates will be shown by treatment group. 
Baseline is defined as the last non-missing assessment of a given endpoint prior to the first dose 
of trial drug unless otherwise specified. 
All assessments will be listed in subject data listings. 
The analyses of the primary, secondary, and exploratory efficacy endpoints will be described in 
the SAP. 
15.6.4. Safety Analyses 
Adverse event verbatim terms will be mapped to preferred terms and related system organ class 
using the Medical Dictionary for Regulatory Activities.  All summaries of AEs will include AEs 
that occur after the beginning of anesthesia.  All summaries of AEs will be based on the safety 
analysis set.  Events that start prior to anesthesia will be identified in listings only.  Incidence 
rates of AEs after the start of anesthesia and the proportion of subjects prematurely withdrawn 
from the study due to an AE will be shown for each treatment group.  Incidence rates will also be 
shown for each treatment group for study drug-related AEs after the start of anesthesia and by 
severity.  Incidence rates of SAEs will also be shown for each treatment group. All incidence 
rates will be categorized and shown by system organ class and preferred term. 
Vital signs and pulse oximetry results will be summarized by treatment group at each assessment 
timepoint.  Summaries will present both actual and change-from-baseline results. Vital signs and 
pulse oximetry results will also be assessed for potentially clinically significant abnormal values. 
The number and percentage of subjects satisfying the potentially clinically significant abnormal 
criteria at any time during the study and at each assessment timepoint will be tabulated by 
treatment and overall treatments.  Details will be described in the SAP. 
15.7. Significance Testing 
Significance testing will be described in the SAP. 


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15.8. Interim Analyses 
After approximately 20 subjects per treatment group are randomized and treated (i.e., a total of 
60 subjects are treated in this study), an interim analysis will be conducted to evaluate and 
compare the clinical efficacy/safety and health economics benefits between the two EXPAREL 
groups against the SOC control group. The primary purpose of this interim analysis is to select 
one EXPAREL treatment group out of the two EXPAREL treatment groups to continue for the 
rest of the study.  The second purpose of this interim analysis is to evaluate the sample size 
assumptions and the selection of the primary/secondary endpoints.  Full details on the planned or 
additional interim analysis will be covered in a prospective interim analysis plan. 


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16. 
REFERENCES 
American Society of Anesthesiologists Task Force on Pain Management.  Practice guidelines 
for acute pain management in the postoperative setting: A report by the American Society 
for Anesthesiologist Task Force on Pain Management Acute Pain Section. Anesthesiology. 
1995;82:1071-81. 
Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: Results from a national 
survey suggests postoperative pain continues to be undermanaged. Anesth Analg. 
2003;97:535-40. 
Berger JS, Gonzalez A, Hopkins A,  T. Alshaeri T, et al. Dose–response of intrathecal morphine 
when administered with intravenous ketorolac for post-cesarean analgesia: a two-center, 
prospective, randomized, blinded trial. International Journal of Obstetric Anesthesia. 
2016;28,3-11. 
Carroll NV, Miederhoff  PA, Cox FM, et al.  Costs incurred by outpatient surgical centers in 
managing postoperative nausea and vomiting. J Clin Anesth. 1994;6:364-9. 
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. 1995a;42:1056-8. 
Chung F, Chan VW, Ong D. A post-anesthetic discharge scoring system for home readiness 
after ambulatory surgery. J Clin Anesth. 1995b;7(6):500-6. 
Elvir-Lazo, O.L. The role of multimodal analgesia in pain management after ambulatory surgery. 
Curr Opin Anaesthesiol. 2010;23(6):697-703. 
EXPAREL Full Prescribing Information, April 2018. 
Feierman DE, Kronenfeld M, Gupta PM.  Liposomal bupivacaine infiltration into the transversus 
abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: Results 
from a cohort of 13 patients. J Pain Res. 2014;7:477-82. 
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):400-6. 
Sternlicht A, Shapiro M, Robelen G, et al.  Infiltration of liposome bupivacaine into the 
transversus abdominis plane for postsurgical analgesia in robotic laparoscopic prostatectomy: 
A pilot study. Local Reg Anesth. 2014;7:69-74. 
Sviggum, H.P., et al., Intrathecal Hydromorphone and Morphine for Postcesarean Delivery 
Analgesia: Determination of the ED90 Using a Sequential Allocation Biased-Coin Method. 
Anesth Analg. 2016.123(3):690-7. 


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Viscusi ER (2009). 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. 
White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? 
Anesthesiology. 2010;112:220-5. 
World Health Organization (2002). Breastfeeding and maternal medication. Recommendations 
for drugs in the eleventh WHO model list of essential drugs. Accessed at http://www.who.int 
/maternal_child_adolescent/documents/55732/en/ 12-Feb-2017. 


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17. 
INVESTIGATOR AGREEMENT 
Printed Name of investigator: 
Printed Title/Position: 
Printed Institution Address: 
  
 
 
 
 
 
 
 
I have reviewed this protocol (including Appendices) and agree: 
• To assume responsibility for the proper conduct of the study at this site; 
• To conduct the study in compliance with this protocol, with any future amendments, 
and with any other study conduct procedures provided by Pacira Pharmaceuticals, Inc. 
(Pacira) or designee.  I also agree to comply with Good Clinical Practice and all 
regulatory requirements; 
• Not to implement any changes to the protocol without agreement from Pacira or designee 
and prior review and written approval from the Independent Ethics Committee, except 
where it is necessary to eliminate an immediate hazard to the subjects or for 
administrative aspects of the study (where permitted by applicable regulatory 
requirements); 
• That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and with other relevant information (e.g., the Investigator’s 
Brochure); 
• To ensure that all persons assisting me with the conduct of this study are adequately 
informed about the investigational product(s) and about their study-related duties and 
functions as described in this protocol; 
• That I am aware that regulatory authorities may require investigators to disclose all 
information about significant ownership interests and/or financial ties related to the 
Sponsor and/or the investigational product(s). Consequently, I agree to disclose all 
such significant financial information to Pacira and to update this information promptly 
if any relevant changes occur during the course of the study through 1 year following 
completion of the study.  I also agree that any information regarding my significant 
financial interest related to Pacira and/or the investigational product(s) will be disclosed 
to the regulatory authorities by Pacira. 
 
 
 
 
Signature of investigator 
Date 


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18. 
APPENDICES 


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18.1. 
Appendix 1: Subject’s Reported Pain (Visual Analog Scale) at Rest 
Subjects will be evaluated for pain intensity scores (general and site of incision) at rest using a 
10 cm VAS at rest at 12, 24, 48, and 72 hours after surgery and then once daily (at noon 
± 4 hours) through Day 14.  For pain intensity scores at 12, 24, 48, or 72 hours, if the subject is 
sleeping, do not wake her to assess pain.  If she awakens within the assessment window 
(i.e., 1 hour for the 12- and 24-hour assessments, 2 hours for the 48-hour assessments, and 
4 hours for the 72-hour assessments), a pain score may be collected. 
If a subject is discharged prior to any of the scheduled VAS assessments to be collected at 12 to 
72 hours after surgery, a member of the study site staff will contact the subject at the appropriate 
scheduled times (i.e., the time of each assessment scheduled to be collected from 12 to 72 hours 
that occurs after hospital discharge) to remind her to complete the VAS assessment and to record 
the scheduled assessment in the device.  This will ensure that, for any subject discharged prior to 
72 hours, all VAS assessments required for calculation of the study endpoints are captured. 
These phone calls will only be made if a subject is discharged prior to 72 hours. 
While in the hospital, subjects will also record an unscheduled VAS pain score immediately 
before any requested opioid pain medication. 
To assess pain intensity (VAS) at rest, the subject should rest quietly in a supine or seated 
position that does not exacerbate her postsurgical pain for 3 to 5 minutes before recording the 
pain score. 
While in the hospital, subjects are to assess, “How much pain are you experiencing right now in 
general?” and “How much pain are you experiencing right now at the site of the incision?”  They 
are advised to place a vertical mark on the line below to indicate the level of pain experienced at 
the time of assessment, with a line closer to the left meaning little or no pain and a line closer to 
the right meaning much pain or pain as bad as it can be.  This should be completed for both the 
general pain and pain at the site of incision (i.e., two VAS scales). 
At home, the subject will assess pain intensity at rest each day at noon (± 4 hours).  This 
assessment should capture her worst pain at rest in the prior 24 hours by assessing, “What was 
your worst pain since your last pain assessment?” (i.e., from noon on the previous day to the 
current assessment) through Day 14. 
Visual Analog Scale (VAS) 
 
 
 
No 
Pain 
 
(For reference only; not for clinical use) 
Pain as bad 
as it could 
possibly be 


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18.2. 
Appendix 2: Discharge Readiness 
The subject’s discharge readiness will be assessed using the Modified Post Anesthesia Discharge 
Scoring System below (Chung 1995a; Chung 1995b). 
The discharge readiness assessment will be used for data collection only and is not intended to 
interfere with the investigational site’s policy for determining when the subject should be 
discharged from the hospital. 
Discharge readiness will be assessed at 24, 48, and 72 hours, or at hospital discharge, or until the 
subject attains score of 9, whichever comes first.  Once a score of 9 is reached, no further 
discharge readiness assessments are required. 
 
Modified Post Anesthesia Discharge Scoring System 
 
Parameter 
Score 
Vital Signs: measure systolic blood pressure, heart rate, respiratory rate, temperature 
• 
All 4 vital signs are within 20% of the preoperative values 
2 
• 
Any of the 4 vital signs are within 20%-40% of the preoperative values and none 
exceeds 40% of the preoperative value 
1 
• 
Any of the 4 vital signs are >40% of the preoperative values 
0 
Ambulation 
• 
Steady gait/no dizziness 
2 
• 
With assistance 
1 
• 
None/dizziness 
0 
Nausea and Vomiting 
• 
Minimal: no nausea/vomiting or nausea not requiring treatment 
2 
• 
Moderate: nausea without vomiting and can tolerate liquids 
1 
• 
Severe: nausea/vomiting and unable to tolerate oral liquids 
0 
Pain 
• 
Minimal: requiring one or less pain rescue in the prior 12 hours 
2 
• 
Moderate: requiring more than one pain rescue in the prior 12 hours 
1 
• 
Severe: requiring supplemental IV analgesia for pain rescue 
0 
Surgical Bleeding 
• 
Minimal: no action required 
2 
• 
Moderate: requires dressing change because it has soaked through or a 
compressive dressing 
1 
• 
Severe: requires a suture or a return to the operating room 
0 


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18.3. 
Appendix 3: Subject Satisfaction with Postsurgical Pain Control 
Subject Satisfaction with Postsurgical Pain Control (Likert Scale) 
The subject's satisfaction with postsurgical pain control will be conducted at 72 hours after 
surgery (or at hospital discharge, whichever occurs first). 
Please circle the number below that best describes your overall satisfaction with your pain 
control, pain management and treatment after surgery. (Select one number only.) 
1. Extremely dissatisfied 
2. Dissatisfied 
3. Neither satisfied nor dissatisfied 
4. Satisfied 
5. Extremely satisfied 


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18.4. 
Appendix 4: Recovery from Cesarean Section Scale (RCSS) 
The RCSS will be assessed at 24, 48 and 72 hours after surgery (or at hospital discharge, 
whichever occurs first). 
Please answer the following questions about your Recovery from Cesarean section by 
circling the number that most applies to you. 
1 indicates strongly disagree, 7 indicates strongly agree. 
 
1. I recovered quickly from my cesarean 
1 
2 
3 
4 
5 
6 
7 
2. I was able to get out of bed soon after my cesarean 
1 
2 
3 
4 
5 
6 
7 
3. My mobility was seriously affected by the cesarean 
1 
2 
3 
4 
5 
6 
7 
4. The cesarean interfered with my ability to care for my baby 
1 
2 
3 
4 
5 
6 
7 
5. The cesarean prevented me from feeding my baby 
1 
2 
3 
4 
5 
6 
7 
6. I was able to change my baby soon after the cesarean 
1 
2 
3 
4 
5 
6 
7 
7. I was able to care for my own hygiene needs soon after surgery 
1 
2 
3 
4 
5 
6 
7 
8. The pain from the surgery prevented me from doing what I wanted 
1 
2 
3 
4 
5 
6 
7 
9. I was tired for a long time after surgery 
1 
2 
3 
4 
5 
6 
7 


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18.5. 
Appendix 5: Clinical Laboratory Tests 
Clinical laboratory tests (hematology and chemistry) will be conducted at screening in 
accordance with the investigator’s SOC including: 
1. Direct bilirubin 
2. Gamma-glutamyl transpeptidase and lactate dehydrogenase 
or 
Alanine transaminase and aspartate transaminase 
3. Serum creatinine 
or 
Blood urea nitrogen 


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18.6. 
Appendix 6: Surgical Fear Questionnaire (SFQ) 
The SFQ will be completed at screening/baseline. 
Patient instructions: 
This questionnaire assesses how afraid you are for various aspects related to the surgical 
procedure you are about to undergo.  Please circle the number that best reflects how you feel 
right now. 
1. I am afraid of the operation 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 
 
2. I am afraid of the anaesthesia 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 
 
3. I am afraid of the pain after the operation 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 
 
4. I am afraid of the unpleasant side effects (like nausea) after the operation 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 
 
5. I am afraid my health will deteriorate because of the operation 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 


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6. I am afraid the operation will fail 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 
 
7. I am afraid that I won’t recover completely from the operation 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 
 
8. I am afraid of the long duration of the rehabilitation after the operation 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
not at all 
very 
afraid 
afraid 


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18.7. 
Appendix 7: Opioid Related Symptom Distress Scale (ORSDS) 
The ORSDS will be assessed at 24, 48, and 72 hours after surgery. 
We have listed 10 symptoms below. Read each one carefully. If you have had the symptoms 
during the past 24 hours, mark how OFTEN you had it, how SEVERE it was usually and how 
much it DISTRESSED or BOTHERED you by placing an “X” in the appropriate box. If you 
DID NOT HAVE the symptoms, please place an “X” in the box marked “Did not have.” 
For the symptoms “retching/vomiting” below, you will indicate the actual number of episodes 
you experienced. 
During the last 24 hours, did you have any of the following? 
 
 
 
 
 
 


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18.8. 
Appendix 8: Calls to Physician (Single Question) 
To be collected at Day 14 as part of the Day 14 phone call. 
Since being discharged from the hospital, how many times have you called your physician about 
pain related to your surgery? 
1. 0 (I have not called my doctor) 
2. 1-2 times 
3. 3-5 times 
4. More than 5 times 


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18.9. 
Appendix 9: Persistent Opioid Use 
To be collected at Day 30 as part of the Day 30 phone call.  The following question will be asked 
to the subject: 
1. Are you currently taking opioids for pain? 
a. Yes 
b. No 


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18.10. Appendix 10: Numeric Rating Scale 
 
Subjects will be asked to rate the intensity of any itching they may have on a Numeric Rating 
Scale (NRS) from 0 to 10; 0 being no itching and 10 being worst itch. 
Itching assessments are to be performed at screening, in the PACU prior to PACU discharge, and 
at 12 hours (±1 hour), 24 hours (±1 hour), 48 hours (±2 hours), and 72 hours (±4 hours). 
 
 
 
No 
Worst 
Itching 
Itch 

SAP_001.pdf: 
DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol Title 
A Multicenter, Randomized, Active-controlled Study to Evaluate 
the Efficacy and Safety of EXPAREL When Administered via 
Infiltration into the Transversus Abdominis Plane (TAP) Versus 
Standard of Care in Subjects Undergoing Elective Cesarean 
Section. 
Protocol Number 
402-C-414 
Protocol Version 
Final 
Protocol Date 
Original: 16 August 2018 
Amendment 1: 15Nov2018. 
Amendment 2: 07 February 2019 
Study Drug 
EXPAREL (bupivacaine liposome injectable suspension) 
Study Phase 
4 
IND Number 
069,198 
Sponsor 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 973-254-3560 
SAP Version 
1.0 
Date 
16 March 2020 


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Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
2 of 139 
16 March 2020 
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

Alfred Mbah, PhD 
Principal Statitician 
Pharma Data Asociates, LLC 

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

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Chao Wang, PhD 
Principal Statitician 
Pharma Data Asociates, LLC 

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Date



Vincent Yu, PhD
Vice President, Biometrics 
Pacira Pharmaceuticals, Inc 

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Date



Alla Nagaev, MD 
Associate Medical Director, Clinical Operations 
Pacira Pharmaceuticals, Inc 

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Date



Julia Yang, MD 
VP, Clinical Research Pacira 
Pharmaceuticals, Inc 

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Date


Michael Rozycki, PhD 
Senior Vice President, Regulatory Affairs 
Pacira Pharmaceuticals, Inc 


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Date


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
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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 
7 
7 
DEFINITIONS 
8 
8 
ANALYSIS SETS 
10 
8.1 
Safety set 
10 
8.2 
Efficacy set 
10 
8.3 
Sensitivity set 
10 
9 
STUDY ENDPOINTS 
10 
9.1 
Efficacy Endpoints 
10 
9.1.1 
Primary Efficacy 
10 
9.1.2 
Key Secondary Efficacy 
10 
9.1.3 
Secondary Efficacy 
10 
9.1.4 
Exploratory Efficacy 
11 
9.2 
Safety Endpoints 
11 
9.3 
Efficacy Assessment 
11 
9.3.1 
Opioid Dose Conversion 
11 
9.3.2 
Average Postsurgical VAS pain Intensity Scores Through 72 Hours or Hospital Discharge, 
Whichever Occurs First. 
12 
9.3.3 
Opioid Related Symptom Distress Scale (ORSDS) 
13 
9.3.4 
Subject Satisfaction with Pain 
13 
9.3.5 
Pain Surgical Fear Questionnaire (SFQ) 
14 
9.3.6 
Pain Calls to Physician (Single Question) 
14 
9.3.7 
Persistent Opioid Use 
14 
9.3.8 
Recovery from Caesarean Section Scale (RCSS) 
14 
10 
STATISTICAL METHODS OF ANALYSIS 
14 
10.1 
General Principles 
14 
10.1.1 
Handling Missing Values 
15 
10.1.1.1 
Total Postsurgery Opioid Consumption 
15 


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10.1.1.2 
Postsurgical Itching Scores through 72 hours 
15 
10.1.1.3 
VAS Pain Intensity Scores 
15 
10.1.1.4 
Exposure, Surgery, and Rescue Medication Date or Time 
16 
10.1.1.5 
Adverse Event or Concomitant Medications Dates or Times 
16 
10.1.1.6 
Adverse Event Severity or Relationship to Study Drug 
16 
10.1.1.7 
Time to Event 
17 
10.1.2 
By-Center Analyses 
17 
10.1.3 
Non-Inferiority Margin (NIM) 
17 
10.2 
Subject Disposition 
17 
10.3 
Description of Demographics and Baseline Characteristics 
18 
10.3.1 
Demographics 
18 
10.3.2 
Baseline Characteristics 
18 
10.4 
Surgery Characteristics 
19 
10.5 
Medications for Surgical Procedures, and Prior and Concomitant Medications 
19 
10.6 
Measurements of Treatment Compliance 
20 
10.7 
Efficacy Analysis 
20 
10.7.1 
Methods of Analysis 
20 
10.7.1.1 
Primary Efficacy Analysis 
20 
10.7.1.2 
Key Secondary Efficacy Analyses 
22 
10.7.1.3 
Secondary Efficacy Analyses 
23 
10.7.1.4 
Exploratory Efficacy Endpoints 
26 
10.8 
Safety Analyses 
28 
10.8.1 
Adverse Events 
28 
10.8.2 
Vital Signs 
30 
10.8.3 
Interim Analysis 
30 
11 
SAMPLE SIZE CALCULATIONS 
30 
12 
REFERENCES 
32 
13 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
33 
14 
OPIOID RELATED SYMPTOM DISTRESS SCALE (ORSDS) 
36 
15 
LAYOUT OF TABLES, LISTINGS AND FIGURES 
37 
16 
LIST OF TABLES 
39 
17 
LIST OF LISTINGS 
99 
18 
LIST OF FIGURES 
138 


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EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
 
 
 
3 LIST OF ABBREVIATIONS 
 
 
Abbreviation 
Description 
 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical therapeutic class 
BMI 
Body mass index 
bpm 
Beats per minute 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CSE 
Combined spinal epidural 
CSR 
Clinical study report 
d 
Day 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
hr, h 
Hour 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IV 
Intravenous 
LOCF 
Last observation carried forward 
LS 
Least square 
MedDRA 
Medical dictionary for regulatory affairs 
MMRM 
Mixed model repeated measures 
MPADSS 
Modified Postanesthesia Discharge Scoring System 
min 
Minutes 
OMED 
Oral morphine equivalent dose in mg 
n 
Number of subjects 
OR 
Operating room 
PACU 
Postanesthesia care unit 
PCA 
Patient-controlled analgesia 
PO 
Oral 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
TAP 
Transversus abdominis plane 
TEAE 
Treatment-emergent adverse event 
TLF 
Table, listings and figures 
TUG 
Timed up-and-go 
VAS 
Visual analog scale 
WHO 
World Health Organization 
WHODD 
World Health Organization – Drug Dictionary 


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EXPAREL 
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Statistical Analysis Plan 
 
 
 
4 INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting of the 
clinical study 402-C-414 titled “A Multicenter, Randomized, Active-controlled Study to Evaluate 
the Efficacy and Safety of EXPAREL When Administered via Infiltration into the Transversus 
Abdominis Plane (TAP) Versus Standard of Care in Subjects Undergoing Elective Cesarean 
Section.” 
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 Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (1998). All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association (1999) and the Royal Statistical 
Society (1993), 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 the clinical study report (CSR), 
regulatory submissions, or manuscripts. Post-hoc exploratory analyses not necessarily 
identified in this SAP may be performed to further examine study data. Any post-hoc, 
unplanned, or exploratory analyses performed will be clearly identified as such in the final CSR. 
The following documents related to clinical study Protocol 402-C-414 were reviewed in 
preparation of this SAP: 
• Original Protocol issued on 16 August 2019. 
• Amendment 1 issued on 15Nov2018 
• Amendment 2 issued on 07Feb2019 
• CRF version 1.0 issued on 04Feb2019 
• CRF version 2.0 issued on 05Apr2019 
• 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 


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EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
 
 
 
collection and timing of planned clinical assessments are not repeated in this SAP  unless 
relevant to the planned analyses. 
 
 
5 STUDY OBJECTIVES 
 
5.1 
Primary Objective 
The primary objective of this study is to compare total opioid consumption through 72 hours 
following EXPAREL infiltration into the transversus abdominis plane (TAP) with standard of care 
(SOC) in subjects undergoing an elective cesarean section (C-section). 
 
5.2 
Secondary Objectives 
The secondary objectives are to assess efficacy and safety parameters and participant 
satisfaction. 
 
 
6 STUDY OVERVIEW 
This is a Phase-4, multicenter, randomized, active-controlled study in approximately 182 adult 
subjects  undergoing  elective  C-section.  All  subjects  will  remain  in  the  hospital  for  up  to 
72 hours postsurgery. 
Subjects will be randomized in a 1:1:1 allocation ratio to receive either: 
• Group 1: 150 mcg Duramorph (SOC). 
• Group 2: 50 mcg Duramorph + EXPAREL TAP infiltration. 
• Group 3: EXPAREL TAP infiltration. 
In all treatment groups, a combined spinal epidural (CSE) anesthesia technique may also be 
used provided the epidural component is not used. 
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 or fails the PO oxycodone rescue, intravenous (IV) morphine or hydromorphone 
may be used as rescue medication. 
Pain will be assessed using a 10 cm visual analog scale (VAS) for general pain and pain at 
incision site. Pain will be assessed at multiple prescheduled time points during the study and 
prior to taking any rescue medication. Subjects will remain in the hospital for up to 72 hours 
postsurgery. 


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EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
 
 
 
Other postsurgical assessments include: 
• Opioid use 
o Total opioid burden 
• Date and time of first unassisted ambulation 
• Pain intensity scores using a 10-cm VAS at rest 
• Discharge readiness 
• Opioid related symptom distress scale 
• Date and time of first bowel movement 
• Incidence of itching 
• Subject's satisfaction with postsurgical pain control 
• Calls to physician about pain 
• Total time in post-anesthesia care unit (PACU) 
• Persistent opioid use at Day 30 
• Emergency department (ED) visits 
• Recovery from Cesarean Section Scale 
 
 
7 DEFINITIONS 
Study Day 
If event occurs earlier than the start of study drug, Study Day is calculated as the date of event 
minus the date of the start of study drug administration. Otherwise Study Day is calculated as 
the date of event minus the date of the start of study drug administration plus one (+1). Study 
Day is based on the calendar dates, thus days before the date of surgery have negative values 
while those on or after the date of surgery are positive. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are the adverse events started on/after the study 
drug administration. 
Time 0 (zero) 
Time 0 is defined as the date and time of the end of surgery. 
Time Periods 
All scheduled times have a window associated with them (see Time and Events Schedule for 
individual time point windows). Various time frames are used in the data analyses which are 
dependent on these windows. 


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EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
 
 
 
Table 1: Time Window for VAS Assessment 
 
Defined time VAS Time Point (hrs) 
Acceptable Window (hrs) 
12, 24 
± 1 
48 
± 2 
72 
± 4 
 
 
If there are two or more VAS data points that fit into the same time window, the data point 
close to the center of the window will be used. If two data points are of equal distance to the 
center, the one with higher VAS score will be used for analysis. For programming purpose, the 
VAS time point for analysis (ANL01FL=Y) will be numbered by their schedule, eg, ATPTN = 12, 
24, …, 72. Other VAS time points will be numbered by the VAS time relative to the surgical end 
time in hours (with 1 decimal point), eg, 47.5. 
If after applying the time window, the VAS data point for the scheduled window becomes 
missing, it will be imputed as per Section 10.1.1.3. 
Baseline 
Baseline is defined as the last available measurement or assessment prior to the start of study 
treatment. 
Ready for Discharge 
Ready for discharge is defined as a total score of 9 or more on the Modified Postanesthesia 
Discharge Scoring System (MPADSS). The total score is the sum of all scores. If there are 
missing data, then the total score will not be calculated. 
Discharge Time 
Discharge time is defined as Discharge day - admission day + 1. 
Time to Event 
Time to event will be calculated as the time from end of surgery to time of event in hours. 
Opioid-free 
Opioid-free is defined as not received opioid rescue medication during the time interval. 
Opioid-sparing 
Opioid-sparing is defined as meeting both of the following conditions: 
• Total opioid consumption through 72 hours (all doses) ≤15mg (oral morphine equivalent 
dose [OMED]) 
• Total itching scores at 12, 24, 48 and 72 hours ≤1; 


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Statistical Analysis Plan 
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• No opioid-related AEs - Nausea/Abdominal distension/Dizziness 
 
 
8 ANALYSIS SETS 
 
8.1 
Safety set 
The safety set will be defined as follows 
• Group 1 subjects who underwent C-section surgery and received SOC as scheduled 
• Group 2 and Group 3 subjects, who underwent C-section surgery and received study 
drug through TAP infiltration as scheduled. 
All analyses based on the safety set will be by actual treatment received. 
 
8.2 
Efficacy set 
All the subjects in Safety Set who completed through 72 hours postsurgery. All analyses based 
on the efficacy set will be by planned treatment at randomization. 
 
8.3      Sensitivity set 
All the subjects in Efficacy set who did not receive the correct TAP infiltration based on 
ultrasound image/video will be excluded from sensitivity analysis. The ultrasound image/video 
for each patient was reviewed by independent ultrasound review committee. Incorrect TAP 
infiltration would only be confirmed if two rejections are received. 
 
 
9 STUDY ENDPOINTS 
 
9.1 
Efficacy Endpoints 
 
9.1.1 Primary Efficacy 
The primary endpoint is the total opioid consumption (in mg of oral morphine equivalent dose 
[OMED, see 9.3.1]) to cover postsurgical pain in morphine equivalents through 72 hours. 
Duramorph, though administered prior to surgery, is used to cover postsurgical pain thus is 
included in opioid consumption to cover postsurgical pain. 
 
9.1.2 Key Secondary Efficacy 
The key secondary endpoint is the average postsurgical itching scores through 72 hours. 
 
9.1.3 Secondary Efficacy 
The following secondary endpoints will be analyzed: 
• Postsurgical itching scores through 12, 24 and 48 


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Statistical Analysis Plan 
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• Total Opioid Consumption through 24 and 48 hours, Day 7 (168 hours) and Day 14 (336 
hours) 
• Average VAS pain intensity scores (general pain and pain at incision site) through 24, 48 
and 72 hours after surgery or hospital discharge, whichever occurs first 
• Percentage of postsurgical opioid-free and opioid-sparing subjects through 72 hours 
 
• ORSDS at 24, 48, and 72 hours after surgery or at hospital discharge, whichever occurs 
first 
• Proportion of subject discharge-ready at 24, 48, and 72 hours or at hospital discharge, 
whichever occurs first 
• Overall assessment of subject satisfaction with pain control at 72 hours or at hospital 
discharge, whichever occurs first 
• Recovery Cesarean Section Scale 
 
9.1.4 Exploratory Efficacy 
• Total  postsurgical  opioid  consumption  (in  mg  of  OMED)  in  morphine  equivalents 
through 72 hours, excluding duramorph administered prior to surgery. 
• Length of hospital stay 
• Number  of  unscheduled  phone  calls  or  office  visits  related  to  pain  from  discharge 
through Day 14 
• ED visits 
• Persistent opioid use at Day 30 
• Time spent in the post-anesthesia care unit (PACU) 
• Time to first unassisted ambulation. 
• Time to first bowel movement 
 
9.2 
Safety Endpoints 
• Safety  will  be  assessed  using  the  following:  Incidence  of  treatment-emergent  AEs 
(TEAEs) and SAEs through Day 14 
• Vital signs at scheduled time points 
 
9.3 
Efficacy Assessment 
 
9.3.1 Opioid Dose Conversion 
Opioids  dose  will  be  converted  to  oral  morphine  equivalent  dose  (OMED  mg)  using  the 
conversion factor from Table 2 for all summaries. 
Total opioid dose is the oral morphine 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
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Statistical Analysis Plan 
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equivalent sum of all opioids taken during the time interval of interest. Subjects with no opioid 
use during the period in question will be assigned a dose of 0 mg for summaries. 
 
Table 2. Conversion Factors to IV and Oral Morphine Equivalent Dose from Other Opioids 
 
 
Medication 
Unit Route 
IV Morphine 
Conversion 
(Multiplication) 
Factor 
Oral 
Morphine 
Conversion 
(Multiplication) 
Factor 
Duramorph 
mcg 
IT 
0.1 
0.3 
Oxycodone, 
Oxycocet, 
Percocet, 
acetaminophen-oxycodone 
mg 
PO 
0.5 
1.5 
Morphine 
mg 
IV, IM, SC 1 
3 
Morphine 
mg 
PO 
0.33 
1 
Hydromorphone (Dilaudid) 
mg 
IV, IM, SC 6.67 
20 
Hydromorphone (Dilaudid) 
mg 
PO 
1.3 
4 
Fentanyl 
mg 
IV, PO, IM 100 
300 
Hydrocodone combination product - Vicodin, 
Norco, 
Lorcet, 
Lortab, 
hydrocodone- 
acetaminophen, Ketobemidone 
mg 
PO 
0.33 
1 
Codeine combination product - Tylenol 3, 
acetaminophen-coedine, Paracetamol Forte, 
Tylenol 4 
mg 
PO 
0.05 
0.15 
Ultram, Tramadol, Tramacol hydrochloride 
mg 
PO, IM 
0.08 
0.25 
Demerol, Meperidine, Pethidine 
mg 
IV, SC 
0.1 
0.3 
Demerol, Meperidine, Pethidine 
mg 
PO 
0.033 
0.1 
Ketobemidone, Oxycodone 
mg 
IV 
1 
3 
Nalbuphine/Nallouphine (Nubain/Manfine) 
mg 
IV, IM, SC 1 
3 
PO = oral, IV = intravenous, IM = Intramuscular, SC = subcutaneous, VAS = visual analog scale. 
 
9.3.2 Average  Postsurgical  VAS  pain  Intensity  Scores  Through  72  Hours  or  Hospital 
Discharge, Whichever Occurs First. 
To calculate average of postsurgical VAS pain intensity score through 72 hours or hospital 
discharge, whichever occurs first, we collected pain scores for each subject at each prespecified 
time. Subjects who did not report  any pain  score at any time point after  surgery will be 
excluded from this analysis. All the pain scores will be first adjusted for rescue medication if 
necessary (see 10.1.1.3). Then the remaining missing pain scores will be imputed the median 
pain score from the patients in the same treatment group and same scheduled time point (see 
Section 10.1.1.3). The area under the pain-time curve (AUC) is derived using the trapezoidal 


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rule (see formula below) on the adjusted and imputed pain scores. AUC will start with the first 
obtained postsurgical pain assessment. All pain assessments through 72 hours after surgery, 
both scheduled and unscheduled ones, will be included in deriving AUC. Exact assessment times 
will be used in deriving AUC. 
 
𝑛𝑛 
𝐴𝐴𝐴𝐴𝐴𝐴 =  {∑(𝑝𝑝𝑖𝑖 + 𝑝𝑝(𝑖𝑖−1))(𝑡𝑡𝑖𝑖 + 𝑡𝑡(𝑖𝑖−1))} /2 
𝑖𝑖=2 
where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery. Note t1 
is 12 hours postsurgery. It is the first time VAS score is collected. 
The next step is to obtain the average pain score through 72 hours or hospital discharge from 
AUC. This will be accomplished by dividing AUC by the time interval between first pain 
assessment and last assessment for the AUC calculation. For example, if the first pain 
assessment time and the last pain assessment time used to calculate AUC for a subject were 5.6 
hours and 72.2 hours respectively, then the average pain score through 72 hours or hospital 
discharge would be AUC divided by 66.6 (72.2-5.6 = 66.6). 
Average postsurgical pain intensity score will be calculated for general pain and pain at incision 
site. 
 
9.3.3 Opioid Related Symptom Distress Scale (ORSDS) 
The Opioid-Related Symptom Distress Scale (ORSDS) is a 4-point scale that evaluates 3 
symptom distress dimensions (frequency, severity, bothersomeness) for 10 symptoms. The 
symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite 
ORSDS is the average of 10 symptom-specific scores (see Section 14). The ORSDS has been 
validated for outpatient laparoscopic cholecystectomy (under general anesthesia) by 
assessment of internal consistency, content validity, construct validity, principal components 
analysis, known group validity, responsiveness, and opioid dose dependency. 
 
9.3.4 Subject Satisfaction with Pain 
The subject's satisfaction with postsurgical pain control will be conducted at 72 hours after 
surgery (or at hospital discharge, whichever occurs first), and will be assessed using a 5-point 
Likert scale as follows: 1. Extremely dissatisfied; 2. Dissatisfied; 3. Neither satisfied nor 
dissatisfied; 4. Satisfied; 5. Extremely satisfied. Sum of the scores will be used for analysis. 


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9.3.5 Pain Surgical Fear Questionnaire (SFQ) 
The SFQ is an eight-item instrument for the assessment of self-reported surgical fear, which can 
be divided into short-term (SFQ-s) and long-term (SFQ-l) surgery-related fears. All items are 
scored on an eleven-point numeric rating scale (NRS) ranging from 0 (not at all afraid) to 10 
(very afraid). This results in a score of 0-40 for each subscale. Items are: 1. afraid of operation, 
2. anesthesia, 3. postoperative pain, 4. Side effects, 5. health deterioration, 6. failed operation, 
7. incomplete recovery, 8. long duration of rehabilitation. Sum of the two subscale SFQ scores 
by treatment group will be used for analysis. 
 
9.3.6 Pain Calls to Physician (Single Question) 
As part of the phone call to physician on Day 14, the subject will be asked pain related to 
surgery, and will be assessed using a 4-point Likert scale as follows: 1. 0 (I have not called my 
doctor); 2. 1-2 times; 3. 3-5 times; 4. More than 5 times. 
 
9.3.7 Persistent Opioid Use 
As part of the phone call to physician on Day 30, subjects will be asked if they were currently 
taking opioid for pain and they can either respond as yes or no. Persistent opioid use is defined 
as those patients who respond yes to the Day 30 opioid use question. 
 
9.3.8 Recovery from Caesarean Section Scale (RCSS) 
At 24, 48, and 72 hours postsurgery or hospital discharge, whichever comes first, subjects are 
asked to rate their answer (1 = strongly disagree and 7 = strongly agree) to each of the 9 RCSS 
questions. 
 
 
10 STATISTICAL METHODS OF ANALYSIS 
 
10.1 General Principles 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). All 
analyses and tabulations will be performed using SAS Version 9.4 or later. Continuous 
variables will be summarized using descriptive statistics [sample size (n), mean, standard 
deviation (SD), minimum, median, and maximum]. Categorical variables will be tabulated with 
number and percentage of unique subjects.  Unless  otherwise noted, percentages will  be 
calculated using the number of subjects in the respective treatment group and analysis set as 
the denominator and presented with only those categories appearing in the data. 
Tables will present 150 mcg Duramorph + SOC, 50 mcg Duramorph + EXPAREL and EXPAREL as 
separate columns. 


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10.1.1 Handling Missing Values 
 
10.1.1.1 
Total Postsurgery Opioid Consumption 
For the calculation of the total postsurgical opioid consumption, both opioid rescue medication 
before hospital discharge and opioid pain medication in the daily diary after discharge will be 
included. If opioid is taken on the discharge day but time of dosing is missing, it will be imputed 
as time of discharge or 12:00 pm on the discharge day, whichever is later. If opioid is taken 
after the day of discharge and time of dosing is missing, it will be imputed as 12:00 pm the day 
after discharge. 
Study subjects will be given an ePRO device or an app on their smart phone to report pain score 
and medications they used at home. We expect that all medications will be entered, except 
when patients discontinued due to AE or death after surgery. 
 
10.1.1.2 
Postsurgical Itching Scores through 72 hours 
No imputation will be done on the missing itching score. The missing mechanism were assumed 
missing at random (MAR). Under this assumption the MMRM analysis (see 10.7.1.2.1) is 
considered unbiased. 
 
10.1.1.3 
VAS Pain Intensity Scores 
VAS pain intensity scores will first be adjusted by the amount of opioid taken before pain 
assessment using following method. 
• For pain intensity scores on or before the scheduled 24 hours (on or before the exact 24 
hours if the scheduled 24 hour pain score is missing), first calculate the total opioid 
amount (oral morphine equivalent dose, see section 9.3.1.3) that have been taken 
before this pain assessment (total_opi). Then the imputed pain score will be the sum of 
the original pain score and one tenth of the natural logarithm of total_opi. 
• For pain intensity scores after the scheduled 24 hours (after the exact 24 hours if the 
scheduled 24 hour pain score is missing), first calculate the total opioid amount that 
have been taken from 24 hours before this pain assessment (total_opi). Then the 
imputed pain score will be the sum of the original pain score and one tenth of the 
natural logarithm of total_opi. 
After adjustment, missing scheduled VAS pain intensity scores will be replaced by the median of 
non-missing scores from the same scheduled time point and same treatment group. 


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10.1.1.4 
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 plus 1 minute. 
 
10.1.1.5 
Adverse Event or Concomitant Medications Dates or Times 
For AEs with missing or partially missing start date/time, the following imputation rules will be 
applied for the determination of treatment-emergent status: 
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 year is known to be different from the year of the first dose, then missing month 
and day will be imputed as the first month and first day of the month. 
• If the year is known to be the year of the first dose, 
a) If the month is unknown or is the same as the month of the first dose, then the 
missing month and day will be imputed by the month and day of the first dose. 
b) If the month is known to be different from the month of the first dose, then the 
missing day is imputed as 01 (first day of the month). 
• If the time is unknown, then: 
a) If the date (day, month, and year) matches the date of the administration of 
study drug, then the time of the study treatment will be used to impute the 
missing time. 
b) Otherwise, ’00:00’ will be assigned. 
For medications with missing or partially missing dates, Section 10.5 provides rules for the 
determination of prior or concomitant status. 
 
10.1.1.6 
Adverse Event Severity or Relationship to Study Drug 
If severity of an AE is not reported, then for tables of AEs by severity, the event will be classified 
as ‘Severe’ and will be footnoted for the table to indicate this imputation. If relationship to 
study drug is not reported for an AE, then for tables of study-drug related AEs, the event will be 
assigned the relationship of ‘definite’. Tables presenting related AEs will include all AEs with 
relationships of ‘possible’, ‘probable’ or ‘definite’ as assessed by the investigator. 


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10.1.1.7 
Time to Event 
For calculating time to an event when only the hour is reported, the minutes will be set to zero. 
 
10.1.2 By-Center Analyses 
By-site summaries will be presented for disposition, demographics, primary efficacy endpoint 
and secondary efficacy endpoints. In the by-site analysis, analysis stratified by site or adjusted 
for site as covariate, the small sites will be pooled into one pseudo site. Pseudo site will be 
numbered as SITEID 999, including SITEID 104,105,108,109,112,116,120,121,122 and 123 
 
10.1.3 Non-Inferiority Margin (NIM) 
For VAS pain scores, several studies used 0.8 or 1 as non-inferiority margin. We chose a more 
conservative NIM of 0.5 which is the same to our previous c-section study named “A 
Multicenter, Randomized, Double-blinded, Active-controlled Study to Evaluate the Safety and 
Efficacy of EXPAREL When Administered via Infiltration into the Transversus Abdominis Plane 
(TAP) Versus Bupivacaine Alone in Subjects Undergoing Elective Cesarean Section”. 
For postsurgical opioid consumption through 72 hours, from our previous c-section study listed 
above, postsurgical opioid consumption for bupivacaine group (which is very similar to 150 mcg 
Duramorph + SOC in this study) is around 30 mg OMED. Some previous studies using opioid 
consumption as primary endpoint use 30 mg in a 24h interval as non-inferiority margin and 
previous literature indicate difference of 10.6 mg in IV morphine equivalent dose (31.8 oral 
morphine equivalent) daily is the clinical different threshold. These difference will be more 
than 1 on natural logarithm scale for 72 hour interval. To be conservative, we choose 0.8 (on 
natural logarithm scale) to be our non-inferiority margin (NIM). 
 
10.2 Subject Disposition 
Subject disposition summaries will include the number of subjects 
• Screened, 
o Screen failure 
o Enrolled (ie, randomized) 
• Randomized 
o Randomized not treated, 
o Randomized treated, 
• In the safety analysis set, 
• In the efficacy set, 
• In the sensitivity set, 
• Completed the study as planned, 
• Discontinued from the study, and 


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o Reasons for discontinuation from the study. 
Percentages will be reported for the screen failures and enrolled using the number of subjects 
screened as the denominator; other percentages will use the number of subjects randomized 
and treated as denominator, unless otherwise noted. 
The safety analysis 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.  This summary table 
will present overall sites and for each site separately. 
 
10.3 Description of Demographics and Baseline Characteristics 
 
10.3.1 Demographics 
The summary of demographic data will present: 
• Age (years) – descriptive statistics 
• Sex – n (%) 
• Ethnicity – n (%) 
• Race – n (%) 
• Country – 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. 
The demographic summary will present the data for each treatment group.  Summaries will be 
provided for each (safety and efficacy) analysis set separately. 
 
10.3.2 Baseline Characteristics 
The summary of baseline characteristic data will present: 
• American Society of Anesthesiologists (ASA) Classification – n (%) 
• Baseline ECG interpretation 
• Height (cm) 
• Weight (kg) 
• Body Mass Index (BMI) (kg/m2) 
• Surgical Fear Questionnaire (SFQ) 
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. 


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Baseline characteristics summaries will present the data for each treatment group. Summaries 
will be provided for each (safety and efficacy) analysis set separately. 
Descriptive statistics (n, mean, SD, median, minimum and maximum)  will be provided for 
continuous variables. The number and percent of subjects will be tabulated for the categorical 
variables. 
 
10.4 Surgery Characteristics 
Surgery characteristics including type of anesthesia (general, spinal, or other), use of 
intraoperative medication (yes or no), use of CSE anesthesia (yes or no), administration of the 
epidural component of the SCE (yes or no), and duration of surgery will be summarized using 
descriptive statistics. Summaries will be provided for each (safety and efficacy) analysis set. 
Duration of surgery is calculated as the difference between the end of surgery and start of 
surgery times and reported in hours. 
 
10.5 Medications for Surgical Procedures, and Prior and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary (WHODDE 
Sep 2018) and will be classified according to the anatomical therapeutic chemical classification 
term (ATC4) and preferred term (PT). 
Preoperative, intraoperative, CSE, multimodal pain, postoperative pain, prescription daily pain, 
and rescue medications are medications given as part of the surgical procedure with start and 
stop dates on the day of surgery and start and stop times overlapping with the surgery start and 
stop times. 
Prior and Concomitant medications are medications collected on the Prior/Concomitant 
Medication eCRF page. 
Prior medications are defined as medications with a stop date and time prior to the start of 
study drug administration. 
Concomitant medications are defined as medications taken after the start of study drug 
administration (i.e., started prior to the start of study drug administration and continued after 
or started after the start of study drug administration). 
For the determination of the prior and concomitant status, these rules will be followed for 
incomplete dates. 
• If the medication stop date is partially missing, 
o If the year and month indicate the stop date is before study drug administration, 
it is Prior medication. 


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o Otherwise, it is concomitant medication. 
• If the medication stop date is completely missing, it is concomitant medication. 
All medications will be summarized separately by category using n (%) of subjects for each 
treatment group and across treatment groups by ATC3 term and PT for the safety analysis set. 
Subjects may have more than one medication per ATC3 and PT. At each level of subject 
summarization, a subject will be counted once if one or more medications are reported by the 
same subject at that level. 
All medications will be included in the data listing. 
 
10.6 Measurements of Treatment Compliance 
Study drug is administered by the site personnel, therefore compliance is assured. 
 
10.7 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. All efficacy analyses will be performed on the efficacy analysis set. 
 
10.7.1 Methods of Analysis 
For Primary and Secondary Efficacy Analyses, descriptive statistics appropriate for the efficacy 
variable will be presented overall and by site. No statistical comparison will be made within a 
site. 
 
10.7.1.1 
Primary Efficacy Analysis 
Total opioid consumption (OMED mg) will be summarized by treatment group for the total dose 
consumed between 0 and 72 hours after the end of surgery. Presurgery duramorph, used to 
treat postsurgery pain, is counted in the total opioid dose consumption. For the frequency 
count of number of subjects receiving opioid medications, subjects will be counted only once 
regardless of how many times subjects have received the medications. The summary table will 
include number of subjects receiving postsurgical opioids, geometric mean and coefficient of 
variation (CV%), median, minimum and maximum. 
Tests for the treatment effect will be based on the following one-sided null hypothesis and 
alternative hypothesis: 
H01: Mean 0-72 hour opioid consumption in EXPAREL group is not different from that in 
150 mcg Duramorph (SOC) group. 
 
• Ha1: Mean 0-72 hour opioid consumption is less in EXPAREL group than in 150 mcg 
Duramorph (SOC) group. 


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x H02:  0HDQKRXURSLRLGFRQVXPSWLRQLQ(;3$5(/PFJ'XUDPRUSKJURXSLV
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x Ha2: Mean 0-72 hour opioid consumption is less in EXPAREL + 50 mcg Duramorph group 
than in 150 mcg Duramorph (SOC) group. 
A one-sided test will be performed at 2.5% level of significance comparing each of the two dose 
arms of EXPAREL (EXPAREL and EXPAREL + 50 mcg Duramorph) versus 150 mcg Duramorph 
(SOC). 
To test for significant differences between each of the two dose arms of EXPAREL (EXPAREL + 
50 mcg Duramorph and EXPAREL) and the 150 mcg Duramorph (SOC), an analysis of covariance 
(ANCOVA) model with treatment and site as the main effects, age and height as covariates will 
be applied to the natural log-transformed total dose. If a subject never received an opioid 
medication, the total dose will be assigned 3.75 mg OMED prior to the log-transformation. The 
LS means of the two doses of EXPAREL (EXPAREL + 50 mcg Duramorph and EXPAREL) and 150 
mcg Duramorph (SOC), LS mean difference (EXPAREL + 50 mcg Duramorph minus 150 mcg 
Duramorph (SOC)and EXPARE minus 150 mcg Duramorph (SOC)), two-sided 95% CI for the LS 
mean difference, and the one-sided p-value will be reported after back transformation (ie, 
taking exponential) to the original OMED scale. 
In addition to the presentation for the between group difference, the percent reduction in total 
OMED will also be presented. The % reduction is derived as follows, 
% Reduction=100% x {LSM*150 mcg Duramorph(SOC) – LSM*EXPAREL+50mcg Duramorph }/LSM*150 mcg 
Duramorph(SOC) 
where LSM* is back-transformed least square mean estimate from the ANCOVA. 
The primary analysis for the primary endpoint is based on the Efficacy evaluable population. 
Multiplicity Adjustments 
For the efficacy analyses, pairwise comparison of the active dose groups (EXPAREL+50 mcg 
Duramorph and EXPAREL) will be compared to 150 mcg Duramorph (SOC) following spinal 
anesthesia using the 1-sided 0.025 alpha level for the efficacy analysis set. 
To control the family-wise error rate at one-sided 2.5% significance level, a fixed sequence 
procedure (Westfall et al 1999) will be performed to test the ordered null hypotheses below at 
2.5% significance level. 
1)
H01: Mean 0-72 hour opioid consumption in EXPAREL group is not different from 
that in 150 mcg Duramorph (SOC) group. 


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2)
H02: Mean 0-72 hour opioid consumption in EXPAREL group is not different from 
that in 150 mcg Duramorph (SOC) group. 
First, H01 will be tested at 2.5% significance level for the primary endpoint. If H01 is rejected, it 
will be claimed that the EXPAREL is superior to 150 mcg Duramorph (SOC), then H02 will be 
tested at 2.5% significance level. If H02 is rejected, then it will be concluded that both EXPAREL 
and EXPAREL + 50 mcg Duramorph groups are superior to 150 mcg Duramorph (SOC) group. If 
H01 is not rejected, then H02 will not be tested and the conclusion will be that neither treatment 
groups are efficacious.
Subgroup Analysis of Primary Efficacy Endpoint 
The analysis of the primary endpoint will be repeated for selected subgroups such as
x
Age (<35, and ш35), 
x Race (White and Non-White), 
x
BMI (<25, 25 to <30, and ш30+ kg/m2) 
x Number of prior C-sections (0, 1+), 
x Discharge Time (Discharged on or before Day 3, Discharged on or after Day 4), and 
x Subjects with or without anxiety medical history. 
Note  because  of  the  small  sample  sizes,  all  subgroup  analysis  will  be  performed  without 
adjusting/stratifying by site 
10.7.1.2
Key Secondary Efficacy Analyses 
Average Postsurgical Itching Scores Through 72 Hours 
Postsurgical itching scores (at PACU, 12, 24, 48, and 72 hrs) will be analyzed using an MMRM 
model with treatment group, site, visit and treatment-by-visit interaction as main effect, age 
and height as covariates. LS means of each treatment group, LS mean differences between each 
pair of treatment groups and p-value of each LS mean differences will be presented. The 
average itching score through 72 hours is estimated by the LS grand mean. 
A sample SAS code is provided as follows. 
PROC MIXED DATA=XXXX ͖ 
CLASS trtp usubjid visit ƐŝƚĞŝĚ͖ 
MODEL Response = siteid age height trtp visit trtp*visit / DDFM=kr2 ͖ 
REPEATED visit / SUBJECT=usubjid(trtp) TYPE=UN ͖ 
LSMEAN trtp*visit/ PDIFF ALPHA=0.05 ͖ 
LSMEAN trtp / PDIFF ͖ 


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ESTIMATE “G1-G3 thru 12h” trtp 1 0 -1 
Trtp*visit 1  1 0 0 0 
0  0 0 0 0 
-1 -1 0 0 0 / divisor=2 ͖ 
ESTIMATE “G1-G3 thru 24h” trtp 1 0 -1 
Trtp*visit 1 1 1 0 0 
0 0 0 0 0 
-1 -1  -1 0 0 / divisor=3 ͖ 
RUN ͖ 
Note: usubjid is subject ID, trtp is treatment variable, visit is the nominal study visit, and 
Response is the itching score at the scheduled time point. Depending on the convergence 
status in the computation, unstructured (UN), Toeplitz (TOEP), 1st order autoregressive [AR(1)] 
and compound symmetry variance-covariance (CS) matrix will be tried in the order. The final 
analysis will be based on the first matrix leading to the convergence in the computation. 
10.7.1.3
Secondary Efficacy Analyses 
Average Postsurgical Itching Scores Through 12, 24, 48 and 72 Hours 
These  endpoints  will  be  analyzed  using  the  same  MMRM  approach  described  in  Section 
10.7.1.2. Between-group simple contrast at each visit will be derived the ESTIMATE statement. 
Total Opioid Consumption Through 24 and 48 Hours, Day 7 (168 hours) and Day 
14 (336 hours) 
Each individual timepoint will be analyzed using the ANCOVA model similar to Section 10.7.1.1. 
Between-group simple contrast will be derived from the LSMEAN statement. 
Average VAS Pain Intensity Scores Through 72 Hours After Surgery or Hospital 
Discharge Whichever Occurs First 
Average VAS pain intensities (general pain and pain at incision site) from 0 to 72 hours or 
hospital discharge whichever comes first will be derived for each subject as described in Section 
9.3.2. They will be analyzed using ANCOVA with treatment and site as main effects, age and 
height as covariates. Based on the model, the  LS Mean and  SE  will be reported for each 
treatment group. Non-inferiority and superiority sequential hypothesis testing  will  be 
performed afterwards, comparing each of the two dose arms of EXPAREL (EXPAREL + 50 mcg 
Duramorph and EXPAREL) versus 150 mcg Duramorph (SOC) simultaneously: (1) EXPAREL + 50 
mcg duramorph vs. 150 mcg duramorph (SOC), and (2) EXPAREL vs. 150 mcg duramorph (SOC). 
LS Mean difference and 95% CI will be reported for each comparison. 


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The testing procedure is the same for each comparison. Here we use (1) EXPAREL + 50 mcg 
duramorph vs. 150 mcg duramorph (SOC) as an example: 
Hypothesis 1 (non-inferiority): 
o H1o1: EXPAREL group is inferior to 150 mcg Duramorph (SOC) group with respect 
to average VAS score. 
o H1a1: EXPAREL group is not inferior to 150 mcg Duramorph (SOC) group with 
respect to average VAS score. 
Hypothesis 2 (superiority): 
o H2o1: EXPAREL group is not superior to 150 mcg Duramorph (SOC) group with 
respect to average VAS score. 
o H2a1: EXPAREL group is superior to 150 mcg Duramorph (SOC) group with respect 
to average VAS score. 
To test the two null hypotheses, a stepdown approach will be used by inspecting the 95% 
confidence interval for group difference as follows: 
• Non-inferiority Test for Hypothesis 1. 
o If the upper bound of the 2-sided 95% confidence interval for the LSM for the 
difference of average VAS score under H1o1 versus H1a1 is > NIM, then stop the 
hypothesis tests and declare that the non-inferiority result is not achieved. NIM 
(non-inferiority margin) = 0.5. 
o If the upper bound of the 2-sided 95% CI is ≤ NIM then declare that the non- 
inferiority of EXPAREL+50 mcg Duramorph to 150 mcg Duramorph (SOC) is 
achieved. Move on to test for H2o1. 
• Superiority Test for Hypothesis 2 
o If the upper bound of the 2-sided 95% CI is ≥0 for the comparison (EXPAREL+50 
mcg Duramorph versus 150 mcg Duramorph (SOC)), then stop the test and 
declare that the superiority is not achieved for H201. 
o If the upper bound is <0 then declare that the superiority of EXPAREL+50 mcg 
Duramorph to 150 mcg Duramorph (SOC)is achieved. 
In the table presentation for the between group comparison, if the superiority test passes, only 
the 1-sided superiority test p-value will be displayed. If the superiority test fails, only the 1- 
sided non-inferiority test p-value will be displayed. Margin used for noninferiority test  will 
be 0.5. 


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Summary  and  analysis  of  (general  and  at  incision  site)  average  VAS  pain  intensity  scores 
through 24, and 48 hours will also be reported. 
Percentage of Postsurgical Opioid-Free and Opioid-Sparing Subjects Through 72 
Hours 
The percentage of opioid-free subjects through 72 hours and hospital discharge will be analyzed 
using the logistic regression model with treatment, site, age, and height as explanatory 
variables. Percentage of opioid-free subjects from the model, odds ratios (EXPAREL+50 mcg 
Duramorph) / 150 mcg Duramorph (SOC) and EXPAREL / 150 mcg Duramorph (SOC), and 95% CI
for the odds ratios and p-values will be presented. 
Percentage of opioid sparing subjects will be analyzed using the same approach described for
percentage of opioid free subjects. 
Pseudo-code for logistic regression method: 
RGVRXWSXW2GGV5DWLRV RU2''65$7,2$1'&/
'LIIV GLIINHHS SURE]6,'('39$/8(
/60HDQV OVPNHHS WUWSQPX352%2)<(6
SURFORJLVWLFGDWD HISORWV QRQH
FODVVVLWHLGWUWSQSDUDP JOP
PRGHODYDOFHYHQW <HV WUWSQVLWHLGDJHKHLJKWEO
OVPHDQVWUWSQSGLII FRQWUROO

LOLQN
UXQ
Opioid Related Symptom Distress Scale (ORSDS) at 24, 48, and 72 Hours After 
Surgery or at Hospital Discharge, Whichever Occurs First 
The ORSDS composite score as well as the 10 symptom-specific ORSDS scores will be 
summarized by treatment at each assessment time points of 24, 48, and 72 hours after surgery 
or at hospital discharge, whichever occurs first. Additionally, the ORSDS composite and each of 
the symptom-specific distress scores will be analyzed using a Mixed-Effect Model for Repeated 
Measures (MMRM). The model includes treatment, visit, and interaction between treatment 
and visit as fixed factors. The model parameters will be estimated using restricted maximum 
likelihood method with unstructured variance-covariance matrix and Kenward-Roger 
approximation to estimate denominator degrees of freedom. The between-group comparison 
will be performed using the simple contrast at the respective visits. The LSM of 150 mcg 
Duramorph (SOC), EXPAREL + 50 mcg Duramorph and EXPAREL, the difference in the LSM 
(EXPAREL + 50 mcg Duramorph minus 150 mcg Duramorph (SOC) and EXPAREL minus 150 mcg 
Duramorph (SOC), and 95% CI for the LSM difference will be calculated. Analysis will be 
performed at 24, 48 and 72 hours. 
A sample SAS code is provided as follows. 
PROC MIXED DATA=XXXX ͖ 


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RUN ͖ 
CLASS trtp usubjid ǀŝƐŝƚ͖ 
MODEL Response = siteid trtp visit trtp*visit / DDFM=kr2 ͖ 
REPEATED visit / SUBJECT=usubjid(trtp) TYPE=UN ͖ 
Lsmeans ƚƌƚƉΎǀŝƐŝƚͬWĚŝĨĨĂůƉŚĂсϬ͘Ϭϱ͖ 
Note: usubjid is subject ID, trtp is treatment variable, visit is the nominal study visit, and 
Response is respective endpoints. Depending on the convergence status in the computation, 
unstructured (UN), Toeplitz (TOEP), 1st order autoregressive [AR(1)] and compound symmetry 
variance-covariance (CS) matrix will be tried in the order.  The final analysis will be based on the 
first matrix leading to the convergence in the computation. 
Proportion of Subjects Discharge-Ready at 24, 48, and 72 Hours or at Hospital 
Discharge, Whichever Occurs First 
Proportion of subject discharge-ready at each timepoint of 24, 48, and 72 hours or at hospital 
discharge, whichever occurs first will be analyzed using logistic regression similar to section 
10.7.1.3.4 
Overall Assessment of Subject Satisfaction with Pain Control at 72 Hours or at 
Hospital Discharge, Whichever Occurs First 
Overall assessment of subject satisfaction with pain control at 72 hours or at hospital discharge, 
whichever occurs first (obtained using a 5-point Likert scale) will be summarized with mean and
SD and tabulated with n (%) by treatment group. The between group comparison will be 
carried out using the using the Cochran-Mantel-Haenszel (CMH) test for row mean score 
difference (RMS) with modified ridit score. 
Pseudo-code for CMH method: 
PROC &ZY͖ 
TABLE siteid*trt*Y / cmh SCORES=modridit ƐĐŽƌŽƵƚ͖ 
ZhE͖ 
where, Y is subject satisfaction scores 
Recovery from Caesarean Section Scale (RCSS)
Subject rating on each of the 9 scales will be summarized descriptively by treatment group at 
24, 48, and 72 hours, or at hospital discharge, whichever occurs first. 
10.7.1.4
Exploratory Efficacy Endpoints 
Total Postsurgical Opioid Consumption (mg) in Morphine Equivalents Through
72 Hours 


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Total postsurgical opioid consumption (mg) in morphine equivalents through 72 hours or 
hospital discharge will be analyzed using ANCOVA similar to section 10.7.1.3.3. Non-inferiority 
comparison will be conducted by comparing the upper bound of the 95% CI for the between 
treatment difference (in the log-transformed scale) against the  noninferiority  margin 
(NIM=0.8). If a subject never received any postsurgical opioid medication, the total dose will be 
assigned 3.75 mg OMED (half of one oral oxycodone dose) prior to the log-transformation. 
Length of Hospital Stay 
Length of hospital stay, defined as the surgical facility discharge date/time minus the facility 
admission date/time, will be summarized descriptively by treatment group. 
Number  of  Unscheduled  Phone  Calls  or  Office  Visits  Related  to  Pain  from 
Discharge Through Day 14 
The number of unscheduled pain-related phone calls per subject after discharge through 
postsurgical Day 14 will be summarized with mean and SD and tabulated with n (%) of subjects 
with 0, 1, 2, 3, etc. phone call by treatment. 
Number of Emergency Department (ED) Visits 
The number of ED visits per subject after discharge will be summarized with mean and SD and 
tabulated with n (%) of subjects with 0, 1, 2, 3, etc. ED visits by treatment. 
Persistent Opioid Use at Day 30
The number (and %) of subjects with persistent opioid use at day 30 after discharge will be 
summarized by treatment group. 
Time Spent in the Post-Anesthesia Care Unit (PACU) 
The time spent (hours) in PACU is defined as date/time of admission to PACU minus date/time 
of discharge from PACU. This endpoint will be analyzed by treatment group using ANCOVA 
similar to Section 10.7.1.1Error! Reference source not found. Baseline value will be included in 
the model as covariate and assuming gamma (or normal) distribution and log link function 
Time to First Unassisted Ambulation 
Time to first unassisted ambulation will be computed in hours as the date and time of the first 
unassisted ambulation minus the date and time of the end of surgery. If a subject is not 
administered an ambulation, the time to first unassisted ambulation will be censored at 72 
hours after surgery or at the time of last follow-up, whichever is early. 


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Time to first unassisted ambulation will be analyzed in two steps: Kaplan-Meier Curves for each 
treatment group with log-rank test for the between group difference. Cox proportional hazards 
regression with treatment and site as factors, age and height as covariates, followed by chi- 
squared test. The n (%) of subjects with unassisted ambulation as well as the n (%) of subjects 
without unassisted ambulation will be presented for each treatment group. 
Time to First Bowel Movement 
Time to first bowel movement will be computed in hours as the date and time of the first bowel 
movement minus the date and time of the end of surgery. If a subject does not have bowel 
movement, the time to first bowel movement will be censored at 72 hours after surgery or at 
the time of last follow-up, whichever is early. Time to first bowel movement will be analyzed by 
the method similar to time to first unassisted ambulation.
10.8 Safety Analyses 
Safety assessments in this study consist of adverse events (AEs) and vital signs (VS). 
10.8.1 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
v21.1).
An AE will be considered TEAE if it starts on/after the start time of the first study medication 
subject received. Specifically, if subjects receive study medications according to the protocol, 
Group 1 and 2 subjects will use Duramorph and Group 3 subjects will use EXPAREL start time 
for reference. 
If an AE has a partial onset date and time the imputed start dates and time will be used to 
determine treatment-emergence (Section 10.1.1.5). All AE summaries will present TEAEs only. 
AEs that are not treatment-emergent will be included in listings but not summarized. 
AEs will be summarized using subject incidence table. An overview of TEAE will be presented. 
This table will include n (%) of subjects with 
x Any TEAE 
R Maximum severity: Mild 
R Maximum severity: Moderate 
R Maximum severity: Severe 
x At least one related TEAE 
x At least one serious TEAE 
x Subjects discontinued due to a TEAE 
x Died on study 


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Additionally, n (%) are calculated based on the number of unique subjects within each MedDRA 
category (eg, preferred term) by treatment group. A subject reporting multiple events of the 
same category will be counted only once for that category. For summary purpose, AE 
relationship to the study drug will be grouped into “Unrelated” for “unrelated” or “unlikely 
related” and “Related” for “possibly”, “probably”, or “definitely related”. For subjects with 
more than one event coded to the same PT, the subjects will be counted for the categories with 
the strongest relationship and the greatest severity. The following subject incidence tables will 
be presented. 
 
• TEAEs by PT (Preferred Term) sorted by the decreasing order of subject incidence in 
the combined group 
• TEAEs by SOC (System Organ Class) and PT sorted alphabetically 
• TEAEs by study drug-relationship by SOC and PT 
• TEAEs by severity and by SOC and PT 
• TEAE of special interest (TEAESI) by SOC and PT 
 
A subject data listing will be provided for all adverse events. Included in the listing are the 
reported term, PT, SOC, TEAE flag, study day when AE starts, duration, relationship, severity, 
action taken, outcome, and seriousness category. 
 
Separate data listings will be provided for subjects who die on study, experience SAEs, have 
TEAEs leading to study discontinuation, or AEs of special interest. 
 
AE of special interest will be extracted based on the MedDRA terms below. 
 
Table 3. Adverse Events of Special Interest 
Group MedDRA System Organ Class 
MedDRA Preferred Terms 
FALL 
Injury, poisoning and procedural complications 
Fall 
LAST 
Cardiac Disorders 
Arrhythmia 
Cardiac Disorders 
Atrial Fibrillation 
Cardiac Disorders 
Atrial Tachycardia 
Cardiac Disorders 
Atrioventricular Block 
Cardiac Disorders 
Atrioventricular Block First Degree 
Cardiac Disorders 
Bradycardia 
Cardiac Disorders 
Bundle Branch Block Left 
Cardiac Disorders 
Bundle Branch Block Right 
Cardiac Disorders 
Cardiac Arrest 
Cardiac Disorders 
Cardiac Failure Acute 
Cardiac Disorders 
Cardiac Failure Congestive 
Cardiac Disorders 
Conduction Disorder 


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Group MedDRA System Organ Class 
MedDRA Preferred Terms 
Cardiac Disorders 
Myocardial Infarction 
Cardiac Disorders 
Sinus Arrest 
Cardiac Disorders 
Sinus Arrhythmia 
Cardiac Disorders 
Sinus Bradycardia 
Cardiac Disorders 
Sinus Tachycardia 
Cardiac Disorders 
Supraventricular Tachyarrhythmia 
Cardiac Disorders 
Supraventricular Tachycardia 
Cardiac Disorders 
Tachyarrhythmia 
Cardiac Disorders 
Tachycardia 
Cardiac Disorders 
Ventricular Extrasystoles 
Cardiac Disorders 
Ventricular Tachycardia 
Nervous System 
Dizziness 
Nervous System 
Dysgeusia 
Nervous System 
Somnolence 
Nervous System 
Tremors 
 
A listing of the mapping of the system organ class and preferred terms to verbatim terms will 
be presented. 
 
10.8.2 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 at each assessment time 
point. Summaries will present both actual and change-from-baseline results. 
 
10.8.3 Interim Analysis 
After approximately 20 subjects per treatment group were randomized and treated (i.e., a total 
of 60 subjects were treated in this study), a preplanned interim analysis was conducted in 
accordance with Amendments 1 & 2 of the study protocol and the 26Sep2019 Interim Analysis 
Plan. The decision from the interim analysis was made to enroll a total of at least 140 treated 
subjects. 
 
 
11 SAMPLE SIZE CALCULATIONS 
Assuming a log-normal distribution for total opioid consumption with a 70% coefficient of 
variation (CV), 5% alpha, an equal randomization ratio, and 80% power, a total of 77 subjects 
per treatment group will be sufficient to detect a 25% reduction in total opioid consumption. 
Assuming 5% of the subjects are not evaluable and one of the two EXPAREL groups will be 
dropped after interim analysis when a total of 60 subjects are treated, a total sample size of 


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approximately 182 treated subjects is needed. This sample size will be re-evaluated after the 
interim analysis. 


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12 REFERENCES 
Newcombe, RG, Interval Estimation for the Difference between Independent Proportions: 
Comparison of Eleven Methods. Statist. Med. 17, 873-890 (1998). 
 
Nieto, FJ and J Coresh. Adjusting Survival Curves for Confounders: A Review and a New Method. 
American Journal of Epidemiology. 1996. Vol. 143, No. 10. 
 
Rubin, DB. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons. 
 
Quale, M, G Cunningham, C Foster, and J Hutchins. Addition of transversus abdominis plane 
infiltration with liposomal bupivacaine to intrathecal morphine for postoperative analgesia 
after Caesarean delivery: a retrospective study. Abstract 1497. American Society of Regional 
Anesthesia and Pain Management. 41st Annual Regional Anesthesiology and Acute Pain 
Medicine Meeting. 31-Mar-2016 to 02-Apr-2016. New Orleans, LA, US. 
 
Saville, BR, JT Connor, GD Ayers, J Alvarez. The Utility of Bayesian Predictive Probabilities for 
Interim 
Monitoring of Clinical Trials. Clinical Trials. May 2014, p485-493, Vol. 11, No. 4. 
 
Schafer, JL. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman & Hall. 


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13 TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
Please see the Protocol for the full “Time and Events Schedule of Study Procedures”. 
 
 


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14 OPIOID RELATED SYMPTOM DISTRESS SCALE (ORSDS) 
 
 


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15 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 mock-ups 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 14.2-1.1a the title in the mock-up appears as: 
Table 14.2-1.1a: Analysis of Postsurgical Total Opioid Consumption 
(OMED mg) Through 72 hours – Efficacy Analysis Set 
but should appear as follows on the final TLF: 
Table 14.2-1.1a 
Analysis of Postsurgical Total Opioid Consumption (OMED mg) through 72 
hours Efficacy Analysis Set 
 
 
The title format in the mock-ups is due to limitations of MS Word. The mock-up format enables 
MSWord to generate a table of contents for the mock-ups. 
For categorical variables, if subjects have missing values (example Race), a “missing” category 
will be added as appropriate. 
All tables will present treatment Active (for EXPAREL+50 mcg Duramorph or EXPAREL) and 150 
mcg Duramorph (SOC) as separate columns. 


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On all figures, EXPAREL+50 mcg Duramorph will be represented in red with solid lines and dots, 
EXPAREL will be represented in blue with solid lines and filled squares and 150 mcg Duramorph 
(SOC) will be represented in black with solid lines and filled diamonds. 
On all listings the treatments, in the order of appearance, are: EXPAREL+50 mcg Duramorph, 
EXPAREL, 150 mcg Duramorph (SOC)and, if applicable, NOT RANDOMIZED. Always insert a 
page break between treatments. 
On all listings sort within treatment by site, subject, with further sorts dependent on listing. 
The shell provides a general guidance for how the data will be presented. The actual 
presentation may be modified to accommodate the page size restriction. 
For TFLs with multiple pages, page numbers will be included. 
All TFLs will have SAS program names and folder names and date/time stamp in the footnote 
for tracking purpose. 


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16   LIST OF TABLES 
TABLE 14.1-1: SUMMARY OF SUBJECT DISPOSITION – ALL SCREENED SUBJECTS 
43 
TABLE 14.1-2.1: SUMMARY OF SUBJECT DEMOGRAPHICS – EFFICACY ANALYSIS SET 
45 
TABLE 14.1-2.2: SUMMARY OF SUBJECT DEMOGRAPHICS – SENSITIVITY ANALYSIS SET 
46 
TABLE 14.1-2.3: SUMMARY OF SUBJECT DEMOGRAPHICS – SAFETY ANALYSIS SET 
46 
TABLE 14.1-3.1: SUMMARY OF SUBJECT BASELINE CHARACTERISTICS – EFFICACY 
ANALYSIS SET 
47 
TABLE 14.1-3.2: SUMMARY OF SUBJECT BASELINE CHARACTERISTICS – SENSITIVITY 
ANALYSIS SET 
49 
TABLE 14.1-3.3: SUMMARY OF SUBJECT BASELINE CHARACTERISTICS – SAFETY 
ANALYSIS SET 
49 
TABLE 14.1-4.1: SUMMARY OF SUBJECT SURGICAL FEAR QUESTIONNAIRE – EFFICACY 
ANALYSIS SET 
50 
TABLE 14.1-4.2: SUMMARY OF SUBJECT SURGICAL FEAR QUESTIONNAIRE – SENSITIVITY 
ANALYSIS SET 
51 
TABLE 14.1-4.3: SUMMARY OF SUBJECT SURGICAL FEAR QUESTIONNAIRE – SAFETY 
ANALYSIS SET 
51 
TABLE 14.1-5.1: SUMMARY OF SURGERY CHARACTERISTICS – EFFICACY ANALYSIS SET 
52 
TABLE 14.1-5.2: SUMMARY OF SURGERY CHARACTERISTICS – SENSITIVITY ANALYSIS SET53 
TABLE 14.1-5.3: SUMMARY OF SURGERY CHARACTERISTICS – SAFETY ANALYSIS SET 
53 
TABLE 14.1-6.1: INCIDENCE OF INTRAOPERATIVE MEDICATIONS - EFFICACY ANALYSIS 
SET 
54 
TABLE 14.1-6.2: INCIDENCE OF INTRAOPERATIVE MEDICATIONS - SAFETY ANALYSIS SET 54 
TABLE 14.2-1.1A: ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) THROUGH 72 
HOURS – EFFICACY ANALYSIS SET 
55 
TABLE 14.2-1.1B: SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) THROUGH 72- 
EFFICACY ANALYSIS SET 
56 
TABLE 14.2-1.2A: SUBGROUP ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY AGE – EFFICACY ANALYSIS SET 
57 
TABLE 14.2-1.2B: SUBGROUP SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY AGE – EFFICACY ANALYSIS SET 
58 
TABLE 14.2-1.3A: SUBGROUP ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY RACE – EFFICACY ANALYSIS SET 
59 
TABLE 14.2-1.3B: SUBGROUP SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY RACE – EFFICACY ANALYSIS SET 
59 
TABLE 14.2-1.4A: SUBGROUP ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY BMI STATUS – EFFICACY ANALYSIS SET 
59 
TABLE 14.2-1.4B: SUBGROUP SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY BMI STATUS – EFFICACY ANALYSIS SET 
59 
TABLE 14.2-1.5A: SUBGROUP ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY NUMBER OF PRIOR C-SECTIONS – EFFICACY  
ANALYSIS SET 
59 


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TABLE 14.2-1.5B: SUBGROUP SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY NUMBER OF PRIOR C-SECTIONS – EFFICACY  
ANALYSIS SET 
59 
TABLE 14.2-1.6A: SUBGROUP ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY DISCHARGE TIME – EFFICACY ANALYSIS SET 
59 
TABLE 14.2-1.6B: SUBGROUP SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY DISCHARGE TIME – EFFICACY ANALYSIS SET 
59 
TABLE 14.2-1.7A: SUBGROUP ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY ANXIETY MEDICAL HISTORY – EFFICACY ANALYSIS 
SET 
60 
TABLE 14.2-1.7B: SUBGROUP SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) 
THROUGH 72 HOURS BY ANXIETY MEDICAL HISTORY – EFFICACY ANALYSIS 
SET 
60 
TABLE 14.2-1.8A: ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) THROUGH 72 
HOURS – 
60 
TABLE 14.2-1.8B: SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) THROUGH 72 
HOURS - 
60 
TABLE 14.2-2A: ANALYSIS OF AVERAGE ITCHING SCORES THROUGH 72 HOURS – 
EFFICACY ANALYSIS SET 
61 
TABLE 14.2-2B: SUMMARY OF AVERAGE ITCHING SCORES THROUGH 72 HOURS – 
EFFICACY ANALYSIS SET 
62 
TABLE 14.2-3.1A: ANALYSIS OF AVERAGE POSTSURGICAL ITCHING SCORES THROUGH 12,  
24 AND 48 HOURS - EFFICACY ANALYSIS SET 
63 
TABLE 14.2-3.1B: SUMMARY OF AVERAGE POSTSURGICAL ITCHING SCORES THROUGH 12, 
24 AND 48 HOURS - EFFICACY ANALYSIS SET 
64 
TABLE 14.2-3.2A: ANALYSIS OF TOTAL OPIOID CONSUMPTION (OMED MG) THROUGH 24 
AND 48 HOURS, DAY 7 (168 HOURS) AND DAY 14 (336 HOURS) - EFFICACY 
ANALYSIS SET 
65 
TABLE 14.2-3.2B: SUMMARY OF TOTAL OPIOID CONSUMPTION (OMED MG) THROUGH 24 
AND 48 HOURS, DAY 7 (168 HOURS) AND DAY 14 (336 HOURS) - EFFICACY 
ANALYSIS SET 
66 
TABLE 14.2-3.3A1: ANALYSIS OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 72 
HOURS AFTER SURGERY OR HOSPITAL DISCHARGE WHICHEVER OCCURS 
FIRST (GENERAL PAIN) - EFFICACY ANALYSIS SET 
67 
TABLE 14.2-3.3B1: SUMMARY OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 72 
HOURS AFTER SURGERY OR HOSPITAL DISCHARGE WHICHEVER OCCURS 
FIRST (GENERAL PAIN) – EFFICACY ANALYSIS SET 
68 
TABLE 14.2-3.4A1: ANALYSIS OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 24 
AND 48 (GENERAL PAIN) - EFFICACY ANALYSIS SET 
69 
TABLE 14.2-3.4B1: SUMMARY OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 24  
AND 48 (GENERAL PAIN) - EFFICACY ANALYSIS SET 
70 
TABLE 14.2-3.3A2: ANALYSIS OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 72 
HOURS AFTER SURGERY OR HOSPITAL DISCHARGE WHICHEVER OCCURS 
FIRST (PAIN AT INCISION SITE) - EFFICACY ANALYSIS SET 
71 


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TABLE 14.2-3.3B2: SUMMARY OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 72 
HOURS AFTER SURGERY OR HOSPITAL DISCHARGE WHICHEVER OCCURS 
FIRST (PAIN AT INCISION SITE) – EFFICACY ANALYSIS SET 
71 
TABLE 14.2-3.4A2: ANALYSIS OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 24 
AND 48 (PAIN AT INCISION SITE) - EFFICACY ANALYSIS SET 
71 
TABLE 14.2-3.4B2: SUMMARY OF AVERAGE VAS PAIN INTENSITY SCORES THROUGH 24  
AND 48 (PAIN AT INCISION SITE) - EFFICACY ANALYSIS SET 
71 
TABLE 14.2-3.5: ANALYSIS OF POSTSURGICAL OPIOID-FREE AND OPIOID-SPARING 
SUBJECTS THROUGH 72 HOURS - EFFICACY ANALYSIS SET 
72 
TABLE 14.2-3.6A: ANALYSIS OF OPIOID RELATED SYMPTOM DISTRESS SCALE (ORSDS) AT 
12, 24, 48 AND 72 HOURS - EFFICACY ANALYSIS SET 
73 
TABLE 14.2-3.6B: SUMMARY OF OPIOID RELATED SYMPTOM DISTRESS SCALE (ORSDS) AT 
12, 24, 48 AND 72 HOURS - EFFICACY ANALYSIS SET 
74 
TABLE 14.2-3.7A: ANALYSIS OF SUBJECTS MEETING MODIFIED POST ANESTHESIA 
DISCHARGE SCORING SYSTEM (MPADSS) CRITERIA FOR DISCHARGE 
READINESS AT 12, 24, 48 AND 72 HOURS - EFFICACY ANALYSIS SET 
75 
TABLE 14.2-3.7B: SUMMARY OF SUBJECTS MEETING MODIFIED POST ANESTHESIA 
DISCHARGE SCORING SYSTEM (MPADSS) CRITERIA FOR DISCHARGE 
READINESS AT EACH ASSESSED TIMEPOINT – EFFICACY ANALYSIS SET 
76 
TABLE 14.2-3.8: SUMMARY OF OVERALL ASSESSMENT OF SUBJECT’S SATISFACTION WITH 
PAIN CONTROL AT 72 HOURS OR HOSPITAL DISCHARGE, WHICHEVER 
OCCURS FIRST AFTER SURGERY – EFFICACY ANALYSIS SET 
77 
TABLE 14.2-3.9: SUMMARY OF RECOVERY FROM CAESAREAN SECTION SCALE AT 24, 48, 
AND 72 HOURS OR HOSPITAL DISCHARGE, WHICHEVER COMES FIRST – 
EFFICACY ANALYSIS SET 
78 
TABLE 14.2-4.1A: ANALYSIS OF TOTAL POSTSURGICAL OPIOID CONSUMPTION (MG) IN 
MORPHINE EQUIVALENTS THROUGH 72 HOURS – EFFICACY ANALYSIS SET 
81 
TABLE 14.2-4.1B: SUMMARY OF TOTAL POSTSURGICAL OPIOID CONSUMPTION (MG) IN 
MORPHINE EQUIVALENTS THROUGH 72 HOURS – EFFICACY ANALYSIS SET 
82 
TABLE 14.2-4.2: SUMMARY OF LENGTH OF HOSPITAL STAY – EFFICACY ANALYSIS SET 
83 
TABLE 14.2-4.3: SUMMARY OF NUMBER OF UNSCHEDULED PHONE CALLS OR OFFICE VISITS 
RELATED TO PAIN FROM DISCHARGE THROUGH DAY 14 – EFFICACY  
ANALYSIS SET 
84 
TABLE 14.2-4.4: SUMMARY OF NUMBER OF EMERGENCY DEPARTMENT (ED) VISITS – 
EFFICACY ANALYSIS SET 
85 
TABLE 14.2-4.5: ANALYSIS OF SUBJECTS WITH PERSISTENT OPIOID USE AT DAY 30 - 
EFFICACY ANALYSIS SET 
86 
TABLE 14.2-4.6A: ANALYSIS OF TIME SPENT IN POST-ANESTHESIA-CARE UNIT (PACU) – 
EFFICACY ANALYSIS SET 
87 
TABLE 14.2-4.6B: SUMMARY OF TIME SPENT IN POST-ANESTHESIA-CARE UNIT (PACU) – 
EFFICACY ANALYSIS SET 
88 
TABLE 14.2-4.7: ANALYSIS OF TIME TO FIRST UNASSISTED AMBULATION - EFFICACY 
ANALYSIS SET 
89 
TABLE 14.2-4.8: SUMMARY OF TIME TO FIRST BOWEL MOVEMENT - EFFICACY ANALYSIS 
SET 
90 


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TABLE 14.3-1.1: OVERVIEW OF TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) - 
SAFETY ANALYSIS SET 
91 
TABLE 14.3-1.2.1: SUMMARY OF INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) BY PREFERRED TERM - SAFETY ANALYSIS SET 
92 
TABLE 14.3-1.2.2: SUMMARY OF SUBJECT INCIDENCE OF TREATMENT-EMERGENT 
ADVERSE EVENTS (TEAES) BY SYSTEM ORGAN CLASS AND PREFERRED 
TERM - SAFETY ANALYSIS SET 
93 
TABLE 14.3-1.3: SUMMARY OF SUBJECT INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) BY SYSTEM ORGAN CLASS, PREFERRED TERM, AND WORST 
SEVERITY - SAFETY ANALYSIS SET 
94 
TABLE 14.3-1.4: SUMMARY OF SUBJECT INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS (TEAES) BY SYSTEM ORGAN CLASS, PREFERRED TERM, AND 
STRONGEST RELATIONSHIP TO STUDY DRUG - SAFETY ANALYSIS SET 
95 
TABLE 14.3-1.5: SUMMARY OF SUBJECT INCIDENCE OF TREATMENT-EMERGENT ADVERSE 
EVENTS OF SPECIAL INTEREST (TEAESI) BY PREFERRED TERM - SAFETY 
ANALYSIS SET 
96 
TABLE 14.3-2: SUMMARY OF VITAL SIGNS BY TIMEPOINT – SAFETY ANALYSIS SET 
97 
TABLE 14.3-3.1: INCIDENCE OF PRIOR MEDICATIONS – SAFETY ANALYSIS SET 
98 
TABLE 14.3-3.2: INCIDENCE OF CONCOMITANT MEDICATIONS – SAFETY ANALYSIS SET 
98 


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Table 14.1-1: Summary of Subject Disposition – All Screened Subjects 
Site: Overall 
 
 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
 
 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
 
 
EXPAREL 
(N=XX) 
n (%) 
 
 
 
Total 
(N=XX) 
n (%) 
Screened [1] 
Screen Failure 
Enrolled 
Randomized 
Not Treated 
Treated 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
TAP Infiltration Error per Ultrasound Image 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Safety Analysis Set [2]# 
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) 
Protocol 
Enrolled under Protocol Amendment2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Enrolled under Protocol 
Enrolled under Original 
Amendment1 
Protocol 
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) 
Discontinued from Study@ 
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) 
Death 
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) 
Lack of Efficacy 
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) 
Withdrawal by Subject 
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) 


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# = as treated 
@ = as randomized 
[1] Signed the informed consent form [2] Received study drug  [3] Received study drug and surgery 
Percentages for screen failure and enrolled based on number screened; others on number randomized. 
 
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 treated 
with...” if no subjects were mistreated, then omit footnote. 


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Table 14.1-2.1: 
Site: Overall 
Summary of Subject Demographics – Efficacy Analysis Set 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
EXPAREL 
(N=XX) 
n (%) 
Total 
n (%) 
n (%) 
(N=XX) 
Age (yrs) 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
Sex 
Female 
Male 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Ethnicity 
Hispanic or Latino 
Not Hispanic or Latino 
n 
n 
(%) 
(%) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
Race 
American Indian/Alaska Native 
n (%) 
Black/African American 
Asian 
White 
Native Hawaiian/Pacific 
n 
n 
n 
n 
(%) 
(%) 
(%) 
(%) 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
Islander 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 


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Note to programmer: Only categories available in the data will appear on the table. 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 mock-up also for table: 
 
 
Table 14.1-2.2: Summary of Subject Demographics – Sensitivity Analysis Set 
Table 14.1-2.3: Summary of Subject Demographics – Safety Analysis Set 


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Table 14.1-3.1: Summary of Subject Baseline Characteristics – Efficacy Analysis Set 
150 mcg 
Duramorph (SOC) 
(N=XX) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
 
EXPAREL 
(N=XX) 
 
Total 
(N=XXX) 
ASA Class 
2 – n (%) 
xx 
xx 
xx 
xx 
3 – n (%) 
xx.x 
xx.x 
xx.x 
xx.x 
4 – n (%) 
x.xx 
x.xx 
x.xx 
x.xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
 
ECG 
Interpretation 
Normal – n (%) 
xx 
xx 
xx 
xx 
Abnormal, NCS – n (%) 
xx.x 
xx.x 
xx.x 
xx.x 
Abnormal, CS – n (%) 
x.xx 
x.xx 
x.xx 
x.xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx
xx.x 
xx, xx 
 
Height (cm) 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
 
Weight (kg) 
n 
Mean 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
BMI (kg/m2) 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 


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150 mcg 
Duramorph (SOC) 
(N=XX) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
 
EXPAREL 
(N=XX) 
 
Total 
(N=XXX) 
Direct Bili 
(unit) 
n 
Mean 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
SD 
Median 
Min, Max 
x.xx 
xx.x 
xx, xx 
x.xx 
xx.x 
xx, xx 
x.xx 
xx.x 
xx, xx 
x.xx 
xx.x 
xx, xx 
GGT (unit) 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
LDH (unit) 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
ALT (unit) 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
AST (unit) 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
BUN (unit) 
n 
Mean 
SD 
xx 
xx.x 
x.xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
x.xx 


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150 mcg 
Duramorph (SOC) 
EXPAREL+50mcg 
Duramorph 
EXPAREL 
Total 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XXX) 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
CS = clinically significant. NCS = not clinically significant. 
 
 
 
Table 14.1-3.2: Summary of Subject Baseline Characteristics – Sensitivity Analysis Set 
 
 
Table 14.1-3.3: Summary of Subject Baseline Characteristics – Safety Analysis Set 


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Table 14.1-4.1: Summary of Subject Surgical Fear Questionnaire – Efficacy Analysis Set 
150 mcg 
Duramorph (SOC) 
(N=XX) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
 
EXPAREL 
(N=XX) 
 
Total 
(N=XXX) 
1. I am afraid 
operation 
of 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
 
2. I am afraid 
anesthesia 
of the 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
 
3. I am afraid of the 
after the operation 
 
 
 
 
 
4. I am afraid of the 
xx 
xx 
xx 
unpleasant side effects 
(like nausea) after the 
operation 
n 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
5. I am afraid my health 
will deteriorate because 
of the operation 
n 
xx 
xx 
xx 
xx 
pain 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 


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Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
6. I am afraid the 
xx 
xx 
xx 
operation will fail 
n 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
8. I am afraid of the long 
duration of the 
xx 
xx 
xx 
rehabilitation after the 
operation 
n 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
0 = not at all afraid, 10 = very afraid. 
 
 
 
Table 14.1-4.2: Summary of Subject Surgical Fear Questionnaire – Sensitivity Analysis Set 
 
 
Table 14.1-4.3: Summary of Subject Surgical Fear Questionnaire – Safety Analysis Set 


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Table 14.1-5.1: Summary of Surgery Characteristics – Efficacy Analysis Set 
150 mcg 
Duramorph 
(SOC) (N=XX) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
EXPAREL 
(N=XX) 
n (%) 
Total 
 
Characteristic 
Statistic 
n (%) 
n (%) 
(N=XX) 
Duration of Surgery (hours) 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx 
xx, xx 
xx 
xx.x 
x.xx 
xx 
xx, xx 
xx 
xx.x 
x.xx 
xx 
xx, xx 
xx 
xx.x 
x.xx 
xx 
xx, xx 
Type of Anesthesia 
General 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Spinal 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Other 
N (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Intraoperative Med Used 
No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
CSE Anesthesia Performed 
No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Epidural Component of CSE 
No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Note, epidural component question is a follow up when CSE answer is Yes. 


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Use this mock-up also for tables: 
 
 
 
Table 14.1-5.2: Summary of Surgery Characteristics – Sensitivity Analysis Set 
Table 14.1-5.3: Summary of Surgery Characteristics – Safety Analysis Set 


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Table 14.1-6.1: Incidence of Intraoperative Medications - Efficacy Analysis Set 
Anatomical Therapeutic 
Preferred Name 
Class (ATC) 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
Subjects 
taking 
at 
least 
one 
medication 
ATC1 
PN1.1 
PN1.2 
ATC2 
PN2.1 
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) 
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) 
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) 
xx (xx.x) 
xx (xx.x) 
ETC. 
 
 
Medications are coded using World Health Organization Drug Dictionary (WHODD September 2018). 
Sorted by descending total incidence by ATC and preferred name within ATC. 
Intraoperative 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. 
 
 
 
Table 14.1-6.2: Incidence of Intraoperative Medications - Safety Analysis Set 
T 


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Protocol: 402-C-414 
 
 
Table 14.2-1.1a: Analysis of Total Opioid Consumption (OMED mg) Through 72 hours – Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
LS Mean [1] 
Standard Error of LS Mean [1] 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
% Reduction [2] 
LSM Treatment Difference [1][3] 
xxx.x 
xxx.x 
xx.x 
xx.x 
95% Confidence Interval [1][3] 
P-value, 1-sided [1][3] 
(xx.x, xx.x) 
0.xxx 
(xx.x, xx.x) 
0.xxx 
LS = Least Square; LSM2 = LS Means in SOC group; LSM1 = LS Means in Active group. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height on total opioid 
consumption. 
Subjects without any opioid use are assigned a value of 0 mg for summaries. 
[2] % Reduction in Total Opioid Dose is calculated as (LSM2-LSM1)/LSM2*100%. 
[3] Test of Ha: LSM (Active) < LSM (SOC). 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Table 14.2-1.1b: Summary of Total Opioid Consumption (OMED mg) Through 72- Efficacy Analysis Set 
 
 
 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
n 
xx 
xx 
xx 
GeoMean 
xx.x 
xx.x 
xx.x 
CV% 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
GeoMean = Geometric mean. CV% = Coefficient of variation (%). 


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Table 14.2-1.2a: Subgroup Analysis of Total Opioid Consumption (OMED mg) Through 72 hours by Age – Efficacy 
Analysis Set 
 
 
 
 
 
Age 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
<35 years 
LS Mean [1] 
xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
xxx.xx 
% Reduction [2] 
LSM Treatment Difference [1][3] 
95% Confidence Interval [1][3] 
P-value, 1-sided [1][3] 
xxx.x 
xx.x 
(xx.x, xx.x) 
0.xxx 
xxx.x 
xx.x 
(xx.x, xx.x) 
0.xxx 
 
>= 35 years 
LS Mean [1] 
xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
xxx.xx 
% Reduction [2] 
xxx.x 
xxx.x 
LSM Treatment Difference [1][3] 
xx.x 
xx.x 
95% Confidence Interval [1][3] 
(xx.x, xx.x) 
(xx.x, xx.x) 
P-value, 1-sided [1][3] 
 
0.xxx 
 
0.xxx 
 
 
LS = Least Square; LSM2 = LS Means in SOC group; LSM1 = LS Means in Active group. 
[1] From an ANCOVA with main effects of treatment and covariates of age and height on total opioid 
consumption. 
Subjects without any opioid use are assigned a value of 0 mg for summaries. 
[2] % Reduction in Total Opioid Dose is calculated as (LSM2-LSM1)/LSM2*100%. 
[3] Test Ha: LSM (Active) < LSM (SOC). 


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Table 14.2-1.2b: Subgroup Summary of Total Opioid Consumption (OMED mg) Through 72 hours by Age – Efficacy 
Analysis Set 
 
Age 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
<35 years 
N 
GeoMean 
CV% 
Median 
Min, Max 
xx 
xxx.x 
xxx.xx 
xxx.x 
xx, xx 
xx 
xxx.x 
xxx.xx 
xxx.x 
xx, xx 
xx 
xxx.x 
xxx.xx 
xxx.x 
xx, xx 
>= 35 years 
N 
GeoMean 
CV% 
Median 
xx 
xxx.x 
xxx.xx 
xxx.x 
xx 
xxx.x 
xxx.xx 
xxx.x 
xx 
xxx.x 
xxx.xx 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
GeoMean = Geometric mean. CV% = Coefficient of variation (%). 


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Use Table 14.2-1.3a and 1.3b shell for (see SAP Section 9.7.2.1.2 for subgroup categories) 
 
Table 14.2-1.3a: Subgroup Analysis of Total Opioid Consumption (OMED mg) Through 72 hours by Race – 
Efficacy Analysis Set 
 
 
Table 14.2-1.3b: Subgroup Summary of Total Opioid Consumption (OMED mg) Through 72 hours by Race – Efficacy 
Analysis Set 
 
 
Table 14.2-1.4a: Subgroup Analysis of Total Opioid Consumption (OMED mg) Through 72 hours by BMI Status – 
Efficacy Analysis Set 
 
 
Table 14.2-1.4b: Subgroup Summary of Total Opioid Consumption (OMED mg) Through 72 hours by BMI Status – 
Efficacy Analysis Set 
 
 
Table 14.2-1.5a: Subgroup Analysis of Total Opioid Consumption (OMED mg) Through 72 hours by Number of 
Prior C-Sections – Efficacy Analysis Set 
 
 
Table 14.2-1.5b: Subgroup Summary of Total Opioid Consumption (OMED mg) Through 72 hours by Number of Prior 
C-Sections – Efficacy Analysis Set 
 
 
Table 14.2-1.6a: Subgroup Analysis of Total Opioid Consumption (OMED mg) Through 72 hours by Discharge Time 
– Efficacy Analysis Set 
 
 
Table 14.2-1.6b: Subgroup Summary of Total Opioid Consumption (OMED mg) Through 72 hours by Discharge Time 
– Efficacy Analysis Set 


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Table 14.2-1.7a: Subgroup Analysis of Total Opioid Consumption (OMED mg) Through 72 hours by Anxiety 
Medical History – Efficacy Analysis Set 
 
 
Table 14.2-1.7b: Subgroup Summary of Total Opioid Consumption (OMED mg) Through 72 Hours by Anxiety Medical 
History – Efficacy Analysis Set 
 
 
 
Table 14.2-1.8a: Analysis of Total Opioid Consumption (OMED mg) Through 72 hours – Sensitivity Analysis Set 
 
 
Table 14.2-1.8b: Summary of Total Opioid Consumption (OMED mg) Through 72 Hours - Sensitivity Analysis Set 


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Table 14.2-2a: Analysis of Average Itching Scores Through 72 hours – Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
LS Mean [1] 
xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1][2] 
95% Confidence Interval [1][2] 
P-value, 1-sided [1][2] 
xx.x 
(xx.x, xx.x) 
0.xxx 
xx.x 
(xx.x, xx.x) 
0.xxx 
[1] From the Mixed Models. 
[2] Test of Ha: LSM (Active) < LSM (150 mcg Duramorph (SOC)). 


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Table 14.2-2b: Summary of Average Itching Scores Through 72 hours – Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
Median 
xx.xx 
xx 
xx.xx 
xx 
xx.xx 
xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 


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Protocol: 402-C-414 
Table 14.2-3.1a: Analysis of Average Postsurgical Itching Scores Through 12, 24 and 48 Hours - Efficacy 
Analysis Set 
 
 
 
 
 
Timepoint 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
12 hours 
LS Mean [1] 
Standard Error of LS Mean 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
LSM Treatment Difference [1] 
95% Confidence Interval 
P-value, 1-sided [2] 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx.x 
(xx.x, xx.x) 
0.xxxx 
 
24 hours 
 
 
48 hours 
 
 
 
 
[1] From the MMRM with age, height, treatment, site, timepoint and treatment-by-timepoint as factors and 
subjects as repeated measure unit over timepoints. 
[2] Test of Ha: LSM (Active) < LSM (150 mcg Duramorph [SOC]). 


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Protocol: 402-C-414 
Table 14.2-3.1b: Summary of Average Postsurgical Itching Scores Through 12, 24 and 48 hours - Efficacy 
Analysis Set 
 
 
 
Timepoint 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
12 hours 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
Median 
xx.xx 
xx 
xx.xx 
xx 
xx.xx 
xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
24 hours 
 
 
48 hours 
 
 
 
 
 


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Protocol: 402-C-411 
Table 14.2-3.2a: Analysis of Total Opioid Consumption (OMED mg) Through 24 and 48 hours, Day 7 (168 hours) 
and Day 14 (336 hours) - Efficacy Analysis Set 
 
 
 
 
 
Statistic 
 
 
24 hrs 
LS Mean [1] 
Standard 
% Reduction [2] 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1][3] 
xx.x 
xx.x 
95% Confidence Interval [1][3] 
(xx.x, xx.x) 
(xx.x, xx.x) 
P-value, 1-sided [1][3] 
 
0.xxx 
 
0.xxx 
 
48 hrs 
LS Mean [1] 
xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
xxx.xx 
% Reduction [2] 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1][3] 
xx.x 
xx.x 
95% Confidence Interval [1][3] 
(xx.x, xx.x) 
(xx.x, xx.x) 
P-value, 1-sided [1][3] 
 
0.xxx 
 
0.xxx 
 
. . . 
 
 
LS = Least Square; LSM2 = LS Means in IR Bupivacaine group; LSM1 = LS Means in EXPAREL 266 mg group. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height on total opioid 
consumption. 
Subjects without any opioid use are assigned a value of 0 mg for summaries. 
[2] % Reduction in Total Opioid Dose is calculated as (LSM2-LSM1)/LSM2*100%. 
[3] Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 
 
 
Note to programmer: Time periods to appear on this table, in order, are 0-24 hrs, 0-48 hrs, Day 7 (168 
hours) and Day 14 (336 hours). Do not split a time period statistics across pages. 
150 mcg 
EXPAREL+50mcg 
EXPAREL 
Duramorph (SOC) 
Duramorph 
(N=XX) 
(N=XX) 
(N=XX) 
n (%) 
n (%) 
n (%) 
Error of LS Mean [1] 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 


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Table 14.2-3.2b: Summary of Total Opioid Consumption (OMED mg) Through 24 and 48 hours, Day 7 (168 hours) 
 
and Day 14 (336 hours) - Efficacy Analysis Set 
150 mcg Duramorph 
EXPAREL+50mcg 
Duramorph 
EXPAREL 
(N=XX) 
Time Interval 
Statistic 
(SOC) (N=XX) 
n (%) 
(N=XX) 
n (%) 
n (%) 
24 hrs 
n 
xx 
xx 
xx 
GeoMean 
xxx.x 
xxx.x 
xxx.x 
CV% 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
48 hrs 
n 
xx 
xx 
xx 
GeoMean 
xxx.x 
xxx.x 
xxx.x 
CV% 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
. . . 
 
 
GeoMean = Geometric mean. CV% = Coefficient of variation (%). 
 
 
 
 
Note to programmer: Time periods to appear on this table, in order, are 0-24 hrs, 0-48 hrs, Day 7 (168 
hours) and Day 14 (336 hours). Do not split a time period statistics across pages. 


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Table 14.2-3.3a1: Analysis of Average VAS Pain Intensity Scores Through 72 Hours After Surgery or Hospital 
Discharge Whichever Occurs First (General Pain) - Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mc 
g Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
 
LS Mean [1] 
 xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
xx.x 
xx.x 
95% Confidence Interval [2] 
(xx.x, xx.x) 
(xx.x, xx.x) 
Noninferiority Test P-value, 1-sided 
 
0.xxx 
 
0.xxx 
Superiority Test P-value, 1-sided 
 
LS = Least Squares; 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height. 
[2] The non-inferiority of Active to 150 mcg Duramorph (SOC)is demonstrated if the upper limit is <=0.5. 
The superiority is demonstrated if the upper limit is <0. 
 
 
Programming 
note: if Superiority 
test fails, ie, p>0.05, then keep non-inferiority 
test and remove 
superiority test. Otherwise, remove non-inferiority test and keep superiority test. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
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(Page X of Y) 
Protocol: 402-C-414 
Table 14.2-3.3b1: Summary of Average VAS Pain Intensity Scores Through 72 Hours After Surgery or Hospital 
Discharge Whichever Occurs First (General Pain) – Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
Median 
xx.xx 
xx 
xx.xx 
xx 
xx.xx 
xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 


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Protocol: 402-C-414 
Table 14.2-3.4a1: Analysis of Average VAS Pain Intensity Scores Through 24 And 48 (General Pain) - Efficacy 
Analysis Set - Multiple Imputation Results 
 
 
 
 
 
Timepoint 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
 
24 hours 
LS Mean [1] 
xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
xx.x 
xx.x 
95% Confidence Interval [2] 
(xx.x, xx.x) 
(xx.x, xx.x) 
Noninferiority Test P-value, 1-sided 
 
0.xxx 
 
0.xxx 
Superiority Test P-value, 1-sided 
 
0.xxx 
 
0.xxx 
 
48 hours 
LS Mean [1] 
xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
95% Confidence Interval [2] 
Noninferiority Test P-value, 1-sided 
xx.x 
(xx.x, xx.x) 
0.xxx 
xx.x 
(xx.x, xx.x) 
0.xxx 
Superiority Test P-value, 1-sided 
0.xxx 
0.xxx 
 
 
LS = Least Squares; 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height. 
[2] The non-inferiority of Active to 150 mcg Duramorph (SOC) is demonstrated if the upper limit is <=0.5. 
The superiority is demonstrated if the upper limit is <0. 
 
 
Programming 
note: if Superiority 
test fails, ie, p>0.05, then keep non-inferiority 
test and remove 
superiority test. Otherwise, remove non-inferiority test and keep superiority test. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Table 14.2-3.4b1: Summary of Average VAS Pain Intensity Scores Through 24 and 48 (General Pain) - Efficacy 
Analysis Set 
 
 
 
Timepoint 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
24  hours 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
Median 
xx.xx 
xx 
xx.xx 
xx 
xx.xx 
xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
48 hours 
 
 
 
 
 


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Table 14.2-3.3a2: Analysis of Average VAS Pain Intensity Scores Through 72 Hours After Surgery or Hospital 
Discharge Whichever Occurs First (Pain at Incision Site) - Efficacy Analysis Set 
 
 
 
Table 14.2-3.3b2: Summary of Average VAS Pain Intensity Scores Through 72 Hours After Surgery or Hospital 
Discharge Whichever Occurs First (Pain at Incision Site) – Efficacy Analysis Set 
 
 
 
Table 14.2-3.4a2: Analysis of Average VAS Pain Intensity Scores Through 24 And 48 (Pain at Incision Site) - 
Efficacy Analysis Set - Multiple Imputation Results 
 
 
Table 14.2-3.4b2: Summary of Average VAS Pain Intensity Scores Through 24 and 48 (Pain at Incision Site) - 
Efficacy Analysis Set 


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Table 14.2-3.5: Analysis of Postsurgical Opioid-Free and Opioid-Sparing Subjects Through 72 hours - 
Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
Opioid-free 
No Opioid-Free Percentage [1] 
Opioid-Free Percentage 
(%) 
(%) 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
Opioid-sparing 
Odds Ratio [2] 
 
 xx.x 
 
 
xx.x 
95% CI for Odds Ratio 
(xx.x, xx.x) 
(xx.x, xx.x) 
P-value, 1-sided [3] 
 
0.xxxx 
 
0.xxxx 
No Opioid-sparing  Percentage [1] 
(%) 
xx.x 
xx.x 
xx.x 
Opioid-sparing Percentage 
(%) 
xx.x 
xx.x 
xx.x 
 
Odds Ratio [2] 
 
 xx.x 
 
 xx.x 
95% CI for Odds Ratio 
(xx.x, xx.x) 
(xx.x, xx.x) 
P-value, 1-sided [3] 
 
0.xxxx 
 
0.xxxx 
P-value, 1-sided [3] 
0.xxxx 
0.xxxx 
 
 
[1] LS Means probability from the logistic regression with treatment, site, age, and height as explanatory 
variables. 
[2] OR of Active over SOC. 
[3] Test of Ha: Odds Ratio >1. 


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Table 14.2-3.6a: Analysis of Opioid Related Symptom Distress Scale (ORSDS) at 12, 24, 48 and 72 hours - 
Efficacy Analysis Set 
 
Composite Score 
 
 
 
Timepoint 
Statistic 
 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
 
EXPAREL 
(N=XX) 
n (%) 
12 hours 
LS Mean [1] 
Standard Error of LS Mean 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
LSM Treatment Difference [1] 
95% Confidence Interval 
P-value, 1-sided [2] 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx.x 
(xx.x, xx.x) 
0.xxxx 
 
24 hours 
 
 
48 hours 
 
72 hours 
 
 
[1] From a Mixed Models with main effects of treatment visit and treatment by visit as covariates. 
[2] Test of Ha: LSM (Active) < LSM (SOC). For Question 7 score, Test of Ha: LSM (Active) > LSM (SOC). 
 
 
Note to programmer: Timepoints to appear on this table, in order, are 24, 48 and 72 hours. 
 
First page is Composite Score, followed by Fatigue Score, Drowsiness Score, Inability to Concentration 
Score, Nausea Score, Constipation Score, Itching …, Difficult with Urination Score, Confusion Score, and 
Retching/Vomiting Score. 
 
Each symptom score is the average of frequency, severity, and botherness dimension scores. 
 
Do not split a question’s statistics across pages. 


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Table 14.2-3.6b: Summary of Opioid Related Symptom Distress Scale (ORSDS) at 12, 24, 48 and 72 hours - 
Efficacy Analysis Set 
 
Composite Score 
Timepoint 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
24 hours 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
Median 
xx 
xx 
xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
48 hours 
 
 
72  hours 
 
 
 
 
Repeat for symptom scores 


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Table 14.2-3.7a: Analysis of Subjects Meeting Modified Post Anesthesia Discharge Scoring System (MPADSS) 
Criteria for Discharge Readiness at 12, 24, 48 and 72 hours - Efficacy Analysis Set 
Time Point 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
24 
Odds Ratio [3] 
95% CI for Odds Ratio 
P-value, 1-sided [4] 
xx.xx 
xx.xxx 
0.xxxx 
xx.xx 
xx.xxx 
0.xxxx 
Etc. 
Odds Ratio 
95% CI for Odds Ratio 
P-value, 1-sided 
xx.xx 
xx.xxx 
0.xxxx 
xx.xx 
xx.xxx 
0.xxxx 
 
 
 
 
 
 
 
[1] Discharge-ready criterion is the MPADSS total score ≥9. Subjects who did not have assessment are 
considered “not ready”. 
[2] LS Means probability from the logistic regression with treatment, site, age, and height as explanatory 
variables. 
[3] Ratio of Active over SOC in the odds of having 0 phone call. 
[4] Test of Ha: Odds Ratio >1 
 
 
 
Note to programmer: Repeat for all valid Time periods for which data is available. 
Do not split a time 
period statistics across pages. 


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Table 14.2-3.7b: Summary of Subjects Meeting Modified Post Anesthesia Discharge Scoring System (MPADSS) 
Criteria for Discharge Readiness at Each Assessed Timepoint – Efficacy Analysis Set 
 
Time Point 
 
 
 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
24 
Criterion Met [1] (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Criterion not Met (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
Criterion Met (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Criterion not Met (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
[1] Discharge-ready criterion is the MPADSS total score ≥9. Subjects who did not have assessment are 
considered “not ready”. 
 
 
 
 
Note to programmer: Repeat for all valid Time periods for which data is available. 
Do not split a time 
period statistics across pages. 


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Table 14.2-3.8: Summary of Overall Assessment of Subject’s Satisfaction with Pain Control at 72 hours or 
Hospital Discharge, Whichever Occurs First After Surgery – Efficacy Analysis Set 
 
 
 
 
 
Score 
Statistic 
150 mcg 
Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
Summary 
n 
Mean 
SD 
Median 
xx 
xx.x 
x.xx 
xx.x 
xx 
xx.x 
x.xx 
xx.x 
xx 
xx.x 
x.xx 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
P-value, 2-sided[1] 
0.xxxx 
0.xxxx 
Score 
1: Extremely dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
2: Dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
3: Neither satisfied nor dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4: Satisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
5: Extremely Satisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
[1] P-value from CMH test performed using the “scores=modridit” option with site as stratification 
 
 
Note to programmer: include all subjects at 72 hours after surgery (or at hospital discharge if earlier 
than 72 hours). 


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Table 14.2-3.9: Summary of Recovery from Caesarean Section Scale at 24, 48, and 72 Hours or Hospital 
Discharge, Whichever Comes First – Efficacy Analysis Set 
150 mcg 
Duramorph 
(SOC) (N=XX) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
EXPAREL 
(N=XX) 
n (%) 
 
Question 
Statistic 
n (%) 
n (%) 
1. I recovered quickly from my cesarean n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
 
2. I was able to get out of 
after my cesarean 
bed soon 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
 
3. My mobility was seriously affected 
xx 
xx 
by the cesarean 
n 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx.x 
xx, xx 
xx.x 
xx, xx 
xx.x 
xx, xx 
 
 
4. The cesarean interfered with my 
xx 
xx 
ability to care for my baby 
n 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
5. The cesarean 
 
prevented me from 
Min, Max 
n 
xx, xx 
xx 
xx, xx 
xx 
xx, xx 
xx 


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150 mcg 
Duramorph 
(SOC) (N=XX) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
EXPAREL 
(N=XX) 
n (%) 
Question 
Statistic 
n (%) 
n (%) 
feeding my baby 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
6. I was able to change my baby soon 
after the cesarean 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
7. I was able to care for my own 
hygiene needs soon after surgery 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
8. The pain from the surgery prevented 
me from doing what I wanted 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
I was tired for a long time after 
surgery 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 


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Question 
Statistic 
150 mcg 
Duramorph 
(SOC) (N=XX) 
n (%) 
 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
 
EXPAREL 
(N=XX) 
n (%) 
 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
0 = strongly disagree and 7 = strongly agree. 


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Table 14.2-4.1a: Analysis of Total Postsurgical Opioid Consumption (mg) in Morphine Equivalents Through 72 
hours – Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mc 
g Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
LS Mean [1] 
xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
95% Confidence Interval [2] 
Noninferiority Test P-value, 1-sided 
xx.x 
(xx.x, xx.x) 
0.xxx 
xx.x 
(xx.x, xx.x) 
0.xxx 
Superiority Test P-value, 1-sided 
 
 
 
LS = Least Square; 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height. 
[2] The non-inferiority of Active to 150 mcg Duramorph (SOC)is demonstrated if the upper limit on logarithm 
scale is <=0.8. The superiority is demonstrated if the upper limit is <0. 
 
 
Programming 
note: if Superiority 
test fails, ie, p>0.05, then keep non-inferiority 
test and remove 
superiority test. Otherwise, remove non-inferiority test and keep superiority test. 


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Table 14.2-4.1b: Summary of Total Postsurgical Opioid Consumption (mg) in Morphine Equivalents Through 72 
hours – Efficacy Analysis Set 
 
 
 
 
 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
n 
xx 
xx 
xx 
GeoMean 
xx.x 
xx.x 
xx.x 
CV% 
Median 
xx.xx 
xx 
xx.xx 
xx 
xx.xx 
xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
GeoMean = Geometric mean. CV% = Coefficient of variation (%). 


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Table 14.2-4.2: Summary of Length of Hospital Stay – Efficacy Analysis Set 
 
 
 
Statistic 
150 mcg Duramorph 
(SOC) 
(N=XX) 
n (%) 
EXPAREL+ 
50mcg Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
 
N 
xx 
xx 
xx 
Mean 
xxx.x 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 


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Table 14.2-4.3: Summary of Number of Unscheduled Phone Calls or Office Visits Related to Pain from 
Discharge Through Day 14 – Efficacy Analysis Set 
 
 
Statistic 
150 mcg Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
 
N 
xx 
xx 
xx 
Mean 
xxx.x 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 


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Table 14.2-4.4: Summary of Number of Emergency Department (ED) Visits – Efficacy Analysis Set 
 
 
Statistic 
150 mcg Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
 
N 
xx 
xx 
xx 
Mean 
xxx.x 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 


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Table 14.2-4.5: Analysis of Subjects with Persistent Opioid Use at Day 30 - Efficacy Analysis Set 
150 mcg Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
No 
xx.x 
xx.x 
xx.x 
Yes 
xx.x 
xx.x 
xx.x 
Note, persistent opioid use is defined for subjects who answered Yes to the question of opioid use at 
Day 30. 


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Table 14.2-4.6a: Analysis of Time Spent in Post-Anesthesia-Care Unit (PACU) – Efficacy Analysis Set 
 
 
 
Statistic 
 
150 mcg Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
 
LS Mean [1] 
 xxx.x 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1][2] 
xx.x 
xx.x 
95% Confidence Interval [1][2] 
(xx.x, xx.x) 
(xx.x, xx.x) 
P-value, 1-sided [1][2] 
 
0.xxxx 
 
0.xxxx 
 
 
 
[1] From the gamma (or normal) distribution and log link function and main effects of treatment and site 
and covariates of age and height on time spent in PACU. 
[2] Test of Ha: LSM (Active) < LSM (150 mcg Duramorph (SOC)). 


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Table 14.2-4.6b: Summary of Time Spent in Post-Anesthesia-Care Unit (PACU) – Efficacy Analysis Set 
 
 
Statistic 
150 mcg Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
 
N 
xx 
xx 
xx 
Mean 
xxx.x 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 


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* indicates censored observation. 
[1] Estimates from the Kaplan-Meier 
[2] P-value for the Active to SOC 
CI = confidence interval 
survival curve. 
comparison using the Cox regression model with treatment and site as 
factors and age and height as covariates. 
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 Table 14.2-4.7: Analysis of Time to First Unassisted Ambulation - Efficacy Analysis Set  
 
 
 
 
 
0-72 hours 
Number of Subjects with 
 
 
Statistic 
150 mcg Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph (N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
Ambulation (observed) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
No Ambulation (censored) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Time to Ambulation 
Quartiles [1] 
First (25% Ambulated) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
Median (50% Ambulated) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
Third (75% 
 
Minimum 
Maximum 
 
Log-rank p-value, 2-sided 
 
Cox regression Hazard Ratio[2] 
Estimate 
xx.xx 
xx.xx 
xx.xx 
P-value, 2-sided 
(95% CI) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
0.xxxx 
(xx.xx, xx.xx) 
0.xxxx 
Ambulated) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
Observed 
xx.xx 
xx.xx 
xx.xx 
Observed 
xx.xx* 
xx.xx* 
xx.xx 


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* indicates censored observation. 
[1] Estimates from the Kaplan-Meier 
[2] P-value for the Active to SOC 
CI = confidence interval 
survival curve. 
comparison using the Cox regression model with treatment and site as 
factors and age and height as covariates. 
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 Table 14.2-4.8: Summary of Time to First Bowel Movement - Efficacy Analysis Set  
 
 
 
 
 
0-72 hours 
Number of Subjects with 
 
 
Statistic 
150 mcg Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph (N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
 
Bowel Movement (observed) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
No Bowel Movement (censored) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Time to Bowel Movement 
Quartiles [1] 
First (25% Bowel Movement) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
Median (50% Bowel Movement) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
 
 
M 
M 
 
 
 
Cox regression Hazard Ratio[2] 
Estimate 
xx.xx 
xx.xx 
xx.xx 
P-value, 2-sided 
(95% CI) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
0.xxxx 
(xx.xx, xx.xx) 
0.xxxx 
Third (75% Bowel Movement) 
Estimate 
xx.xx 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
inimum 
Observed 
xx.xx 
xx.xx 
xx.xx 
aximum 
Observed 
xx.xx* 
xx.xx* 
xx.xx 
Log-rank p-value, 2-sided 


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Table 14.3-1.1: Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
 
 
 
Number of 
150 mcg 
Duramorph (SOC) 
(N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
 
 
Subjects with Any TEAE 
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) 
Maximum Severity of Moderate 
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) 
 
At Least One Related 
 
At Least One Serious 
 
Subjects Discontinued due 
 
Died on Study 
 
 
 
 
Note to programmer: All categories on this table should appear, even if not present in the data. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
to TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Table 14.3-1.2.1: Summary 
Safety Analysis Set 
of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Preferred Term - 
Preferred Term 
150 mcg 
Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
Total 
(N=XX) 
(N=XX) 
n (%) 
n (%) 
Subjects with ≥1 TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PT1 
PT2 
PT3 
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) 
xx (xx.x) 
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 v21.1). 
Sorted by descending order of Total incidence. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 


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Table 14.3-1.2.2: Summary of Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ 
Class and Preferred Term - Safety Analysis Set 
 
 
System Organ Class 
Preferred Term 
150 mcg 
Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
 
 
Subjects 
 
SOC1 
PT1.1 
PT1.2 
 
SOC2 
PT2.1 
PT2.2 
 
ETC. 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA v21.1). 
Sorted by system organ class and preferred term in alphabetical order. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
with ≥1 TEAE 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(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) 
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) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Table 14.3-1.3: Summary of Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ 
 
Class, Preferred Term, and Worst Severity - Safety Analysis Set 
150 mcg Duramorph 
EXPAREL+50mcg 
Duramorph 
EXPAREL 
(N=XX) 
Total 
(N=XX) 
System Organ Class 
Preferred Term 
Worst 
Severity 
(SOC) (N=XX) 
n (%) 
(N=XX) 
n (%) 
n (%) 
n (%) 
Subjects with ≥1 TEAE 
Mild 
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) 
Severe 
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) 
Moderate 
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) 
PT1.1 
Mild 
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) 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PT1.2 
Mild 
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) 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
... 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA v21.1). 
Sorted by descending order of Total incidence by system organ class and preferred term. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 


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Table 14.3-1.4: Summary of Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ 
Class, Preferred Term, and Strongest Relationship to Study Drug - Safety Analysis Set 
System Organ Class 
Preferred Term 
Strongest 
Relation 
150 mcg 
Duramorph 
(N=XX) 
n (%) 
(SOC) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
Subjects with ≥1 TEAE 
Not 
Related 
Related 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
SOC1 
Not 
Related 
Related 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
PT1.1 
Not 
Related 
Related 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA v21.1). 
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. 
“Related” is “possible”, “probable”, or “definite” and “Not Related” is “unlikely” or “unrelated” by the 
investigator’s assessment. 


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Table 14.3-1.5: Summary of Subject Incidence of Treatment-Emergent Adverse Events of Special Interest 
(TEAESI) by Preferred Term - Safety Analysis Set 
150 mcg 
Duramorph 
(SOC) 
 
 
EXPAREL+50mcg 
Duramorph 
 
EXPAREL 
(N=XX) 
n (%) 
 
Total 
(N=XX) 
n (%) 
Group 
Preferred Term 
(N=XX) 
n (%) 
(N=XX) 
n (%) 
Subjects with ≥1 TEAESI 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
FALL 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Cardiac TEAESI 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Angina 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Myocardial infarction 
... 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Neurologic TEAESI 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Tinnitus 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Perioral numbness 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
... 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA 21.1). 
Sorted by system organ class and preferred term in alphabetical order. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
 
 
 
Note to programmer: see SAP the list of AESI 


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 Table 14.3-2: Summary of Vital Signs by Timepoint – Safety Analysis Set  
 
Heart Rate (bpm) 
 
 
 
Timepoint 
Value 
Statistic 
150 mcg 
Duramorph 
(SOC) (N=XX) 
n (%) 
EXPAREL+50mcg 
Duramorph 
(N=XX) 
n (%) 
EXPAREL 
(N=XX) 
n (%) 
Total 
(N=XXX) 
Baseline 
Actual 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx.x 
xx, xx 
 
OR 
Baseline 
[1] 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx.x 
xx, xx 
 
Actual 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx.x 
xx, xx 
 
Change 
n 
xx 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
x.xx 
Median 
Min, Max 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx, 
xx.x 
xx 
xx.x 
xx, xx 
[1] Baseline (prior to surgery) for subjects with data at the timepoint. 


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Note to programmer: Vital signs are ‘Resting Heart Rate (bpm)’, ‘Systolic Blood Pressure (mmHg)’ and 
‘Diastolic Blood Pressure (mmHg)’. Timepoints to appear on this table are, in order of appearance, Baseline 
(prior to surgery), OR, PACU and Discharge. Do not split timepoint statistics across pages. 
 
Note to programmer: Use mock-up 14.1-6.1 for tables: 
 
Table 14.3-3.1: Incidence of Prior Medications – Safety Analysis Set. 
 
On this table change the footnote ‘Intraoperative medications are those indicated as such by the 
investigator’ to read ‘Prior medications are those stopped before start of study drug administration.’ 
 
Table 14.3-3.2: Incidence of Concomitant Medications – Safety Analysis Set. 
 
On this table change the footnote ‘Intraoperative medications are those indicated as such by the 
investigator’ to read ‘Concomitant medications are those taken after the start of study drug administration 
and are not designated intraoperative medications.’ 


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17  LIST OF LISTINGS 
LISTING 16.2-1: SUBJECT DISPOSITION – ALL RANDOMIZED SUBJECTS 
101 
LISTING 16.2-2: RANDOMIZATION AND ANALYSIS SETS – ALL RANDOMIZED SUBJECTS 
102 
LISTING 16.2-3: INCLUSION/EXCLUSION CRITERIA – FAILURES – ALL RANDOMIZED 
SUBJECTS 
103 
LISTING 16.2-4: DEMOGRAPHICS – ALL RANDOMIZED SUBJECTS 
104 
LISTING 16.2-5: HEIGHT AND WEIGHT – ALL RANDOMIZED SUBJECTS 
105 
LISTING 16.2-6: SURGERY – ALL RANDOMIZED SUBJECTS 
106 
LISTING 16.2-7: VISUAL ANALOG SCALE (VAS) – ALL RANDOMIZED SUBJECTS 
107 
LISTING 16.2-8.1: POSTSURGICAL TOTAL OPIOID DOSE (OMED MG) AND OPIOID-FREE 
STATUS – ALL RANDOMIZED SUBJECTS 
108 
LISTING 16.2-8.2: POSTSURGICAL OPIOID DOSING – ALL RANDOMIZED SUBJECTS 
109 
LISTING 16.2-9: PRESCRIPTION DAILY PAIN MEDICATION – ALL RANDOMIZED SUBJECTS110 
LISTING 16.2-10: RESCUE MEDIATION – ALL RANDOMIZED SUBJECTS 
111 
LISTING 16.2-11: OPIOID RELATED SYMPTOM DISTRESS SCALE (ORSDS) – ALL  
RANDOMIZED SUBJECTS 
112 
LISTING 16.2-12.1: RECOVERY FROM CAESAREAN SECTION SCALE (RCSS) – QUESTION   
TEXT 
113 
LISTING 16.2-12.2: RECOVERY FROM CAESAREAN SECTION SCALE (RCSS) – ALL 
RANDOMIZED SUBJECTS 
114 
LISTING 16.2-13: MODIFIED POST-ANESTHESIA DISCHARGE SCORING SYSTEM (MPADSS) – 
ALL RANDOMIZED SUBJECTS 
115 
LISTING 16.2-14.1: SURGICAL FEAR QUESTIONNAIRE (SFQ) – QUESTION TEXT 
116 
LISTING 16.2-14.2: SURGICAL FEAR QUESTIONNAIRE (SFQ) – ALL RANDOMIZED SUBJECTS117 
LISTING 16.2-15: PULSE OXIMETRY (LOG FORM) – ALL RANDOMIZED SUBJECTS 
118 
LISTING 16.2-16: SUBJECT SATISFACTION WITH POST-SURGICAL PAIN CONTROL AT 72 
HOURS – ALL RANDOMIZED SUBJECTS 
119 
LISTING 16.2-17: DAY 14 PHONE CALL – ALL RANDOMIZED SUBJECTS 
120 
LISTING 16.2-18: VITAL SIGNS ASSESSMENT – ALL RANDOMIZED SUBJECTS 
121 
LISTING 16.2-19: ELECTROCARDIOGRAM FINDINGS AT SCREENING – INVESTIGATOR 
ASSESSMENT – ALL RANDOMIZED SUBJECTS 
122 
LISTING 16.2-20: PAIN INTENSITY SCALE‐  TIMEPOINT QUESTIONS – ALL RANDOMIZED 
SUBJECTS 
123 
LISTING 16.2-21: ASSESSMENT OF ITCHING – ALL RANDOMIZED SUBJECTS 
124 
LISTING 16.2-22.1: ALL ADVERSE EVENTS – ALL RANDOMIZED SUBJECTS 
125 
LISTING 16.2-22.2: TREATMENT-EMERGENT ADVERSE EVENTS – ALL RANDOMIZED 
SUBJECTS 
125 
LISTING 16.2-22.3: ALL SERIOUS ADVERSE EVENTS – ALL RANDOMIZED SUBJECTS 
125 
LISTING 16.2-22.4: TREATMENT-EMERGENT ADVERSE EVENTS OF SPECIAL INTEREST – 
ALL RANDOMIZED SUBJECTS 
125 


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LISTING 16.2-23.1: PRIOR MEDICATIONS – ALL RANDOMIZED SUBJECTS 
126 
LISTING 16.2-23.2: CONCOMITANT MEDICATIONS – ALL RANDOMIZED SUBJECTS 
126 
LISTING 16.2-24: MEDICAL HISTORY/SURGERY – ALL SUBJECTS 
127 
LISTING 16.2-25: INTRAOPERATIVE MEDICATIONS – RANDOMIZED SUBJECTS 
128 
LISTING 16.2-26: STUDY DRUG ADMINISTRATION – RANDOMIZED SUBJECTS 
129 
LISTING 16.2-27: STANDARD OF CARE – RANDOMIZED SUBJECTS 
130 
LISTING 16.2-28: PHYSICAL EXAMINATION – RANDOMIZED SUBJECTS 
131 
LISTING 16.2-29: URINE DRUG SCREEN, ALCOHOL BLOOD TEST AND PREGNANCY TEST – 
ALL SUBJECTS 
132 
LISTING 16.2-30: ADMISSION AND DISCHARGE – RANDOMIZED SUBJECTS 
133 
LISTING 16.2-31: IMPORTANT PROTOCOL DEVIATIONS - RANDOMIZED SUBJECTS 
134 
LISTING 16.2-32: ULTRASOUND COLLECTION – RANDOMIZED SUBJECTS 
135 
LISTING 16.2-33: UNIQUE ADVERSE EVENTS TERMS AND ASSOCIATED CODED TERMS 
136 
LISTING 16.2-34: UNIQUE MEDICATION TERMS AND ASSOCIATED CODED TERMS 
137 


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Listing 16.2-1: Subject Disposition – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Date of 
Subject 
Last Visit (Day) 
End of Study Status 
Specify 
 
 
XXX-YYYY 
DDMONYYYY (XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 Randomized Subjects 
 
Randomization 
Subject 
Date and Time 
Number 
Treatment 
Group 
Safety 
Efficacy 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXXXX 
EXPAREL+50 
mcg 
Duramorph 
X 
X 
EXPAREL 
SOC 
 
 
 
 
 
 
 
 
 
 
Note to programmer: Analysis set will by ‘Y’ if subject in set, blank otherwise. 


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Listing 16.2-3: Inclusion/Exclusion criteria – Failures – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Subject 
Visit 
Protocol 
Version 
Enrolled Under 
Criteria Not Met 
 
 
XXX-YYYY 
DDMONYYYY 
Amendment 1 
xxxxxxxxxx 
Amendment 2 
 
 
 
 
 
 
 
 
 
 


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 Listing 16.2-4: Demographics – All Randomized Subjects  
 
 TREATMENT: treatment-name  
 
 
Subject 
Initials 
Birth Date 
Age(yrs) 
Sex 
Race 
Ethnicity 
ASA Class 
XXX-YYYY 
AMZ 
DDMONYYYY 
XX 
XXXXXX 
XXXXXXXXX 
XXXXXXXXX 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note to programmer: If race is ‘other’ then race should be ‘Other: other-specify-text’. 


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Listing 16.2-5: Height and Weight – All Randomized Subjects 
 
TREATMENT: treatment-name 
Body Mass Index 
Subject 
Collection Date (Day) 
Height (cm) 
Weight (kg) 
(kg/m2) 
XXX-YYYY 
DDMONYYYYTHH:MM (-XX) 
XXX.X 
XXX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 


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Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
106 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-6: Surgery – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
 
Star 
 
 
Durati 
 
Incisi 
on 
 
SOC 
Admi 
Intraoperat 
ive 
Medications 
CSEPerforme 
d/ 
Component 
of 
CSE 
Administer 
 
Subje 
ct 
Date 
(Day) 
t 
Time 
Stop 
Time 
on 
(hrs) 
Locati 
on 
Length 
(cm) 
n 
Time 
Anesthes 
ia Type 
Administere 
d 
ed 
XXX- 
YYYY 
DDMONYY 
YY (XX) 
HH:M 
M 
HH:M 
M 
X.X 
XXXXX 
XX.X 
HH:M 
M 
Yes 
Yes 
No 
No 
Yes 
No 
Yes 
 
 
 
 
 
 
 
 
 
Note to programmer: If anesthesia type is ‘other’ then text should read ‘other: specify-text’. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
107 of 139 
16 March 2020 
 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-7: Visual Analog Scale (VAS) – All Randomized Subjects 
TREATMENT: treatment-name 
Time From Dose 
Subject 
Date Time (Day) 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(hrs) 
VAS 
(cm) 
Pain-Free 
(VAS ≤ 1.5cm) 
XXX-YYYY 
DDMONYYYYTHH:MM (X) 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
VAS: 0=No pain to 10=Worst Pain Imaginable 
ND=Not Done NA=Not Applicable 
 
 
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. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
108 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Listing 16.2-8.1: Postsurgical Total Opioid Dose (OMED mg) and O
-free Status – 
Protocol: 402-C-414 
All Randomized Subjects  
Subject 
0 to ≤72 hrs or at hospital 
discharge 
Opioid-Free 
XXX-YYYY 
XXX-YYYY 
XXXX.X 
- 
NO 
YES 
 
 
 
 
 
 
 
 
 
 
 
 
Total dose is dose from end of surgery through timepoint. 
 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’. 
Sort by date and 
time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
109 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-8.2: Postsurgical Opioid Dosing – All Randomized Subjects 
 
TREATMENT: treatment-name 
Time 
to 
Dosing 
 
 
Dose 
 
 
Conversion 
 
Dose 
(OMED 
Frequency 
Reason 
for 
Use 
 
Subject Date and Time 
(hr) 
Medication 
(units) Factor 
mg) 
Route 
XXX- 
xxx 
XXXXXXX 
YYYY 
DDMONYYYYTHH:MM XXX.X 
XXXXXXXXXXXX (XXXXX) X.XX 
XXX.X 
XXXXXXX 
DDMONYYYYTHH:MM XXX.X 
XXXXXXXXXXXX (XXXXX) X.XX 
XXX.X Xxx 
XXXXXXX XXXXXXX 
DDMONYYYYTHH:MM XXX.X 
XXXXXXXXXXXX (XXXXX) X.XX 
XXX.X Xxx 
XXXXXXX XXXXXXX 
DDMONYYYYTHH:MM XXX.X 
XXXXXXXXXXXX (XXXXX) X.XX 
XXX.X Xxx 
XXXXXXX XXXXXXX 
 
 
 
 
 
 
 
 
 
Time to Postsurgical Opioid Dosing is time from end of surgery to Postsurgical Opioid medication dose. 
 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’. 
Sort by date and 
time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
110 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-9: Prescription Daily Pain Medication – All Randomized Subjects 
 
TREATMENT: treatment-name 
Subject 
Date and Time 
Time to 
Dosing (hr) Medication 
Dose 
(units) 
Route 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXXXXXXXXXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXX 
(XXXXX) 
(XXXXX) 
(XXXXX) 
(XXXXX) 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
 
 
 
 
 
 
 
 
 
Time to dosing is time from end of surgery to pain medication dose. 
 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’. 
Sort by date and 
time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
111 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-10: Rescue Mediation – All Randomized Subjects 
 
TREATMENT: treatment-name 
Subject 
Date and Time 
Time to 
Dosing (hr) Medication 
Dose 
(units) 
Route 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXXXXXXXXXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXX 
(XXXXX) 
(XXXXX) 
(XXXXX) 
(XXXXX) 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
 
 
 
 
 
 
 
 
 
Time to rescue dosing is time from end of surgery to rescue medication dose. 
 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’. 
Sort by date and 
time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
112 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-11: Opioid Related Symptom Distress Scale (ORSDS) – All Randomized Subjects 
 
Treatment: treatment-name 
Subjec 
t 
Date 
and 
Time 
(Day) 
Time point  
Question 
Symptoms 
Answer 
Score 
 
 
XXX- 
YYYY 
DDMONYYYYTHH:MM 
(XX) 
24 hrs  
Fatigue 
Frequency 
Rarely 
1 
Severity 
Slight 
1 
Bothersomeness 
Not at all 
1 
Average 
1 
Drowsiness 
Frequency 
Occasionally 
2 
Severity 
Severe 
3 
Bothersomeness 
Very Much 
5 
Average 
3.3 
Inability 
to 
Concentrate Nausea  
Frequency 
Severity 
Bothersomeness 
…. 
…. 
 
Composite Score 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
113 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-12.1: Recovery from Caesarean Section Scale (RCSS) – Question Text 
 
Question No. 
Question Text 
 
1 
I recovered quickly from my caesarean 
2 
I was able to get out of bed soon after my caesarean 
3 
My mobility was seriously affected by the caesarean 
4 
The caesarean interfered with my ability to care for my baby 
5 
The caesarean prevented me from feeding my baby 
6 
I was able to change my baby soon after the caesarean 
7 
I was able to care for my own hygiene needs soon after surgery 
8 
The pain from the surgery prevented me from doing what I wanted 
9 
I was red for a long home after surgery 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
114 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-12.2: Recovery from Caesarean Section Scale (RCSS) – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Assessment 
Question 
Actual 
Deviation 
Total 
Subject 
Date and Time (Day) 
Scheduled 
(hrs) 
(hrs) 
1 2 3 4 5 6 7 8 9 Score 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
72 hrs 
XX.X 
XX.X 
X X X X X X X X X XX 
DDMONYYYYTHH:MM (XX) 
Early Discharge 
XX.X 
XX.X 
X X X X X X X X X XX 
 
 
Note to programmer: Sort by date and time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
115 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-13: Modified Post-Anesthesia Discharge Scoring System (MPADSS) – All Randomized Subjects 
TREATMENT: treatment-name 
 
Assessment 
Question 
 
Subject 
Date and Time (Day) 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
1 
2 
3 
4 
5 
Total 
Score 
 
 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
24 
XX.X 
XX.X 
X 
X 
X 
X 
X 
XX 
DDMONYYYYTHH:MM (XX) 
48 
XX.X 
XX.X 
X 
X 
X 
X 
X 
XX 
 
 
 
Total score = sum of scores. 
Question: 
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 
 
 
Note to programmer: Sort by date and time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
116 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-14.1: Surgical Fear Questionnaire (SFQ) – Question Text 
 
Question No. 
Question Text 
 
1 
I am afraid of the operation 
2 
I am afraid of the anesthesia 
3 
I am afraid of the pain after the operation 
4 
I am afraid of the unpleasant side effects (like nausea) after the operation 
5 
I am afraid my health will deteriorate because of the operation 
6 
I am afraid the operation will fail 
7 
I am afraid that I won’t recover completely from the operation 
8 
I am afraid of the long duration of the rehabilitation after the operaon 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
117 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-14.2: Surgical Fear Questionnaire (SFQ) – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Assessment 
Question 
Subject 
Date 
and 
(Day) 
Time 
Scheduled 
Actual 
(hrs) 
Deviation 
(hrs) 
1 2 3 4 5 6 7 8 
Total 
Score 
XXX-YYYY 
DDMONYYYYTHH:MM 
(XX) 
72 hrs 
XX.X 
XX.X 
X X X X X X X X 
XX 
DDMONYYYYTHH:MM 
(XX) 
Early 
Discharge 
XX.X 
XX.X 
X X X X X X X X 
XX 
 
 
Note to programmer: Sort by date and time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
118 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-15: Pulse Oximetry (Log Form) – All Randomized Subjects 
 TREATMENT: treatment-name  
 
 
 
Subject 
Date and Time 
Time Point 
Oxygen Saturation (%) 
 
XXX- YYYY 
DDMONYYYYTHH:MM 
0 hr 
XX.X 
1 hr 
XX.X 
2 hrs 
XX.X 
3 hrs 
XX.X 
 
 
 
 
 
 
 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
119 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-16: Subject Satisfaction with Post-Surgical Pain Control at 72 hours – All Randomized Subjects 
Treatment: treatment-name 
 
Subject 
Date and Time (Day) 
Rating 
Score 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
EXTREMELY DISSATISFIED 
1 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DISSATISFIED 
2 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
NEITHER SATISFIED NOR DISSATISFIED 
3 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
SATISFIED 
4 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
EXTREMELY SATISIFIED 
5 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
EXTREMELY SATISIFIED 
5 
 
 
 
 
 
 
 
 
 
 
Note to programmer: Sort by date and time within subject. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
120 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-17: Day 14 Phone Call – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
 
Day 14 Phone Call 
No. 
of 
Pain- 
Related 
Unscheduled 
No. of Hosp 
Readmission 
Currently Taking 
Opioid Pain 
Schedule Actual Deviation Phone 
No. of ER 
AE 
Subject 
Date 
(days) 
(days) (days) 
Calls Visits 
Visit 
Assessed 
XXX-YYYY DDMONYYYY 14 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXXX 
Y 
Y 
XXX-YYYY DDMONYYYY 14 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXXX 
Y 
N 
XXX-YYYY DDMONYYYY 14 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXXX 
N 
Y 
 
Note to programmer: If the leading question “were there any …” is No, then “No. of …” is 0. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
121 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
 Listing 16.2-18: Vital Signs Assessment – All Randomized Subjects  
 
 TREATMENT: treatment-name  
 
 
Assessment 
Heart Rate 
(bpm) 
 Blood Pressure (mmHg)  
 
Systolic 
Diastolic 
Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Actual 
Change 
Actual 
Change 
Actual 
Change 
XXX-YYYY DDMONYYYYTHH:MM 
Screening 
- 
- 
XX 
- 
XXX 
- 
XX 
- 
DDMONYYYYTHH:MM 
OR 
- 
- 
XX 
XX 
XXX 
-X 
XX 
X 
DDMONYYYYTHH:MM 
PACU 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
 
DDMONYYYYTHH:MM 
12 hr 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
DDMONYYYYTHH:MM 
24 hr 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
DDMONYYYYTHH:MM 
48 hr 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
DDMONYYYYTHH:MM 
72 hr 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
*=out of window 
@=potentially clinically significant value 
Change is change from baseline (Preop). 
 
 
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. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
122 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-19: Electrocardiogram Findings at Screening – Investigator Assessment – All Randomized 
Subjects 
Treatment: treatment-name 
Subject 
Date and Time 
Date 
Time 
Finding 
XXX-YYYY 
DDMONYYYYTHH:MM 
Normal 
XXX-YYYY 
DDMONYYYYTHH:MM 
Abnormal, clinically significant 
XXX-YYYY 
DDMONYYYYTHH:MM 
Abnormal, not clinically significant 
XXX-YYYY 
XXX-YYYY 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
Normal 
Normal 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
123 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-20: Pain Intensity Scale‐ Timepoint Questions – All Randomized Subjects 
 
Treatment: treatment-name 
Timepoint at Which Subjects was Asleep 
Subject 
12 hrs 
24 hrs 
48 hrs 
72 hrs 
XXX-YYYY 
Yes 
No 
Yes 
No 
Yes 
Yes 
No 
Unknown 
Yes 
No 
Unknown 
 
 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
124 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
Listing 16.2-21: Assessment of 
(Page X of Y) 
Itching – All Randomized Subjects 
Protocol: 402-C-414 
Treatment: treatment-name 
Any  Itching 
at Screening 
Severity 
of 
Subject 
Visit 
Visit? 
Date/Time 
Itching* 
Reason Not Done 
XXX-YYYY 
Screening 
DDMONYYYYTHH:MM 
0 
xxxxxxxxxxxxxxxxxxxxxx 
Day 1 
No 
DDMONYYYYTHH:MM 
1 
xxxxxxxxxxxxxxxxxxxxxx 
Day 1-3 
Yes 
DDMONYYYYTHH:MM 
2 
xxxxxxxxxxxxxxxxxxxxxx 
No 
DDMONYYYYTHH:MM 
3 
xxxxxxxxxxxxxxxxxxxxxx 
Yes 
DDMONYYYYTHH:MM 
10 
xxxxxxxxxxxxxxxxxxxxxx 
*= 0= No Itching and 10= Worst Itch 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
125 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-22.1: All Adverse Events – All Randomized Subjects 
 
Treatment: treatment-name 
Subject 
TEAE Data Type 
Data 
XXX-YYYY 
N 
Start (Day) 
DDMONYYYYTHH:MM (XX) 
Stop (Day) 
DDMONYYYYTHH:MM (XX) 
AE Number 
X 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
Preferred 
XXXXXXXXXXXXXXXXXXXX 
Verbatim 
XXXXXXXXXXXXXXXXXXXXXX 
Severity 
XXXXXXXX 
Relationship to Study Drug 
XXXXXXXX 
Action Taken 
XXXXXXXXXXXXXXXXXXXXX 
Outcome 
XXXXXXXXXXXXXX 
Serious 
Yes/No 
Serious Cause(s) 
Hospitalization 
AE of Special Interest 
Yes/No 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
 
 
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 mock-up for the following listings: 
 
Listing 16.2-22.2: Treatment-emergent Adverse Events – All Randomized Subjects 
Listing 16.2-22.3: All Serious Adverse Events – All Randomized Subjects 
Listing 16.2-22.4: Treatment-emergent Adverse Events of Special Interest – All Randomized Subjects 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
126 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-23.1: Prior Medications – All Randomized Subjects 
 
Treatment: treatment-name 
Subject 
Category 
Data Type 
Data 
XXX-YYYY 
Start (Day) 
DDMONYYYYTHH:MM (XX) 
Stop (Day) 
DDMONYYYYTHH:MM (XX) 
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 
 
 
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 mock-up for the following listings: 
 
Listing 16.2-23.2: Concomitant Medications – All Randomized Subjects 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
127 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-24: Medical History/Surgery – All Subjects 
 
Treatment: treatment-name 
Subject 
Data Type 
Data 
XXX-YYYY 
Start (Day) 
DDMONYYYY (XX) 
Stop (Day) 
DDMONYYYY (XX) 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
Preferred 
XXXXXXXXXXXXXXXXXXXX 
History Verbatim 
XXXXXXXXXXXXXXXXXXXXXX 
 
Start (Day) 
DDMONYYYY (XX) 
Stop (Day) 
DDMONYYYY (XX) 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
Preferred 
XXXXXXXXXXXXXXXXXXXX 
History Verbatim 
XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
128 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-25: Intraoperative Medications – Randomized Subjects 
TREATMENT: treatment-name 
Subject 
Start Date/Time 
End Date/Time 
Administered 
Name 
Dose 
Unit 
Route 
XXX-YYYY 
XXX-YYYY 
DDMMYYYY/HH:MM 
DDMMYYYY/HH:MM 
YES 
NO 
OPIOID-NAME 
XXX.XX 
(UNITS) 
XXXX 
 
 
 
 
 
 
 
 
 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
129 of 139 
16 March 2020 
 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
 Listing 16.2-26: Study Drug Administration – Randomized Subjects  
 
 
Treatment 
Start 
Stop 
Total Volume 
Subject 
Date 
Time 
Time 
(mL) 
XXX-YYYY 
Right Study Drug 
DDMONYYYY 
HH:MM 
HH:MM 
XXX 
Left Study Drug 
 
 
 
 
 
 
 
 
 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
130 of 139 
16 March 2020 
 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
 Listing 16.2-27: Standard of Care – Randomized Subjects  
 
 
Subject 
TAP 
Performed/Medication Date 
Start 
Time 
Dose (Unit) 
XXX-YYYY 
Yes/XXXXXX 
No 
DDMONYYYY 
HH:MM 
Xxxxxx(xxx) 
 
 
 
 
 
 
 
 
 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
131 of 139 
16 March 2020 
 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-28: Physical Examination – Randomized Subjects 
 
TREATMENT: treatment-name 
 
Subject 
Date/Time 
Body System 
Findings 
Details 
if 
Abnormal 
Reason Not Done 
 
 
XXX-YYYY 
DDMONYYYY 
HH:MM 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
132 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-29: Urine Drug Screen, Alcohol Blood Test and Pregnancy Test – All Subjects 
TREATMENT: treatment-name 
Subject 
Visit 
Urine Drug 
Blood 
Alcohol 
Pregnancy 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
133 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-30: Admission and Discharge – Randomized Subjects 
 
TREATMENT: treatment-name 
 
Date and Time (Day) 
Subject 
 
Admission to Surgical Facility 
Admission to PACU 
Discharge to PACU 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
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 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
134 of 139 
16 March 2020 
 
 
 
Listing 16.2-31: Important Protocol Deviations - Randomized Subjects 
TREATMENT: treatment-name 
Site Subject 
Date (day) 
Epoch 
Deviation Code 
Description 
XXX 
XXX-YYYY DDMONYYYY (XX) 
XXX 
XXX 
XXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
Note to programmer: Subjects may have multiple deviations. 
Sort deviations by subject and date. 
Select 
DVDECOD, 
eg, 
“Restricted 
Medications 
Taken”, “Non-Compliance/Ultrasound”, 
“Primary Efficacy 
Assessments”, “Other Important Deviations”, “Improper Informed Consent Procedure” as specified by the 
sponsor. 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
135 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-414 
Listing 16.2-32: Ultrasound Collection – Randomized Subjects 
TREATMENT: treatment-name 
 
 
Ultrasound Image/Video captured of the TAP 
needle after saline hydrodissection 
Ultrasound Image/Video captured of 
the TAP needle placement after study 
drug infiltration 
 
 
Subject 
Ultrasound Guidance used 
to perform TAP needle 
placement/Reason if No 
Right Side/ Reason  if 
No 
Left Side/ Reason if No 
Right Side/ Reason 
if No 
Left Side/ Reason 
if No 
XXX-YYYY 
Yes 
Yes 
Yes 
Yes 
Yes 
XXX-YYYY 
No/xxxxxxx 
No/xxxxxx 
No/xxxxxx 
No/xxxxxx 
No/xxxxxx 
 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
136 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-327 
Listing 16.2-33: 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 v21.1. 
Note to programmer: Sort by SOC and preferred term in alphabetical order 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
137 of 139 
16 March 2020 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-327 
Listing 16.2-34: 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 September 2018. 
 
 
Note to programmer: Sort by ATC1, ATC2, ATC3, ATC4 and preferred name in alphabetical order 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
138 of 139 
16 March 2020 
 
 
 
18  LIST OF FIGURES 
FIGURE 1: MEAN (+/- 95% CI) OF VAS GENERAL PAIN INTENSITY OVER TIME - EFFICACY 
ANALYSIS SET 
139 
FIGURE 2: MEAN (+/- 95% CI) OF VAS INCISION SITE PAIN INTENSITY OVER TIME - EFFICACY 
ANALYSIS SET 
139 


DocuSign Envelope ID: BE18CA33-D067-4B40-BC34-0049A46DD5F7 
Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-414 (C-section TAP) 
Statistical Analysis Plan 
CONFIDENTIAL 
139 of 139 
16 March 2020 
 
 
 
 
Figure 1: Mean (+/- 95% CI) of VAS General Pain Intensity Over Time - 
Efficacy Analysis Set 
 
Figure 2: Mean (+/- 95% CI) of VAS Incision Site Pain Intensity Over Time - 
Efficacy Analysis Set 
 
Programming note: include all scheduled VAS pain scores